TWI790510B - Use of reboxetine to treat nervous system disorders - Google Patents

Abstract

Described herein are methods of treating cataplexy narcolepsy comprising administering reboxetine (including oxetine) to a human in need thereof. Reboxetine (including oxepoxetine) is also used in the manufacture of drugs for the treatment of cataplexy narcolepsy. This paper also discloses a kit, which includes a pharmaceutical composition containing reboxetine (including oxetine), and instructions for using the pharmaceutical composition to treat human cataplexy-type narcolepsy.

Description

Use of reboxetine in the treatment of nervous system disorders

This invention claims U.S. Patent Application Serial No. 16/740,329 filed January 10, 2020; U.S. Patent Application Serial No. 16/740,409 filed January 11, 2020; U.S. Patent Application Serial No. filed January 11, 2020 16/740,410; U.S. Patent Application Serial No. 16/740,411 filed January 11, 2020; U.S. Patent Application Serial No. 62/943,077 filed December 3, 2019; and U.S. Patent Application Serial No. 62/943,077 filed December 10, 2019 Priority of Application Serial No. 62/946,295; all of these documents are hereby incorporated by reference in their entirety.

Narcolepsy is a serious and debilitating neurological disorder that causes disturbances in the sleep-wake cycle and is clinically characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and Disrupted nocturnal sleep. Narcolepsy is estimated to afflict an estimated 185,000 individuals in the United States. Cataplexy is observed in an estimated 70% of narcolepsy patients and is a sudden decrease or loss of muscle tone while the patient is awake, usually triggered by strong emotions such as laughter, fear, anger, nervousness, or excitement. Narcolepsy type 1 includes cataplexy, whereas narcolepsy type 2 does not. Narcolepsy interferes with cognitive, psychological, and social function, increases the risk of work- and driving-related accidents, and is associated with a 1.5-fold higher mortality rate. According to reports, up to 57% of patients suffer from depression. Unfortunately, few currently approved treatments are available for this underdiagnosed orphan condition and are subject to variability in efficacy between patients, tolerability issues, and concerns about U.S. Drug Enforcement Administration (DEA) scheduling. limitations of needs.

Described herein are methods of treating neurological disorders comprising administering to a person in need thereof an antidepressant, such as a selective norepinephrine inhibitor, such as Atomole Atomoxetine, edivoxetine, reboxetine, or S,S-reboxetine.

Described herein is a method of treating cataplexy narcolepsy comprising administering to a person in need thereof an antidepressant, such as a selective norepinephrine inhibitor, such as atomoxetine, idexetine, or Reboxetine (including S,S-reboxetine).

Some embodiments include antidepressants (such as selective norepinephrine inhibitors, such as atomoxetine, idexitine, or reboxetine (including S,S-reboxetine)) in the treatment of cataplexy Use in the manufacture of a medicament for narcolepsy.

Some embodiments include a kit comprising an antidepressant (e.g., a selective norepinephrine inhibitor, such as atomoxetine, idexetine, or reboxetine (including S,S-Ripple). The pharmaceutical composition of cetine)), and the instructions for use of said pharmaceutical composition to treat people's cataplexy type narcolepsy.

In some embodiments, an antidepressant (eg, a selective norepinephrine inhibitor, such as atomoxetine, idexetine, or reboxetine (including S,S-reboxetine)) is administered at least once daily lasts longer than two weeks. In some embodiments, as a result of said treatment, said person experiences a decrease in the number of cataplexy episodes, a decrease in the Epworth Sleepiness Scale (ESS) score, a decrease in the Maintenance of Wakefulness Test (Maintenance of Wakefulness Test, MWT) score decreased, Narcolepsy Symptom Assessment Score (NSAQ) decreased, Patient Global Impression of Severity (PGI-S) score decreased, Patient Global Impression of Change (Patient Global Impression of Severity) decreased. Global Impression of Change (PGI-C) score below 4, or Hamilton Depression Rating Scale (HAM-D) reduction, or improved ability to concentrate (eg, on the NSAQ).

Some embodiments include a method of rapidly reducing the number of cataplexy episodes in a human having cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, Wherein one week after initiation of treatment, the human has at least 30% fewer cataplexy episodes compared to baseline, and the reduction in the number of cataplexy episodes is statistically significant compared to administration of placebo, wherein p<0.01. In some embodiments, with the administration of placebo The reduction in the number of cataplexy episodes was statistically significant, where p<0.001.

Some embodiments include a method of improving the ability to concentrate comprising administering to a mammal or human in need thereof an antidepressant, such as a selective norepinephrine inhibitor, such as atomoxetine, idecillin Reboxetine or reboxetine (including S,S-reboxetine).

Some embodiments include a method of improving the ability to concentrate in a human suffering from cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein Before the treatment started, the person had an "average", "poor" or "very poor" ability to concentrate and two weeks after the start of the treatment, the person had a "good" or "very good" Concentration ability, as determined by the Concentration Ability item of the Narcolepsy Symptom Rating Questionnaire. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, the reboxetine is esreboxetine.

Some embodiments include a method of reducing the number of unintended naps in a human with cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein at Two weeks after the start of treatment, the person has at least 20% less weekly accidental naps compared to the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of improving sleep quality in a human suffering from cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein at the Two weeks after the start of the treatment, the person reported having improved sleep quality compared to the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of reducing nocturnal awakenings in a human with cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein at the Two weeks after the start of the treatment, the person reported having fewer nocturnal awakenings compared to the week before the patient first received reboxetine. in some implementations In the method, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of reducing sleep paralysis in a human with cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein at Two weeks after the start of the treatment, the person reported having fewer sleep paralysis episodes than in the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of reducing hypnagogic hallucinations in a human with cataplexy narcolepsy comprising administering to the human in need thereof about 8 mg to about 10 mg of reboxetine daily for at least two weeks, wherein at Two weeks after the start of the treatment, the person reported having fewer hypnagogic hallucinations than in the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of improving the ability to concentrate in a human with narcolepsy comprising administering reboxetine to the human in need thereof. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of treating cataplexy narcolepsy comprising administering reboxetine to a human in need thereof, wherein reboxetine is administered at least once daily for more than two weeks, wherein as a result of the treatment, Two weeks after initiation of treatment, the person experiences a decrease in the number of cataplexy episodes within a week, a decrease in the Epworth Sleepiness Scale score, a decrease in the cataplexy sub-score of the Ullanlinna Narcolepsy Scale (UNS), or Remaining awake test scores decreased.

Some embodiments include the use of reboxetine in the manufacture of a medicament for the treatment of cataplexy narcolepsy, wherein reboxetine is administered at least once daily for at least three weeks. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a kit comprising a pharmaceutical composition comprising reboxetine, and instructions for using the pharmaceutical composition to treat cataplexy narcolepsy in a human, wherein reboxetine is administered at least once daily Last for at least three weeks. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxetine.

Some embodiments include a method of treating fibromyalgia comprising administering oxetine to a human in need thereof, wherein the daily dose of oxetine is from about 1 mg to about 2 mg for at least six weeks, wherein during treatment During the procedure, the person experiences a greater reduction in fibromyalgia pain than the person experiences by administering a placebo, as measured by a Visual Analog Scale (VAS) score.

Some embodiments include a method of treating fibromyalgia comprising administering oxetine to a human in need thereof, wherein the daily dose of oxetine is from about 2 mg to about 4 mg for at least six weeks, wherein during treatment During the procedure, the person experiences a reduction in pain greater than the reduction in pain experienced by the person by administering a placebo, as measured by Visual Analog Scale (VAS) scores.

Some embodiments include a method of treating fibromyalgia comprising administering oxetine to a human in need thereof, wherein the daily dose of oxetine is from about 0.5 mg to about 1 mg for at least six weeks, wherein at During the course of treatment, the person experiences a reduction in pain greater than the reduction in pain experienced by the person by administration of a placebo, as measured by Visual Analog Scale (VAS) scores.

Figure 1 depicts the weekly change in cataplexy episodes in human patients receiving reboxetine and placebo as described in Example 22.

Figure 2 depicts the number of human patients receiving reboxetine or placebo as described in Example 22 with a 50% or greater reduction in weekly cataplexy episodes.

Figure 3 depicts the number of human patients receiving reboxetine or placebo as described in Example 22 with a 75% or greater reduction in weekly cataplexy episodes.

4 depicts the change in Epworth Sleepiness Scale score in human patients receiving reboxetine and placebo as described in Example 22.

5 depicts the reduction in the frequency of weekly accidental naps in human patients receiving reboxetine and placebo as described in Example 22.

Figure 6 depicts the number of human patients receiving reboxetine or placebo as described in Example 22 with a 50% or greater reduction in unintended dozing.

FIG. 7 depicts improvement in attention span score in human patients receiving reboxetine and placebo as described in Example 22.

Figure 8 depicts the number of human patients with "very good" or "good" concentration ability, where the human patients received reboxetine or placebo as described in Example 22.

Figure 9 depicts the proportion of human patients showing improvements in sleep quality, night awakenings, sleep paralysis episodes, and hypnagogic hallucinations.

Antidepressants, such as reboxetine or S,S-reboxetine, are useful in the treatment of conditions such as neurological disorders, including addictive disorders (including those caused by alcohol, nicotine, and other psychoactive substances), withdrawal depression syndrome, adjustment disorder (including depressive mood, anxiety, mixed anxious and depressive mood, conduct disorder, and mixed mood and conduct disorder), depression (including major depressive disorder alone or in combination with other antidepressants), age-related learning or mental disorders (including Alzheimer's disease), anorexia nervosa, apathy, attention-deficit (or another cognitive) disorder due to a general medical condition, attention-deficit hyperactivity disorder Disorder, ADHD), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, conduct disorder, cyclothymic disorder, depression (including adolescent depression and mild depression), mood disorders , fibromyalgia and other somatoform disorders (including somatization disorder, conversion disorder, pain disorder, depressed affective disorder, body dysmorphic disorder, undifferentiated somatization disorder, and somatized NOS), generalized anxiety disorder Disorder (GAD), urinary incontinence (ie, stress incontinence, true stress incontinence, and mixed incontinence), stress urinary incontinence (stress urinary incontinence), aspiration disorder, intoxication disorder (alcohol addiction), mania, migraine, obesity (eg, weight loss in obese or overweight patients), obsessive-compulsive disorder or related spectrum disorder, oppositional defiant disorder, panic disorder, peripheral neuropathy, post-traumatic stress disorder, Premenstrual mood disorders (i.e., premenstrual syndrome and late luteal phase anxiety), psychotic disorders (including schizophrenia, negative symptoms of schizophrenia, schizoaffective or schizophrenia-like disorders, either alone or as adjunct therapy), seasonal affective disorder, sleep disorders (such as narcolepsy or enuresis), social phobia (including social anxiety disorder), specific developmental disorders, Selective Serotonin Reuptake Inhibition , SSRI) "burnout" syndrome (i.e., in which the patient fails to maintain a satisfactory response to SSRI therapy after an initial period of such response), TIC disorders (e.g., Tourette's disease), banded Postherpetic pain, painful diabetic peripheral neuropathy, postherpetic neuralgia, syncope, and/or vasovagal syncope, etc. In some embodiments, S,S-Reboxetine is used to treat fibromyalgia. In some embodiments, reboxetine is used to treat fibromyalgia.

Treatment with reboxetine (including S,S-reboxetine) resulted in improvement of disease symptoms. For example, for a pain condition such as fibromyalgia, a patient may experience a pain reduction measured on a Visual Analog Scale (VAS), eg, 0-100 mm, that is greater than would be experienced by administration of a placebo. In some embodiments, the improvement in VAS score is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 70% greater than the improvement in VAS score that would be experienced by administration of a placebo , at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50- 60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100 %, for example at least about 50mm, at least about 40mm, at least about 30mm, at least about 20mm, at least about 10mm, about 0-10mm, about 10-20mm, about 20-30mm, about 30-40mm, about 40-50mm, about 0-25mm, or about 25-50mm. In some embodiments, the VAS score is improved by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40% -50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example at least about 50mm, at least about 40mm, at least about 30mm, at least about 20mm, at least about 10mm, about 0-10mm, about 10-20mm, about 20-30mm, about 30-40mm, about 40-50mm, about 0-25mm, or about 25-50mm.

Antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, Imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, Isoxazole, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindan, benetizine, escitalopram, fluvoxamine, Wen Lafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, busofensine, Moclobemide, Rasagiline, Nyalamide, Iproniazid, Iprochlorazine, Toloxadone, Buttiline, Dothiapine, Diphenazepine, Iprindole, Lofepa ketamine, opipramol, norfluoxetine, dapoxetine, ketamine, etc., including norepinephrine reuptake inhibitors (such as atomoxetine, idexetine, or reboxetine (including S,S - Reboxetine)), which has the potential to treat the symptoms of narcolepsy.

Many antidepressants, such as norepinephrine reuptake inhibitors (such as atomoxetine, idexitine, or reboxetine (including S,S-reboxetine)), lack DEA scheduling, which would represent a negative Significant benefit for patients suffering from this condition.

A person may have narcolepsy type 1 if criteria A and B are met:

A. The patient has a daily irrepressible need for sleep or periods of daytime falling asleep that persist for at least 3 months

B. One or both of the following are present:

2個睡眠開始快速眼動睡眠(Rapid Eye Movement，REM)期(Sleep-Onset REM Periods，SOREMP)。在先前的基於實驗室的多頻道睡眠記錄(polysomnography，PSG)上的SOREMP(在睡眠開始的15分鐘內)可取代MSLT上的SOREMP中的一個 1. Cataplexy (as defined under Basic Characteristics) on the Mean Sleep Latency Test (MSLT) performed according to standard techniques, with a mean sleep latency of <8 minutes, and

2 sleep start rapid eye movement sleep (Rapid Eye Movement, REM) period (Sleep-Onset REM Periods, SOREMP). A SOREMP on previous laboratory-based polysomnography (PSG) (within 15 minutes of sleep onset) may replace one of the SOREMPs on MSLT

2. CSF hypocretin-1 concentration measured by immunoreactivity <110 pg/mL or <1/3 of the mean value obtained in normal subjects using the same assay

In young children, narcolepsy sometimes manifests as prolonged nocturnal sleep or resumption of previously interrupted daytime naps. If there is a strong clinical suspicion of narcolepsy type 1, but B2 criteria are not met, a possible strategy is to repeat the MSLT.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have a daily irrepressible need for sleep or The period of daytime falling asleep occurs for at least about 3 months, at least 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months months, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 40 years years, at least about 50 years, at least about 60 years, about 3-9 months, about 9-18 months, about 18 months to about 2 years, about 2-5 years, about 5-10 years, about 10- 15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-50 years, about 50-60 years or more.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, about 0.1-1 minutes, about 1-2 minutes, about 2-3 minutes , about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes , an average sleep latency of about 6 minutes, about 7 minutes, or about 8 minutes.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected for MSLT performed according to standard techniques ( Average sleep latency test) with at least 2, at least 3, or at least 4 SOREMPs. 15 minutes of sleep onset on previous night PSG The SOREMP within may replace one of the SOREMPs on MSLT.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have less than CSF hypothalamus of about 40 pg/mL, less than about 50 pg/mL, less than about 60 pg/mL, less than about 70 pg/mL, less than about 80 pg/mL, less than about 90 pg/mL, less than about 100 pg/mL, less than about 110 pg/mL Secretin-1 concentration.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have The CSF hypocretin-1 concentration is less than about 1/10, less than about 1/9, less than about 1/8, less than about 1/7, less than about 1/6, less than about 1/5, less than about 1/4, or less than about 1/3.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may and/or may be selected to present with symptoms of excessive nocturnal sleep toddler.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may and/or may be selected to exhibit daytime napping with prior interruptions of recovered toddlers.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have Diagnosis of cataplexy narcolepsy according to the third edition (ICSD-3) criteria.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have narcolepsy in Ullanlinna The cataplexy sub-score on the score (UNS) is at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, About 11, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10 -11, about 2-4, about 4-6, about 6-8, about 8-10, about 2-6, or about 6-10, or any number between 1 and 11.

Some antidepressants (including norepinephrine inhibitors such as Ripple A patient treated with xetine (including S,S-reboxetine) can have and/or can be selected to have a score on the Epworth Sleepiness Scale (ESS) of at least about 10, greater than about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, At least about 24, about 10-11, about 11-12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 10-13, about 13-16, about 16-19, about 19-22, or about 22-24.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have at least about 7, at least about 8 times, at least about 9 times, at least about 10 times, at least about 11 times, at least about 12 times, at least about 13 times, at least about 14 times, at least about 15 times, at least about 16 times, at least about 17 times, at least about 18 times, at least about 19 times, at least about 20 times, at least about 21 times, at least about 28 times, at least about 35 times, about 7-14 times, about 14-21 times, about 21-28 times, about 28-35 times , about 35-49, or about 49-70 cataplexy episodes per week.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have less than about 1 minute, less In about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, less than about 9 minutes, less than about 10 minutes, less than about 11 minutes, less than about 12 minutes, less than about 13 minutes, less than about 14 minutes, less than about 15 minutes, less than about 16 minutes, less than about 17 minutes, less than about 18 minutes , less than about 19 minutes, less than about 20 minutes, about 0-1 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14- 15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12 minutes , about 12-16 minutes, about 16-20, or about 0-19 minutes of keeping awake test (MWT) score.

In some embodiments, prior to treatment with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), the patient has Have and/or can be selected to have symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, About 70-75 years, or longer than 75 years.

In some embodiments, prior to treatment with an antidepressant, including a norepinephrine inhibitor, such as reboxetine (including S,S-reboxetine), the patient has and/or can be selected to have about 0-18 years old, about 18-100 years old, about 0-5 years old, about 5-10 years old, about 10-15 years old, about 15-18 years old, about 18-20 years old, about 15-20 years old, about 18- 25 years old, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old , about 60-65 years old, about 65-70 years old, about 70-75 years old, or an age greater than 75 years old.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, can and/or can be chosen to be female. In some embodiments, patients can be selected as non-lactating and non-pregnant females.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, can and/or can be chosen to be male.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have any concomitant sleep disturbance. Some narcolepsy (e.g., cataplexy and/or EDS narcolepsy), may have and/or may be selected to have no sleep apnea other than mild sleep apnea (<15 events/hour) or mild to moderate sleep apnea (<30 events/hour ) other than any accompanying sleep disturbance. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) patients, may not have and/or may be chosen not to have any Clinically significant symptoms of EDS. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have any clinically significant mental disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have any type of depression not caused by narcolepsy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have any sleepiness resulting from depression not due to narcolepsy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have an affective disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) A patient, may not have and/or may be selected not to have a mental disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a brain dysfunction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a movement disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have dementia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have motor neurone disease.

Some antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), are used to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy). Sleep sickness) patients are not taking sodium oxybate at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking stimulants at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking anticonvulsants at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking clonidine at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not be taking a selective serotonin reuptake inhibitor (SSRI) at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking serotonin and norepinephrine reuptake inhibitor (Serotonin and Norepinephrine Re-uptake Inhibitor, SNRI) at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients are not taking monoamine oxidase inhibitors (Monoamine Oxidase Inhibitor, MAOI) at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking tricyclic antidepressant (Tricyclic Antidepressant, TCA) at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking hypnotics at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking anti-anxiety drugs at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) patient, Not while taking a sedating antihistamine. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient is not taking antipsychotics at the same time. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not be taking any other medications for narcolepsy or cataplexy at the same time.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a neurodegenerative disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have an epileptic disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a convulsive disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected as not having a diagnosis of cancer (except possibly basal cell carcinoma) within the last 5 years.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a bilirubin level greater than 2 times the upper limit of normal. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have an alanine aminotransferase level greater than 2 times the upper limit of normal. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have aspartate aminotransferase levels greater than 2 times the upper limit of normal. some with antidepressants (including norepinephrine inhibitors, Patients with narcolepsy (eg, cataplexy and/or EDS narcolepsy), such as reboxetine (including S,S-reboxetine), may not have and/or may be selected not to have more than Alkaline phosphatase levels 2 times the upper limit of normal.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have clinically significant hypertension. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have uncontrolled hypertension. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patient, may not have and/or may be selected not to have a history of cardiovascular disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a myocardial infarction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have angina. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a dysrhythmia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have heart failure.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a history of narrow angle glaucoma. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) suffer from Or, may not have and/or may choose not to have gastric bypass. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have any condition that would be expected to affect drug absorption.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have headache. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have major depressive disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have treatment resistant depression.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have treatment resistant bipolar depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have bipolar disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patient, may not have and/or may be selected not to have cyclothymia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have seasonal affective disorder. Some treatment of narcolepsy (eg, cataplexy and/or EDS narcolepsy) with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) , may not have and/or may be selected not to have a mood disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have chronic depressive disorder (eg, dysthymia). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have psychotic depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have a history of psychotic episodes. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a significant risk of self-harm, suicide, or attacking others.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have postpartum depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have premenstrual dysphoric disorder (Premenstrual Dysphoric Disorder, PMDD). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have situational depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have atypical depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have mania. Some antidepressants, including norepinephrine, suppress Patients with narcolepsy (eg, cataplexy and/or EDS narcolepsy), such as reboxetine (including S,S-reboxetine), may not have and/or may be chosen not to Have an anxiety disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Attention Deficit Disorder (ADD).

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Attention Deficit Disorder with Hyperactivity (ADDH). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Attention Deficit/Hyperactivity Disorder (AD/HD). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a manic disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have OCD. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have binge eating disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have obesity or weight gain. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have chronic fatigue syndrome.

Some antidepressants (including norepinephrine inhibitors such as Ripple Xetine (including S,S-reboxetine) for the treatment of narcolepsy (such as cataplexy-type and/or EDS-type narcolepsy) in patients who may not have and/or may be selected not to have PMS sign. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be chosen not to have substance addiction or abuse. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a nicotine addiction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have psycho-sexual dysfunction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have pseudobulbar affect. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have emotional lability.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have an anxiety disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a phobia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have generalized anxiety disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have social anxiety disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-Ray Poxetine)) for the treatment of narcolepsy (eg cataplexy and/or EDS narcolepsy) in patients who may not have and/or may be selected not to have panic disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have agoraphobia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have OCD. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have post-traumatic stress disorder (Post-Traumatic Stress Disorder, PTSD). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have mania.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have bipolar disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have hypomania. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have unipolar depression. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a stress disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a somatoform disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) are used to treat narcolepsy (eg Patients such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected not to have a personality disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a psychosis.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have schizophrenia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a delusional disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have schizoaffective disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a schizophrenic pathology. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have aggressive behavior. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have aggressive behavior in Alzheimer's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have agitation. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have the agitation in Alzheimer's disease.

Some antidepressants (including norepinephrine inhibitors such as Ripple Patients with narcolepsy (such as cataplexy and/or EDS narcolepsy) treated with cetine (including S,S-reboxetine) may be drug-free and/or may be selected to be drug-free. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have a cocaine addiction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have psychostimulant addiction or dependence on psychostimulants. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have crack addiction or dependence on crack. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cocaine addiction or dependence on cocaine. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have fast pill addiction or dependence on fast pills. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have methamphetamine addiction or dependence on methamphetamine. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have nicotine addiction or dependence on nicotine.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have alcohol addiction or dependence on alcohol. Some treatment of narcolepsy (eg, cataplexy and/or EDS narcolepsy) with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) patients, may not have and/or may be selected not to have opioid addiction or dependence on opioids. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have anxiolytic and/or hypnotic addiction or dependence on anxiolytics and/or hypnotics. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cannabis (marijuana) addiction or dependence on cannabis. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have amphetamine addiction or dependence on amphetamines. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have hallucinogen addiction or dependence on hallucinogens. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have phencyclidine addiction or dependence on phencyclidine.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have volatile solvent addiction or dependence on volatile solvents. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have volatile nitrite addiction or dependence on volatile nitrite. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Alzheimer's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS-type narcolepsy disease), may not have and/or may be selected not to have Alzheimer-type dementia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have memory loss. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have amnesia/amnesia syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have epilepsy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have confusion.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have coma. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have decreased attention span. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a speech impairment. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have vocal spasms. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Parkinson's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) patients, may not have and/or may be selected not to have Lennox-Gastaut syndrome.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have autism. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have hyperactivity syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have schizophrenia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have stroke. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a cerebral infarction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cerebral hemorrhage. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cerebral arteriosclerosis. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cerebral venous thrombosis. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a head injury.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have akinesia. some use Antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) in patients with narcolepsy (such as cataplexy-type and/or EDS-type narcolepsy), May be free and/or may be selected to be free of athetosis. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have ataxia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have ballismus. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have hemithrombotic syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have bradykinesia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cerebral palsy.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have chorea. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Huntington's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have rheumatic chorea. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Sidenham's chorea. one Some patients with narcolepsy (such as cataplexy and/or EDS narcolepsy) treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) The patient, may not have and/or may be selected not to have a movement disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have tardive dyskinesia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have dystonia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have blepharospasm.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have spastic torticollis. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have dopamine-responsive dystonia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have restless legs syndrome (RLS). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have tremors. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have essential tremors. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Tourette's syndrome. one Some patients with narcolepsy (such as cataplexy and/or EDS narcolepsy) treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) The patient, may not have and/or may be selected not to have Wilson's disease.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have vascular dementia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have dementia with Lewy bodies. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have mixed dementia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have frontotemporal dementia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Creutzfeldt-Jakob disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have normobaric hydrocephalus. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Wernicke-Korsakoff syndrome.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Pick's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) patient, may not have With and/or can be selected without progressive bulbar palsy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Primary Lateral Sclerosis (PLS). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have progressive muscular atrophy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have post-polio syndrome (PPS). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have spinal muscular atrophy (SMA).

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have spinal motor atrophy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Tay-Sach's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Sandhoff's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have hereditary spastic paraplegia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Alzheimer's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine)) for the treatment of narcolepsy (eg, cataplexy and/or EDS narcolepsy) in patients who may not have and/or may be selected to be free of prion-related disorders. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have cerebellar ataxia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have spinocerebellar disorder (Spinocerebellar Ataxia, SCA).

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have spinal muscular atrophy (SMA). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have bulbar muscular atrophy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Friedrich's ataxia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Lewy body disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient may not have and/or may be selected not to have Multiple Sclerosis (MS). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) suffer from Or, may not have and/or may be selected not to have multiple system atrophy.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Shy-Drager syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have corticobasal degeneration. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have progressive supranuclear palsy.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Wilson's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Menkes disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have adrenoleukodystrophy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients may not have and/or may be selected as not having Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have muscular dystrophy.

Some antidepressants (including norepinephrine inhibitors such as Ripple Xetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) in patients who may not have and/or may be selected not to have Schamadur Three disease (Charcot-Marie-Tooth disease, CMT). Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have familial spastic paraplegia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have neurofibromas. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have pontocerebellar atrophy or degeneration. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have striatonigral degeneration. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Guillain-Barré syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have spastic paraplegia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have non-epileptic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have epilepsy. Some antidepressants (including norepinephrine inhibitors such as reboxetine (including S,S-reboxetine)) Patients treated for narcolepsy (eg, cataplexy and/or EDS narcolepsy) may not have and/or may be selected not to have febrile seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have partial seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have isolated partial seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have Jacksonian seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have complex partial seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have partial persistent status epilepticus. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have generalized seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have generalized tonic-clonic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have absence seizures.

Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have atonic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-Ray Poxetine)) for the treatment of narcolepsy (eg, cataplexy and/or EDS narcolepsy) may not have and/or may be selected not to have myoclonic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have juvenile myoclonic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have infantile spasms. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have status epilepticus. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have Rett syndrome. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have tinnitus. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have a disorientation disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have sexual dysfunction. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have voice disturbance due to uncontrolled spasm of the laryngeal muscles. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have abduction spastic dysphonia. Some treated with antidepressants (including norepinephrine inhibitors such as reboxetine (including S,S-reboxetine)) Patients with narcolepsy (eg, cataplexy and/or EDS narcolepsy) may not have and/or may be selected not to have adductive spasmodic dysphonia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have, and/or may be selected to not have, dysphonia. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have voice tremors. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have diabetic neuropathy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may be free and/or may be selected to be free of chemotherapy-induced neurotoxicity. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) Patients, may not have and/or may be selected not to have methotrexate neurotoxicity. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have stress urinary incontinence. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have urge incontinence. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have fecal incontinence. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for the treatment of narcolepsy (such as cataplexy and/or EDS narcolepsy) The patient, may not have and/or may be selected not to have erectile dysfunction.

Cataplexy involves a sudden decrease or loss of muscle tone while the patient is awake, which can Affects a specific part of the body or the whole body, such as drooping eyelids, head, drooping and/or twitching of the face, slurred speech, weakness of the jaw, weakness of the arms, shoulders, or hands, and/or buckling of the knees. Cataplexy may be characteristic of narcolepsy. Cataplexy can be triggered by strong emotions such as laughter, elation, surprise, or anger. Cataplexy can be partial or localized (approximately 75% of cases) and is usually of short duration. The frequency of cataplexy can vary widely. Cataplexy narcolepsy can be socially disabling and socially isolating.

Some patients who are being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have and/or may be selected to have cataplexy narcolepsy is an autoimmune disorder that results in the loss of hypocretin (orexins)-producing neurons in the CNS. Hypothalamic secretin (orexin) is a hypothalamus-specific trait with neuroexcitatory activity. Patients with cataplexy-type narcolepsy who are being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), are and can be selected for specific genetic markers Specific genetic markers include human leukocyte antigen (HLA DQB1-06:02) and/or T cell receptor alpha variant. Some patients who are being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may not have and can be selected not to have hypocretin neurons associated with Loss-related narcolepsy. Some patients who are being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), may have or may be selected to have Narcolepsy caused by streptococcal infection, H1N1 influenza, and/or H1N1 vaccination.

Conventional narcolepsy treatments address only some of the symptoms of narcolepsy, provide variable efficacy, and have significant side effects. Additionally, all known therapeutics are controlled substances.

According to the FDA, “there is a continued need for additional effective and tolerable treatment options for patients to improve their daily functioning (there is still a need for additional effective and tolerable treatment options for patients to improve their daily functioning).” (The Voice of the Patient, A series of reports from the US Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative, Narcolepsy , June 2014, p. 25)

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (Including active controls such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, selective serotonin reprogramming Reduction of daytime sleepiness by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30% compared to an SSRI or a selective norepinephrine reuptake inhibitor (SNRI) %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 5-10%, about 10-20%, About 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1 -25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least About 80%, at least about 90%, about 1-5%, about 5-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60% , about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

0.05)。這種改善可為快速的。例如，在用瑞波西汀治療人的時刻或治療的一周內，猝倒發作的平均減少可為至少約10%、約10-20%、約20-30%、約30-40%、約40-50%、約40-45%、約45-50%，或約50-60%。 In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% reduction in the number of partial cataplexy episodes %, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75% -100%, at least about 1 time/week, at least about 2 times/week, at least about 3 times/week, at least about 4 times/week, at least about 5 times/week, at least about 6 times/week, at least about 7 times/week /week, at least about 8 times/week, at least about 9 times/week, at least about 10 times/week, at least about 12 times/week, at least about 13 times/week, at least about 14 times/week, at least about 15 times/week Weekly, at least about 16 times/week, at least about 18 times/week, at least about 20 times/week, at least about 22 times/week, at least about 24 times/week, at least about 26 times/week, at least about 28 times/week , at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week, about 5-6 times/week, about 6-7 times/week, about 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week Week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, About 17-18 times/week, about 18-19 times/week, about 19-20 times/week, about 1-10 times/week, about 10-20 times/week, about 20-30 times/week, about 30 - 40 times/week, about 40-50 times/week, about 50-60 times/week or more. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05). This improvement can be rapid. For example, the average reduction in cataplexy episodes can be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40% at the time of treatment of a human with reboxetine or within one week of treatment. -50%, about 40-45%, about 45-50%, or about 50-60%.

0.05)。這種改善可為快速的。例如，在用瑞波西汀治療人的時刻或治療的一周內，猝倒發作的平均減少可為至少約10%、約10-20%、約20-30%、約30-40%、約40-50%、約40-45%、約45-50%，或約50-60%。 In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the number of complete cataplexy attacks is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% %, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75% -100%, at least about 1 time/week, at least about 2 times/week, at least about 3 times/week, at least about 4 times/week, at least about 5 times/week, at least about 6 times/week, at least about 7 times/week /week, at least about 8 times/week, at least about 9 times/week, at least about 10 times/week, at least about 12 times/week, at least about 13 times/week, at least about 14 times/week, at least about 15 times/week Weekly, at least about 16 times/week, at least about 18 times/week, at least about 20 times/week, at least about 22 times/week, at least about 24 times/week, at least about 26 times/week, at least about 28 times/week , at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week, about 5-6 times/week, about 6-7 times/week, about 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week Week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, About 17-18 times/week, about 18-19 times/week, about 19-20 times/week, about 1-10 times/week, about 10-20 times/week, about 20-30 times/week, about 30 - 40 times/week, about 40-50 times/week, about 50-60 times/week or more. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05). This improvement can be rapid. For example, the average reduction in cataplexy episodes can be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40% at the time of treatment of a human with reboxetine or within one week of treatment. -50%, about 40-45%, about 45-50%, or about 50-60%.

0.05)。這種改善可為快速的。例如，在用瑞波西汀治療人的時刻或治療的一周內，猝倒發作的平均減少可為至少約10%、約10-20%、約20-30%、約30-40%、約40-50%、約40-45%、約45-50%，或約50-60%。 In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the total number of cataplexy episodes (partial + complete) is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% %, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45% -50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75% %, about 75-100%, about 40-60%, at least about 1 time/week, at least about 2 times/week, at least about 3 times/week, at least about 4 times/week, at least about 5 times/week, at least About 6 times/week, at least about 7 times/week, at least about 8 times/week, at least about 9 times/week, at least about 10 times/week, at least about 12 times/week, at least about 13 times/week, at least about 14 times/week, at least about 15 times/week, at least about 16 times/week, at least about 18 times/week, at least about 20 times/week, at least about 22 times/week, at least about 24 times/week, at least about 26 times/week times/week, at least about 28 times/week, at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, at least about 60 times/week, at least about 70 times/week, at least about 80 times/week /week, at least about 90 times/week, at least about 100 times/week, at least about 110 times/week, at least about 120 times/week, at least about 130 times/week, at least about 140 times/week, about 10-20 times/week /week, about 12-18 times/week, about 14-16 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week , about 5-6 times/week, about 6-7 times/week, about 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, about 17- 18 times/week, about 18-19 times/week, about 19-20 times/week, about 1-10 times/week, about 10-20 times/week, about 20-30 times/week, about 30-40 times /week, about 40-50 times/week, about 50-60 times/week, about 60-70 times/week, about 70-80 times/week, about 80-90 times/week, about 90-100 times/week , about 100-120 times/week, about 120-140 times/week, or more times. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05). This improvement can be rapid. For example, the average reduction in cataplexy episodes can be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40% at the time of treatment of a human with reboxetine or within one week of treatment. -50%, about 40-45%, about 45-50%, or about 50-60%.

0.05)。 In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, such as reboxetine (including S,S-reboxetine), can result, for example, in comparison to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the proportion of patients achieving a 50% or greater reduction in the number of weekly cataplexy episodes is about 40-50%, about 50-60%, about 50-55%, 55-60%, about 60-70%, about 60-95%, about 70-80%, about 70-75%, about 75-80%, or about 74-78%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05).

0.05)。 In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, such as reboxetine (including S,S-reboxetine), can result, for example, in comparison to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the proportion of patients achieving a 75% or greater reduction in the number of weekly cataplexy episodes is about 15-20%, about 20-30%, about 20-25%, about 25-30%, about 30-40%, About 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 60-95%, or about 70-80%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05).

0.05、0.01-0.05、<0.01、0.005-0.01、0.001-0.005、或約0.003。 In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result, for example, in comparison to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the Epworth Sleepiness Scale (ESS) score is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, At least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70% %, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least About 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14 , at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, about 24, about 1-2, about 2-3, About 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11-12, about 12-13, About 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, About 23-24, about 1-4, about 4-8, about 8-12, about 12-16, about 16-20, about 20-24, about 1-12, or about 12-24. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant compared to administration of placebo, where the p value

0.05, 0.01-0.05, <0.01, 0.005-0.01, 0.001-0.005, or about 0.003.

0.05、0.03-0.05、0.01-0.05、<0.01、0.005-0.01、0.001-0.005、約0.003、或<0.001。患者可基於具有意外打盹(例如與發作性睡病(有或沒有猝倒)相關的意外打盹)的問題而被選擇進行治療。 In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% less in the number of weekly accidental naps %, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, about 20-40%, about 30- 35%, or about 30-33%, at least about 1 nap/week, at least about 2 naps/week, at least about 3 naps/week, at least about 4 naps/week, at least about 5 naps/week, About 1-3 naps/week, About 2-4 naps/week, About 3-4 naps/week, About 3-5 naps/week, About 4-6 naps/week, About 5-6 naps nap/week. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant compared to administration of placebo, where the p value

0.05, 0.03-0.05, 0.01-0.05, <0.01, 0.005-0.01, 0.001-0.005, about 0.003, or <0.001. Patients may be selected for treatment based on problems with unexpected dozing off, such as that associated with narcolepsy (with or without cataplexy).

0.05)。 In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, such as reboxetine (including S,S-reboxetine), can result, for example, in comparison to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the proportion of patients achieving a 50% or greater reduction in the number of weekly accidental naps is about 15-20%, about 20-30%, about 30-40%, about 30-35%, about 35-40%, about 40-50%, about 50-60%, about 60-70%, or about 70-80%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in, for example, comparison with baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , a reduction in the Keeping Wake Test (MWT) score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least About 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70% , about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, About 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10 minutes -11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes minutes, about 19-20 minutes, about 20-21 minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about 24-26 minutes, about 1-4 minutes, about 4-8 minutes, About 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes. This improvement in reboxetine treatment can Observed, eg, at 1 week, 2 weeks, overall, or any other relevant time (eg, 1 month, 6 months, 1 year, 2 years, etc.).

0.05)，例如p=0.01-0.05、<0.01、0.001-0.01、0.001-0.005、0.005-0.01、0.002或0.007。患者可以基於具有降低的認知功能，例如與發作性睡病(有或沒有猝倒)相關聯的降低的認知功能而被選擇進行治療。 In some embodiments, administration of antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), improves cognitive function, for example, over a 1-week period or a 2-week period, such as Measured by the NSAQ's Concentration Ability Item. For example, the improvement of the concentration ability score on a 5-point scale (1=very good, 2=good, 3=average, 4=poor, and 5=very poor) can be, for example, compared to baseline, placebo, or some other suitable Controls (including active controls such as stimulants (e.g., methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs ) compared to at least about -0.1, at least about -0.2, at least about -0.3, about -0.05 to about -0.5, about -0.05 to about -0.2, about -0.2 to about -0.3, about 0.3 to about -0.4, From about -0.4 to about -0.5, from about -0.5 to -0.6, from about -0.6 to about -0.7, or from about -0.7 to about -0.8, wherein "-" indicates a decreased ability to concentrate. In some embodiments, the number of patients with "very good" or "good" ability to concentrate can be compared, for example, to baseline, placebo, or some other suitable control (including active controls, such as stimulants ( such as methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), at least about 20%, at least 25%, At least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40 %, about 30-35%, about 35-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 15-25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60%, about 35-40%, or about 40-45%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05), for example p=0.01-0.05, <0.01, 0.001-0.01, 0.001-0.005, 0.005-0.01, 0.002 or 0.007. Patients may be selected for treatment based on having reduced cognitive function, such as that associated with narcolepsy (with or without cataplexy).

In some embodiments, the person has "average", "poor" or "very poor" ability to concentrate before treatment begins, and one week after treatment begins, the person has Possesses "good" or "very good" ability to concentrate.

In some embodiments, the human has an "average" ability to concentrate prior to initiation of treatment, and the human has "good" ability to concentrate one week after initiation of treatment.

In some embodiments, the person has "average" concentration ability before treatment begins, and the person has "very good" concentration ability one week after treatment initiation.

In some embodiments, the human has "poor" concentration skills before treatment begins, and the human has "good" concentration skills one week after treatment begins.

In some embodiments, the person has "poor" concentration ability before treatment begins, and the person has "very good" concentration ability one week after treatment initiation.

In some embodiments, the human has "very poor" concentration skills before treatment begins, and the human has "good" concentration skills one week after treatment begins.

In some embodiments, the person has "very poor" concentration ability before treatment begins and the person has "very good" concentration ability one week after treatment initiation.

In some embodiments, the person has "average," "poor," or "very poor" concentration ability before treatment begins, and two weeks after treatment begins, the person has "good" or "very poor" concentration ability. Very good" ability to concentrate.

In some embodiments, the human has "average" concentration ability before treatment begins, and the human has "good" concentration ability two weeks after treatment initiation.

In some embodiments, the person has "average" concentration ability before treatment begins, and the person has "very good" concentration ability two weeks after treatment initiation.

In some embodiments, the human has "poor" concentration ability prior to initiation of treatment and the human has "good" concentration ability two weeks after initiation of treatment.

In some embodiments, the person has "poor" concentration ability before treatment begins, and the person has "very good" concentration ability two weeks after treatment initiation.

In some embodiments, the person has "very poor" concentration ability before treatment begins and the person has "good" concentration ability two weeks after treatment initiation.

In some embodiments, the person has "very poor" concentration ability before treatment begins and the person has "very good" concentration ability two weeks after treatment initiation.

0.05)，例如p=0.01-0.05、<0.01、0.001-0.01、0.001-0.005、0.005-0.01、或0.007。患者可基於具有睡眠品質問題，例如與發作性睡病(有或沒有猝倒)相關聯的睡眠品質問題而被選擇進行治療。 In some embodiments, administration of antidepressants, including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine), improves sleep quality. For example, patients may report improved sleep quality. In some embodiments, the number of patients reporting improved sleep quality can be compared, for example, to baseline, placebo, or some other suitable control (including an active control, such as a stimulant (e.g., methylphenidate, amphetamine, etc.). at least about 20%, at least about 30%, at least about 40%, at least about 50% compared to %, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60% , about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, About 40-60%, about 42-47%. In some embodiments, a patient may have improved sleep quality compared to, for example, baseline, placebo, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamines), at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least About 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40% -45%, about 45-40%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50% %, about 50-75%, or about 75-100%, about 40-60%, about 42-47%, or about 45%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05), for example p=0.01-0.05, <0.01, 0.001-0.01, 0.001-0.005, 0.005-0.01, or 0.007. Patients may be selected for treatment based on having sleep quality problems, such as those associated with narcolepsy (with or without cataplexy).

0.05)，例如p=0.01-0.05、0.04-0.05或0.044。患者可基於具有夜間覺醒問題，例如與發作性睡病(有或沒有猝倒)相關聯的夜間覺醒問題而被選擇進行治療。 In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, eg, reboxetine (including S,S-reboxetine), reduces the number of nocturnal awakenings, eg, as reported by the patient. For example, the number of patients reporting a reduction in the number of nocturnal awakenings can be compared, for example, to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamines), molars, etc. at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60- 70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60% %, about 42-47%. In some embodiments, the reduction in the number of nocturnal awakenings that a patient has can be compared, for example, to baseline, placebo, or some other suitable control (including an active control such as a stimulant (e.g. methylphenidate, amphetamine) , modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs), at least about 20%, at least about 30%, at least about 40%, at least about 50%, At least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75% -100%, about 40-60%, about 42-47%, or about 30%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p

0.05), for example p=0.01-0.05, 0.04-0.05 or 0.044. Patients may be selected for treatment based on having nocturnal awakening problems, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, eg, reboxetine (including S,S-reboxetine), reduces the number of sleep paralysis episodes, eg, as reported by the patient. For example, the number of patients with a reduction in the number of sleep paralysis episodes can be compared, for example, to baseline, placebo, or some other suitable control (including an active control such as a stimulant (e.g. methylphenidate, amphetamine) , modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs), at least about 20%, at least about 30%, at least about 40%, at least about 50%, At least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 50% -70%, about 52-57%. In some embodiments, the reduction in the number of sleep paralysis episodes that a patient has can be compared, for example, to baseline, placebo, or some other suitable control (including an active control, such as a stimulant (e.g., methylphenidate, amphetamine, etc.). at least about 20%, at least about 30%, at least about 40%, at least about 50% compared to %, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50% , about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or About 75-100%, about 50-70%, about 52-57%, or about 55%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on having sleep paralysis problems, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants, including norepinephrine inhibitors, eg, reboxetine (including S,S-reboxetine), can reduce the number of hypnagogic hallucinations, eg, as reported by patients. For example, the number of patients with reduced hypnagogic hallucinations can be compared, for example, to baseline, placebo, or some other suitable control (including active controls, such as stimulants (such as methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), at least about 10%, at least about 20%, at least about 30%, at least about 40%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, About 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%. In some embodiments, the reduction in the number of hypnagogic hallucinations that a patient has can be compared, for example, to baseline, placebo, or some other suitable control (including an active control, such as a stimulant (e.g., methylphenidate, amphetamine, etc.). ), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs) at least about 10%, at least about 20%, at least about 30%, at least about 40% , about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%, or about 40%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with having hypnic hallucinations, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in, for example, comparison with baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the cataplexy score on the UNS is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 45-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75% -100%, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11, about 2- 3. About 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4, about 4-6, about 6- 8. About 8-10, about 10-11, about 2-6, or about 6-10, about 5-11. This improvement in reboxetine treatment It can be observed, for example, at 1 week, 2 weeks, overall, or any other relevant time (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result, for example, in comparison to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , prolongation of sleep latency on the MSLT by at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 50-60%, greater than 55% %, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-100%, for at least about 1 minute, at least about 2 minutes, at least About 3 minutes, greater than 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, About 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10 minutes -11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes minutes, about 19-20 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes . Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the Patient Global Impression of Severity (PGI-S) score is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1- 25%, about 25-50%, about 50-75%, about 75-100%, at least about 0.1, at least about 0.5, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least About 3.5, about 0.1-0.5, about 0.5-1, about 1-1.5, about 1.5-2, about 2-2.5, about 2.5-3, about 3-3.5, or about 3.5-4. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, such as reboxetine (including S,S-reboxetine), results in a Patient Global Impression of Change (PGI-C) score of about 1- 2. About 2-3, or about 3-4, or for example with baseline, placebo, or some other suitable control (including active controls such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least About 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30- 40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50% , about 50-75%, about 75-100%, at least about 0.5, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, about 0.5-1, about 1-2, about 2 -3, about 3-4, about 4-5, or about 5-6. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in, for example, comparison with baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the Hamilton Depression Rating Scale (HAM-D) score is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70- 80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least about 3. At least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, At least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 30, at least about 40, about 1-2, about 2-3, About 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11-12, about 12-13, About 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-27, about 27-30, about 30-35, about 35-40, about 40-45, about 45-50, about 1-4, about 4-8, about 8-12, about 12-16, About 16-20, about 20-24, about 24-30, about 30-40, about 40-50, about 1-12, about 12-24, about 24-36, or about 36-50. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , a reduction in nightmares or unpleasant dreams (e.g., frequent nightmares or frequent unpleasant dreams) of at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30% -40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50% %, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients can include nightmares or unpleasant dreams associated with narcolepsy (with or without cataplexy) based on having nightmares or unpleasant dreams (eg, frequent nightmares or frequent unpleasant dreams). Dreaming (such as frequent nightmares or frequent unpleasant dreams) is selected for treatment.

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , reducing hallucinations by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with hallucinations, such as hallucinations associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , sleep paralysis is reduced by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, At least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70% %, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with sleep paralysis, such as sleep paralysis associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active controls such as stimulants (e.g. methylphenidate, Amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs) reduce nocturnal sleep disturbances by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, About 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90% -100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with nocturnal sleep disturbances, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , narcolepsy-related incidents are reduced by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on questions about incidents associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , the impairment associated with narcolepsy is reduced by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50% -60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75- 100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can be compared, for example, to baseline, placebo, or some other suitable control. (including active comparators such as stimulants (e.g. methylphenidate, amphetamines), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRIs or SNRIs) compared to , a reduction in narcolepsy-related fatalities of at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, At least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60% , about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such improvement in reboxetine treatment may be observed, eg, at 1 week, 2 weeks, overall, or any other relevant time period (eg, 1 month, 6 months, 1 year, 2 years, etc.). Patients can be selected for treatment based on their risk of narcolepsy-related fatality for narcolepsy patients with or without cataplexy.

Reboxetine (having the structure shown below) (including S,S-reboxetine, such as having the structure shown below) is a highly selective and potent norepinephrine reuptake inhibitor with the ability to resolve paroxysmal Key symptoms of sleeping sickness, such as cataplexy or potential for EDS. Unlike conventional narcolepsy treatments, reboxetine is not a controlled substance. Therefore, treatment with reboxetine will not be scheduled.

Unless otherwise stated, any reference to a compound herein, such as reboxetine, by structure, name, or any other means, includes pharmaceutically acceptable salts; free acids or bases; alternate solid forms, such as polymorphs forms, solvates, hydrates, etc.; tautomers; enantiomers; deuterium-modified compounds, such as deuterium-modified reboxetine; Any chemical substance that converts rapidly to a compound described herein.

In some embodiments, reboxetine is in salt form, free base form, or may contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) %) of (+)-reboxetine (also known as S,S-reboxetine or oxetine); or excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95% %, at least 97%, or at least 99%) of (-)-reboxetine.

For the treatment of narcolepsy, can lead to 1) the first local maximum of reboxetine (including S,S-reboxetine) plasma concentration and 2) reboxetine (including S,S-reboxetine) plasma Reboxetine (including S,S-reboxetine) was administered in such a way that the second local maximum of the concentration was reached.

There are a number of modes of administration that can lead to a first local maximum in plasma concentrations of reboxetine (including S,S-reboxetine) and a second local maximum in plasma concentrations of reboxetine (including S,S-reboxetine) Potential pathways for reboxetine (including S,S-reboxetine). A local maximum as described herein is the maximum value of a plasma concentration in an individual patient during the time period of interest, which maximum value is not necessarily a _Cmax . The local maximum may be lower than or equal to _Cmax . Administering Ripple in a manner that results in a first local maximum in the plasma concentration of reboxetine (including S,S-reboxetine) and a second local maximum in the plasma concentration of reboxetine (including S,S-reboxetine) A potential route for sitine (including S,S-reboxetine) is to administer a first dosage form containing reboxetine (including reboxetine) and at a later time to administer The second dosage form of Xetine). Administering said drug at a time that results in a first local maximum in plasma concentration of reboxetine (including S,S-reboxetine) and a second local maximum in plasma concentration of reboxetine (including S,S-reboxetine) dose. For example, it may be less than half a day after the first dosage form, such as about 1-8 hours, about 8-12 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3 hours after the first dosage form. -4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours Hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or any period of time within the range bounded by any of these values, the second dosage form is administered.

Another method involves administering a single dosage form comprising a first release component and a second release component. Both the first release component and the second release component contain reboxetine (including S,S-reboxetine).

In some embodiments, the first dosage form administered on a day (either the only dosage form administered on that day, or the first of two or more dosage forms administered on that day) is on waking Administered shortly thereafter, eg, within about 3 hours, within about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes of waking up from overnight sleep.

For a single dosage form comprising a first release component and a second release component administered throughout the day, about 0-30 minutes, about 30-60 minutes, about 60-90 minutes, or about 90 minutes after oral administration of the dosage form - 120 minutes, or any time period within the range bounded by any of these values, the first release component can release reboxetine (including S,S-reboxetine), can start releasing reboxetine (including S,S-reboxetine), or can cause reboxetine (including S,S-reboxetine Poxetine) first local maximum of plasma concentration. The second release component may release reboxetine (including S, S-reboxetine) after the first release component releases reboxetine (including S, S-reboxetine); or may release reboxetine (including S,S-reboxetine) about 1-10 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6- 8 hours, or about 7-10 hours later, or after the first local maximum of reboxetine (including S,S-reboxetine) plasma concentration, or any of the ranges limited by any of these values Time points leading to an increase in plasma concentrations of reboxetine (including S,S-reboxetine) or a second local maximum in plasma concentrations of reboxetine (including S,S-reboxetine).

The first release component and the second release component may be incorporated into a single dosage form such as a pill, tablet, capsule, caplet or chewing gum. In one embodiment, the first release component will be in one of the outer layers of the dosage form and the second release component will be in one of the inner layers of the same dosage form.

In another embodiment, the first release component is located in a first layer of the dosage form and the second release component is located in a second layer of the same dosage form. The two layers are distinct and may or may not be in contact with each other. In some embodiments, the two layers are stacked on top of each other and physically bonded in a bilayer structure (eg, the largest surfaces of the two layers are in contact with each other, or the layers are relatively thin compared to other dimensions of the layers). In some embodiments, the two layers are placed adjacent to each other and are physically bonded in a bilayer structure (eg, wherein the layer is thick compared to the other dimensions of the layer).

In another embodiment, the first release component and the second release component may be separately constructed in the form of their own specific particles, particles, etc., wherein the first release component particles are formulated to release Reboxetine (including S,S-reboxetine) is released before reboxetine (including S,S-reboxetine), and wherein both the first release component particles and the second release component particles are combined together to form A single dosage form, such as a capsule, pill, tablet, caplet, chewing gum, etc., and the two release components may or may not be physically associated with each other.

In some embodiments, the first local maximum plasma concentration of reboxetine (including S,S-reboxetine) occurs about 1-30 minutes, About 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4 hours, or any time within the range bounded by any of these values. Typically, the second maximum local plasma concentration of reboxetine (including S,S-reboxetine) occurs less than half a day after the first local maximum plasma concentration of reboxetine (including S,S-reboxetine), e.g. About 1-10 hours, about 1-2 hours, about 2-6 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7 hours - 8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or within these Any time period within the range bounded by any of the values.

For dosage forms containing a first release component and a second release component, the first release component is associated with the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine), because the first release component Partially released reboxetine (including S,S-reboxetine) contributed to the first local maximum of reboxetine (including S,S-reboxetine) plasma concentrations. For example, the first release component may release reboxetine (including S,S-reboxetine) faster or more rapidly than the second release component such that reboxetine (including S,S-reboxetine) is induced Most of the first local maximum plasma concentration of reboxetine (including S,S-reboxetine) is released from the first release component.

For dosage forms containing a first release component and a second release component, the second release component is associated with a second local maximum in the plasma concentration of reboxetine (including S,S-reboxetine), because the second release component Partially released reboxetine (including S,S-reboxetine) contributed to the second local maximum of reboxetine (including S,S-reboxetine) plasma concentrations. For example, the second release component can delay its reboxetine (including S,S-reboxetine) release such that when the reboxetine (including S,S-reboxetine) plasma concentration is after the first local maximum While decreasing, the second release component releases sufficient reboxetine (including S,S-reboxetine) to increase the reboxetine (including S,S-reboxetine) plasma concentration again in order to reach reboxetine (including S,S-reboxetine) the second local maximum of plasma concentration.

For dosage forms containing a first release component and a second release component, any suitable amount of reboxetine (including S,S-reboxetine) may be present in the first release component, for example about 1-10 mg, about 0.1 -2mg, about 0.5-1.5mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5- 5.5mg, About 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 1-3mg, about 2-4mg, about 3-5mg, about 4-6mg, about 5-7mg, About 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021- 0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within the range bounded by any of these values.

For dosage forms comprising a first release component and a second release component, any suitable amount of reboxetine (including S,S-reboxetine) may be present in the second release component, for example about 0.1-2 mg, about 0.5 -1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 2-4 mg, about 3-5 mg, about 3.5-4.5 mg, about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 4-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 5-7mg, about 7 -10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol , about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within the range bounded by any of these values.

In some embodiments, the first release component may contain more reboxetine (including S,S-reboxetine) than the second release component, for example about 10-20% more than the second release component. About 20-30% more, or about 30-40% more reboxetine (including S,S-reboxetine).

While the dosing schedule given above may be useful in many situations, the daily dosing schedule may vary from the above described dosing schedule. For example, a once-daily dose may be administered. The twice daily dose may be administered by any suitable route, for example in the morning and evening, in the manner described above, or by some other route.

In some embodiments, the daily dose of reboxetine (including S,S-reboxetine) can be about 0.5-1 mg, about 1-1.5 mg, about 1.5-2 mg, about 1-2 mg, about 2-3 mg, About 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 10-11mg, about 11-12mg, about 12-13mg, About 13-14mg, about 14-15mg, about 15-16mg, about 16-17mg, about 2-5mg, about 5-8mg, about 8-11mg, about 11- 14mg, about 14-17mg, about 17-20mg, about 8-10mg, about 8-12mg, about 0.0015-0.003mmol, about 0.003-0.0045mmol, about 0.0045-0.006mmol, about 0.003-0.006mmol, about 0.006-0.009 mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, about 0.033-0.036mmol, about 0.036-0.039mmol, about 0.039-0.042mmol, about 0.042-0.045mmol, about 0.045-0.048mmol, about 0.048-0.051mmol, about 0.051-0.054mmol, about 0.054-0.057mmol, about 0.057 -0.06mmol, about 0.06-0.063mmol, about 0.063-0.066mmol, about 0.066-0.069mmol, about 0.006-0.01mmol, about 0.01-0.02mmol, about 0.02-0.03mmol, about 0.03-0.04mmol, about 0.04-0.05 mmol, about 0.05-0.06 mmol, about 0.06-0.07 mmol, or about 0.07-0.08 mmol. The daily dose refers to the total amount of reboxetine administered in a single day. The daily dose may be administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, At least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years or longer. In some embodiments, the daily dose is administered for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

The dose of reboxetine (including S,S-reboxetine) can be gradually increased to a maintenance dose over time (for example, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days), The maintenance dose is the total dose given per day (eg, a 10 mg maintenance dose may be a 10 mg dose once daily, a 6 mg dose in the morning and a 4 mg dose in the afternoon, or a 5 mg dose given twice daily to achieve a total of 10 mg per day). In some embodiments, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11mg, about 11-12mg, about 12-13mg, about 13-14mg, about 14-15mg, about 15-16mg, about 16-17mg, about 2-5mg, about 5-8mg, about 8-11mg mg, about 11-14mg, about 14-17mg, about 17-20mg, about 8-10mg, about 8-12mg, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol , about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, about 0.033-0.036mmol, about 0.036-0.039mmol, about 0.039-0.042mmol, about 0.042-0.045mmol, about 0.045-0.048mmol, about 0.048-0.051mmol, about 0.051-0.054mmol, about 0.054-0.057mmol, about 0.057-0.06mmol, about 0.06-0.063mmol, about 0.063-0.066mmol, about 0.066- 0.069mmol, about 0.006-0.01mmol, about 0.01-0.02mmol, about 0.02-0.03mmol, about 0.03-0.04mmol, about 0.04-0.05mmol, about 0.05-0.06mmol, about 0.06-0.07mmol, or about 0.07-0.08 mmol. In some embodiments, the first dose (eg, the first dose administered in the morning) may contain more reboxetine (including S, S-reboxetine). For example, the first dose of the day (e.g., the first dose administered in the morning) may have about 10-20% more, about 20-30% more, than the second dose of the day (e.g., the second dose administered in the afternoon). %, or more than about 30-40% of reboxetine (including S,S-reboxetine). A maintenance dose may be administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, At least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years or longer. In some embodiments, the maintenance dose is administered for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

In some embodiments, the patient receives about 110-130 mg of reboxetine (including S,S-reboxetine) over a two-week period.

In some embodiments, the first release component provides immediate release of reboxetine, including S,S-reboxetine. In some embodiments, the first release component provides delayed release of reboxetine, including S,S-reboxetine. In some embodiments, the first release component provides For sustained release of reboxetine (including S,S-reboxetine).

In some embodiments, the second release component provides immediate release of reboxetine, including S,S-reboxetine. In some embodiments, the second release component provides delayed release of reboxetine, including S,S-reboxetine. In some embodiments, the second release component provides sustained release of reboxetine, including S,S-reboxetine.

In some embodiments, the first release component provides immediate release of reboxetine (including S,S-reboxetine) and the second release component provides release of reboxetine (including S,S-reboxetine). delayed release. In some embodiments, the first release component provides immediate release of reboxetine (including S,S-reboxetine) and the second release component provides release of reboxetine (including S,S-reboxetine). Sustained release.

Regarding the administration of reboxetine (including S,S-reboxetine) in a first dosage form containing reboxetine (including S,S-reboxetine) and in a second dosage form containing Reboxetine), any suitable amount of reboxetine (including S,S-reboxetine) may be present in the first dosage form, such as about 1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5- 1.5.mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5- 5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 2-4mg, about 3-5mg, about 4-6mg, about 5-7mg, about 7 -10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol , about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within the range bounded by any of these values.

Regarding the administration of reboxetine (including S,S-reboxetine) in a first dosage form containing reboxetine (including S,S-reboxetine) and in a second dosage form containing Reboxetine), any suitable amount of reboxetine (including S,S-reboxetine) can be present in the second dosage form, such as about 0.1-1mg, about 0.1-2mg, about 0.5-1.5mg, about 1 -3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5-5.5mg, about 5- 6mg, about 6-7mg, about 7-8mg, About 8-9mg, about 9-10mg, about 2-4mg, about 3-5mg, about 4-6mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.006- 0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol , or any quantity within the range bounded by any of these values.

In some embodiments, the first dosage form may contain more reboxetine (including S,S-reboxetine) than the second dosage form, for example about 10-20% more, about 20-30% more than the second dosage form , or more than about 30-40% reboxetine (including S, S-reboxetine).

In some embodiments, the first dosage form provides immediate release of reboxetine, including S,S-reboxetine. In some embodiments, the first dosage form provides delayed release of reboxetine, including S,S-reboxetine. In some embodiments, the first dosage form provides sustained release of reboxetine, including S,S-reboxetine.

In some embodiments, the second dosage form provides immediate release of reboxetine, including S,S-reboxetine. In some embodiments, the second dosage form provides delayed release of reboxetine, including S,S-reboxetine. In some embodiments, the second dosage form provides sustained release of reboxetine (including S,S-reboxetine).

For a single dosage form containing both the first release component and the second release component, in some embodiments, the single dose is administered within two hours of waking from overnight sleep.

For some embodiments in which more than one dosage form is administered, the first dosage form may be administered within two hours of waking from overnight sleep.

Many factors can affect the overall time required for a drug, such as reboxetine (including S,S-reboxetine), to be completely absorbed and/or to reach maximum plasma concentration in humans. Some of these factors include the human patient's age, weight, sex, stress level, gastric contents, gastric pH level, and the presence of other medications. The time required to achieve maximum plasma concentration of a drug (e.g., reboxetine (including S,S-reboxetine)) may also be affected by the day in which the drug (e.g., reboxetine (including S,S-reboxetine) ) time and the effect of physical activity levels in human patients. Another can affect the maximum blood pressure achieved for drugs such as reboxetine (including S,S-reboxetine). A factor of the time required for slurry concentration is the presence or absence of a release-controlling coating on the drug, eg, reboxetine (including S,S-reboxetine).

Controlled release includes: immediate release of a drug (such as reboxetine (including S,S-reboxetine)) at a certain time or at a certain area of the body; delayed release of a drug; Sustained release of a drug at a certain time or at a certain location in the body; or extended release of a drug such as reboxetine (including S,S-reboxetine).

Reboxetine (including S,S-reboxetine) is generally rapidly absorbed in human patients, reaching maximum plasma concentrations in about 2-4 hours. In order to achieve a delay in the time required to achieve maximum plasma concentration, a controlled release coating or admixture may be employed.

Delayed release is a general drug delivery term that describes an oral drug form that does not immediately release its active drug ingredient in the patient's mouth or stomach. Although there are many possible ways to achieve delayed release, delayed release of reboxetine (including S,S-reboxetine) can be achieved completely or completely by using a coating or layer that does not dissolve immediately when swallowed (such as an internal release control coating). This is achieved by partially enclosing reboxetine (including S,S-reboxetine), for example in the second release component. For example, the material of the coating or layer may slowly dissolve in the stomach and/or slowly disintegrate in the stomach by a chemical reaction (e.g., by hydrolysis) until the layer is no longer able to block reboxetine (including S,S- Xetine) in contact with gastric juice.

In some embodiments, the delayed release coating ensures delivery through the stomach and into the intestine. Once in the duodenum, the coating can begin to break down and release reboxetine (including S,S-reboxetine). In some cases, reboxetine (including S,S-reboxetine) can be completely released in the duodenum. In some embodiments, reboxetine (including S,S-reboxetine) may be released partially in the duodenum and partially in the jejunum. In some cases, reboxetine (including S,S-reboxetine) can be completely released in the jejunum. In some cases, reboxetine (including S,S-reboxetine) may be released partially in the jejunum and partially in the ilium. In some cases, reboxetine (including S,S-reboxetine) can be completely released in the ilium. In some cases, reboxetine (including S,S-reboxetine) can be partially released in the duodenum, jejunum and ilium. In some embodiments, reboxetine (including S,S-reboxetine) can be released partly in the ilium and partly in the colon. In some cases, reboxetine (including S,S-reboxetine) can be completely released in the colon.

The time of delayed release, such as the time between the release of the first reboxetine (including S,S-reboxetine) component and the second reboxetine (including S,S-reboxetine) component, can be determined by Using materials that dissolve or disintegrate more or less slowly in the digestive system, adjusting the thickness of the coating layer or coating material (for example, a thicker layer will provide a longer time) and/or by using properties that are pH-sensitive material to adjust. For example, a material that is less stable to acidic pH, or more soluble at acidic pH, may dissolve or disintegrate more quickly in the stomach because the pH of the stomach is lower than that of the intestine. Conversely, materials that are stable at low pH but less stable at higher pH may dissolve or disintegrate later due to the time it takes for the dosage form to travel through the gastrointestinal tract.

Controlled-release formulations containing reboxetine (including S,S-reboxetine) may be coated with one or more functional or non-functional coatings. Examples of functional coatings include controlled release polymer coatings (ie, controlled release coatings), moisture barrier coatings, enteric polymer coatings, and the like.

Depending on the structure of the dosage form, release-controlling polymers can be used to slow or delay release. For example, distributing reboxetine (including S,S-reboxetine) throughout a controlled release polymer can provide sustained release because the drug will be released as long as the polymer is present in the gastrointestinal tract. Delayed release can be achieved by creating a barrier (e.g. coating) that is intended to last for a short period of time (e.g. less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) so that when the barrier is penetrated , reboxetine (including S,S-reboxetine) was released freely. The thickness of the barrier can be used to control the delay time.

Any suitable controlled release polymer may be used, such as acrylic and methacrylic acid copolymers and their various esters, such as methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methyl methacrylate, aminoalkyl acrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), poly Acrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer.

Other suitable release-controlling polymers include polymerizable quaternary ammonium compounds such as quaternized aminoalkyl esters of acrylic and methacrylic acid and aminoalkylamides such as beta-methylpropane Acryloxyethyltrimethylammonium methylsulfate, β-acryloxypropyltrimethylammonium chloride, and trimethylaminomethacrylamide methylsulfate. The quaternary ammonium atom can also be part of a heterocycle, as in methacryloxyethylmethylmorpholine chloride or the corresponding piperidinium salt, or it can be passed through a heteroatom-containing group such as polyethylene glycol ether groups) are linked to acrylic or methacrylic groups. Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl substituted nitrogen heterocycles such as methyl-vinylpyridinium salts, quaternized vinyl esters of aminocarboxylic acids, styryltrialkylammonium salts wait. Other polymerizable quaternary ammonium compounds include benzyldimethylammonium ethyl-methacrylate chloride, diethylmethylammonium ethyl-acrylate and -methacrylate methylsulfate, N-trimethylammonium Propylmethacrylamide chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

Delayed release may also be achieved through the use of controlled release polymers targeted to a specific pH, where it is understood that the specific pH may correspond to a specific time after administration, with appropriate fasting or feeding.

For some controlled release polymers, the acrylic or methacrylic polymers include one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers, such as those sold under the trade marks EUDRAGIT® RS and RL by Evonik, are all-polymeric copolymers of acrylates and methacrylates with a low content of quaternary ammonium groups. The ammonium group is appended to the ester portion of the methacrylate (as 2-trimethylammonium-ethyl ester). The charged ammonium groups in these polymers make them insoluble and highly permeable with pH-independent swelling. These properties make these polymers useful for tailored, time-controlled release of coated drugs. In order to obtain the desired solubility characteristics for a given therapeutically active agent, such as reboxetine (including S,S-reboxetine), two or more ammonium methacrylate copolymers with different physical properties may be incorporated. For example, it is known that the permeability of the resulting coating can be modified by varying the molar ratio of prepolymerized material containing quaternary ammonium groups to prepolymerized material containing uncharged neutral methacrylate or acrylate.

In other embodiments, the controlled release coating further comprises a polymer whose permeability is pH dependent, such as anionic polymers synthesized from methacrylic acid and methyl methacrylate. Such polymers are commercially available, for example from Evonik under the trade names EUDRAGIT® L and EUDRAGIT® S. The ratio of free carboxyl groups to esters is known to be 1:1 in EUDRAGIT® L, and And in EUDRAGIT® S it is 1:2. EUDRAGIT® L is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0. This makes EUDRAGIT® L suitable for the targeted release of coated drugs such as coated reboxetine (including S,S-reboxetine) in the duodenum and jejunum of the small intestine. Therefore, compared to uncoated or immediate release drugs (such as reboxetine (including S,S-reboxetine) in the first release component), EUDRAGIT® L coated drugs can achieve about Maximum plasma concentration is delayed by 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, or about 3.5-4 hours.

UDRAGIT® S is similar to EUDRAGIT® L except that it becomes increasingly permeable above pH7. This makes EUDRAGIT® S suitable for targeted release of coated drugs such as coated reboxetine (including S,S-reboxetine) in the ileum of the small intestine as well as in the colon. Therefore, EUDRAGIT® S-coated drugs can achieve approximately 1-2 hours relative to uncoated or immediate-release drugs (such as reboxetine (including S,S-reboxetine) in the first release component). , about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10 hours Delayed maximum plasma concentration.

Hydrophobic acrylic polymer coatings may also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylates (such as EUDRAGIT® E, commercially available from Evonik). EUDRAGIT® E is insoluble in saliva (making it useful for taste and odor masking), but is soluble in gastric juice at pH 5 or lower, which provides immediate release of the drug in the stomach. EUDRAGIT® E The reboxetine (including S,S-reboxetine) surrounded by the coating can release reboxetine (including S,S-reboxetine), and can start to release reboxetine (including S,S-reboxetine), Or can lead to the first local maximum of reboxetine (including S,S-reboxetine) plasma concentration.

The hydrophobic acrylic polymer coating may comprise polymethacrylate based neutral copolymers such as EUDRAGIT® NE (NE=neutral ester) commercially available from Evonik. The EUDRAGIT® NE 30D paint film is insoluble in water and digestive fluids, but is permeable and swellable, thus providing another option for time-controlled release. EUDRAGIT® NE has A pH-independent slow-release effect that releases a drug such as reboxetine (including S,S-reboxetine) over a period of time, or that delays release for a period of time, wherein the release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the controlled release coating comprises a polymer comprising ethyl acrylate and methyl methacrylate in a 2:1 ratio (KOLLICOAT® EMM 30 D, BASF). KOLLICOAT® EMM 30 D has a pH-independent sustained-release effect, which releases drugs such as reboxetine (including S,S-reboxetine) over a period of time, or delays the release over a period of time, wherein the release Or the delayed time is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the controlled release coating comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate, such as KOLLICOAT® SR30D (BASF). The dissolution characteristics can be varied by varying the relative amounts of different acrylic lacquers included in the coating. Furthermore, by varying the molar ratio of polymerizable permeation enhancer (eg, quaternary ammonium compound) to neutral methacrylate, the permeation properties (which affect dissolution properties) of the resulting coating can be altered. KOLLICOAT® SR30D is another coating with a pH-independent sustained-release effect that releases drugs such as reboxetine (including S,S-reboxetine) over a period of time, or delays release for a period of time time, wherein the release or delay time is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours Hour.

In some embodiments, the controlled release coating comprises ethylcellulose, which can be used as a dry polymer (e.g. ETHOCEL™, Dow Chemical Company) solubilized in an organic solvent prior to use, or as an aqueous dispersion body. A suitable commercially available aqueous dispersion of ethylcellulose is Aquacoat® (Danisco). Aquacoat® ECD (Ethylcellulose Aqueous Dispersion), Aquacoat® ARC (Alcohol Resistant Ethylcellulose Aqueous Dispersion), and Aquacoat® CPD (Aqueous Cellulose Acetate Phthalate Dispersion) are commercially available Available controlled release coatings. Another suitable aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc.). This product can be manufactured by The dispersion is prepared by incorporating a plasticizer during the process. A hot melt of polymer, plasticizer (such as dibutyl sebacate) and stabilizer (such as oleic acid) can be mixed and prepared into a homogeneous mixture, which is then diluted with an alkaline solution to obtain a ready-to-apply Aqueous dispersions onto substrates. These coatings have a pH-independent sustained-release effect that releases a drug such as reboxetine (including S,S-reboxetine) over a period of time, or that delays release over a period of time, where the release or delayed The period of time is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

Other examples of polymers that can be used in controlled release coatings include cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropylmethylcellulose phthalate, hydroxypropyl Methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carboxymethylcellulose, carboxy Calcium methylcellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethylcellulose, methylcellulose, ethylcellulose, gelatin, starch, and cellulose-based crosslinked polymers (wherein the degree of crosslinking low to promote water adsorption and swelling of the polymer matrix), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen Egg white, casein, agar, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymer) poly(hydroxyalkyl methacrylate) (molecular weight 5k to 5000k), polyvinylpyrrolidone (molecular weight 10k to 360k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohols with low acetate residues, swellable mixtures of agar and carboxymethylcellulose, maleic anhydride and styrene, ethylene, Copolymers of propylene or isobutylene, pectin (molecular weight 30k to 300k), polysaccharides such as agar, acacia, karaya, tragacanth, algin and guar, polyacrylamide, POLYOX® polyoxyethylene ( Molecular weight 100k to 5000k, Dow), AQUA KEEP® Acrylate Polymer (consisting mainly of acrylic acid polymer, sodium salt), diesters of polydextrose, cross-linked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, hydrophilic Polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, nitrocellulose, carboxymethylcellulose, Cellulose ether, methyl ethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, Glyceryl fatty acid esters, polyacrylamide, polyacrylic acid, natural gum, lecithin, pectin, alginate, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar and gum For example, gum arabic, karaya, locust bean, tragacanth, carrageenan, guar gum, xanthan gum, scleroglucan, and mixtures and blends thereof.

In some embodiments, dosage forms of reboxetine (including S,S-reboxetine) are coated with a polymer to promote mucoadhesion within the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic acid, Carbopol ^™ (Lubrizol), polycarbophil, gelatin, and other natural or synthetic polymers.

The polymer coating of the present invention can be any one of the coatings, or can be a combination of two or more coatings in the coatings to achieve reboxetine (including S,S- desired release profile for release of cetine).

In addition to the modified release dosage forms described herein, other modified release techniques known to those skilled in the art can be used to achieve the modified release formulations of the present invention, i.e. when administered (e.g. orally or by other modes of administration) Formulations that provide mean _Tmax and/or other pharmacokinetic parameters of the drugs described herein in human patients. Such formulations may be prepared as modified release oral formulations in the form of suitable tablets or multiparticulate formulations known to those skilled in the art. In either case, the modified release dosage form may optionally comprise a controlled release carrier which is incorporated with the drug into a matrix or applied as a controlled release coating.

Any dosage form containing an effective amount of reboxetine (including S,S-reboxetine) may also contain binders, lubricants and other conventional inert excipients.

Binders (sometimes called tackifiers) can be added to drug-filler mixtures to increase the mechanical strength of granules and tablets during formation. The binder can be added to the formulation in different ways: (1) as a dry powder, which is mixed with the other ingredients prior to wet agglomeration, (2) as a solution, which is used as the agglomeration liquid during wet agglomeration and is called as a solution binder, and (3) as a dry powder that is mixed with the other ingredients prior to compaction. In this form, the adhesive is known as a dry adhesive. Solution binders are a common route to incorporate binders into particles. In certain embodiments, the binder used in the tablet is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin, Higher fatty alcohols, higher fatty acids, long-chain fatty acids, fatty acid esters, waxy substances such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, having a hydrocarbon backbone Hydrophobic and hydrophilic polymers, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (such as hydroxypropyl methylcellulose (Hydroxypropyl Methylcellulose, HPMC) and hydroxypropyl cellulose (Hydroxypropyl Methylcellulose, HPC )), polyvinyl alcohol, and mixtures thereof. The binder may be present in any suitable amount, for example about 0.5-5% by weight, about 5-10% by weight, about 10-15% by weight, about 15-20% by weight, about 20-25% by weight based on the dry weight of the tablet , about 0.5-25% by weight, about 0.5-15% by weight, about 1-6% by weight, or about 3% by weight. In some embodiments, the binder is polyvinyl alcohol.

Lubricants can be added to drug formulations to reduce any friction that occurs between the solids and the walls of the mold during tablet manufacture. High friction during tablet compression can lead to a range of problems including improper tablet quality (tablets capped or even broken during ejection, and vertical scratches on tablet edges) and may even stop production. Therefore, lubricants may be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils such as hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM), and hydrogenated soybean oil and castor wax (STEROTEX® HM). ® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol , ethylene oxide polymers (available, for example, under the registered trademark CARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate , DL-leucine, colloidal silicon dioxide, mixtures thereof, and others known in the art. In some embodiments, the lubricant is glyceryl behenate (e.g., COMPRITOL® 888). Any A suitable amount of binder, for example about 0.5-5% by weight, about 5-10% by weight, about 10-15% by weight, about 15-20% by weight, about 20-25% by weight, about 0.5% by weight, based on the dry weight of the tablet - 25% by weight, about 0.5-15% by weight, about 1-6% by weight, or about 3% by weight.

In some embodiments, reboxetine (including S,S-reboxetine) is administered once daily or twice daily for at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least About 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 4 months, at least about 5 months, at least about 6 months months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years , at least about 4 years, at least about 5 years, about 0.1-5 years, about 5-10 years, at least about 10 years, about 10-15 years, at least about 15 years, about 15-20 years, at least about 20 years or longer. In some embodiments, administering reboxetine (including S,S-reboxetine) continues for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

Examples (without attempting to limit the scope of the invention) of useful compositions for dosage forms containing about 5-10 mg reboxetine (including S,S-reboxetine) are shown in Table 1 below:

Treatment of cataplexy narcolepsy with reboxetine (including S,S-reboxetine) in the dosage forms described herein may not have the significant side effects of conventional treatment options. Treatment of cataplexy narcolepsy with reboxetine (including S,S-reboxetine) in the dosage forms described herein is well tolerated in mammals such as humans.

Some embodiments include a kit comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120- 180, about 180-360 or about 360-720 unit dosage forms), wherein one unit dosage form contains about 0.1-5 mg of reboxetine (including S,S-reboxetine); and the drug Instructions for use of a composition for the treatment of narcolepsy.

Some embodiments include a kit comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90- 120, about 120-180, about 180-360 or about 360-720 unit dosage forms), wherein one unit dosage form contains about 5-10 mg of reboxetine (including S,S-reboxil Ting); and the instructions for using the pharmaceutical composition to treat narcolepsy.

Some embodiments include a kit comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120- 180, about 180-360 or about 360-720 unit dosage forms), wherein one unit dosage form contains about 10-15 mg of reboxetine (including S,S-reboxetine); and the drug Instructions for use of a composition for the treatment of narcolepsy.

Some embodiments include a kit comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120- 180, about 180-360 or about 360-720 unit dosage forms), wherein one unit dosage form contains about 15-20 mg of reboxetine (including S,S-reboxetine); and the drug Instructions for use of a composition for the treatment of narcolepsy.

Some embodiments include a kit comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120- 180, about 180-360 or about 360-720 unit dosage forms), wherein one unit dosage form contains about 5-20 mg of reboxetine (including S,S-reboxetine); and the drug Instructions for use of a composition for the treatment of narcolepsy.

Specifically consider the following embodiments.

A method of treating cataplexy-type narcolepsy comprising administering reboxetine to a human in need thereof, wherein reboxetine is administered at least once daily for more than two weeks, wherein as a result of the treatment, the For two weeks, the person experiences a decrease in the number of cataplexy episodes during the week, a decrease in the Epworth Sleepiness Scale score, a decrease in the Ullanlinna Narcolepsy Scale (UNS) cataplexy sub-score, or a decrease in the Remaining Awake Test score.

Use of reboxetine for the manufacture of a medicament for the treatment of cataplexy narcolepsy, wherein reboxetine is administered at least once a day for at least three weeks.

A kit, the kit includes a pharmaceutical composition containing reboxetine, and instructions for using the pharmaceutical composition to treat human cataplexy narcolepsy, wherein: Administer reboxetine at least once daily for at least three weeks.

The method, use or kit of embodiment 1, 2 or 3, wherein reboxetine is administered twice daily, wherein the first dosage form is administered in the morning and the second dosage form is administered about 2 hours to about 6 hours later.

The method, use or kit of embodiment 4, wherein the second dosage form is administered about 2 hours to about 3 hours after the first dosage form.

The method, use or kit of embodiment 4, wherein the second dosage form is administered about 3 hours to about 4 hours after the first dosage form.

The method, use or kit of embodiment 4, wherein the second dosage form is administered about 4 hours to about 5 hours after the first dosage form.

The method, use or kit of embodiment 4, wherein the second dosage form is administered about 5 hours to about 6 hours after the first dosage form.

The method, use or kit according to embodiment 1, wherein a single dosage form is administered daily, wherein the single dosage form contains a first release component comprising reboxetine and a second release component comprising reboxetine, wherein the The first release component provides a first local maximum of the plasma concentration of reboxetine, and the second release component provides a second local maximum of the plasma concentration of reboxetine, wherein the first local maximum of the plasma concentration of reboxetine The maximum occurs about 2 to about 6 hours before the second local maximum of reboxetine plasma concentration.

The method, use or kit of embodiment 9, wherein the second local maximum of reboxetine plasma concentration occurs about 2 to about 3 hours after the first local maximum of reboxetine plasma concentration.

The method, use or kit of embodiment 9, wherein the second local maximum of reboxetine plasma concentration occurs about 3 to about 4 hours after the first local maximum of reboxetine plasma concentration.

The method, use or kit of embodiment 9, wherein the second local maximum of reboxetine plasma concentration occurs about 4 to about 5 hours after the first local maximum of reboxetine plasma concentration.

The method, use or kit according to embodiment 9, wherein Ruibo The second local maximum of the plasma concentration of reboxetine occurs about 5 to about 6 hours after the first local maximum of the plasma concentration of reboxetine.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, 12 or 13, wherein said person is selected not to suffer from depression .

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the dose of reboxetine is increased by 1 days to 7 days, and then kept constant at a total daily dose of about 0.006 mmol to about 0.01 mmol.

According to the method, use or kit described in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dosage of reboxetine is Increased by 1 day to 7 days, then kept constant at a total daily dose of about 0.01 mmol to about 0.02 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days and then kept constant at a total daily dose of about 0.02 mmol to about 0.03 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days, then kept constant at a total daily dose of about 0.03 mmol to about 0.04 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days, then kept constant at a total daily dose of about 0.04 mmol to about 0.05 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days, then kept constant at a total daily dosage of about 0.05 mmol to about 0.06 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days and then kept constant at a total daily dose of about 0.06 mmol to about 0.07 mmol.

The method, use or kit according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dose of reboxetine is increased 1 day to 7 days and then kept constant at a total daily dose of about 0.07 mmol to about 0.08 mmol.

The method according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 , a use or a kit, wherein reboxetine is in a dosage form and said dosage form contains about 5 mg of reboxetine.

The method according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 , a use or a kit, wherein reboxetine is in a dosage form and said dosage form contains about 10 mg of reboxetine.

The method, use or kit of embodiment 23, wherein the dosage form is administered once a day or twice a day for at least three weeks.

The method, use or kit of embodiment 24, wherein the dosage form is administered once a day or twice a day for at least three weeks.

According to Embodiments 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 or 26, wherein the human experiences prolonged sleep latency on the Multiple Sleep Latency Test (MSLT).

The method, use or kit of embodiment 27, wherein said human experiences at least a 10% increase in sleep latency on the MSLT.

The method, use or kit of embodiment 27, wherein said human experiences at least a 20% increase in sleep latency on the MSLT.

The method, use or kit of embodiment 27, wherein said human experiences at least a 30% increase in sleep latency on the MSLT.

The method, use or kit of embodiment 27, wherein said human experiences at least a 40% increase in sleep latency on the MSLT.

The method, use or kit of embodiment 27, wherein said human experiences at least a 50% increase in sleep latency on the MSLT.

The method, use or kit of embodiment 27, wherein said human experiences a sleep latency increase of at least 60% on the MSLT.

According to Embodiments 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, The method, use or kit of 29, 30, 31, 32 or 33, wherein said human experiences at least a 15% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein the human experiences at least a 20% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein said human experiences at least a 30% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein the human experiences at least a 40% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein said human experiences at least a 50% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein said human experiences at least a 60% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein said human experiences at least a 70% reduction in the cataplexy sub-score on the UNS.

The method, use or kit of embodiment 34, wherein the human has a cataplexy sub-score of about 0.

A method of improving the ability to concentrate in a person suffering from narcolepsy comprising administering reboxetine to the person in need thereof.

A method according to embodiment 42, wherein the person is selected as needing improved ability to concentrate or having difficulty concentrating.

The method of embodiment 42 or 43, wherein the human has an improvement of at least about -0.1 on the NSAQ's ability to concentrate attention item compared to before administration of any reboxetine.

A method of treating fibromyalgia, said method comprising administering oxepoxetine to a human in need thereof, wherein the administration of oxexetine in a daily dose of about 1 mg to about 2 mg continues for at least six weeks, wherein during the course of treatment, as The person experiences a reduction in fibromyalgia pain that is greater than the person experiences by administering a placebo, as measured by a Visual Analog Scale (VAS) score.

The method according to embodiment 45, wherein about 1 mg to about 2 mg of oxexetine is administered once daily.

The method according to embodiment 45, wherein about 0.5 mg to about 1 mg of oxexetine is administered twice daily.

The method of embodiment 45, 46 or 47, wherein the human is selected to have a Global Fatigue Index score of at least about 8.

The method according to embodiment 45, 46, 47 or 48, wherein after daily administration of oxepoxetine for six weeks, the human's VAS score for fibromyalgia pain is comparable to that immediately following the first dose of oxepoxetine VAS scores for fibromyalgia pain were reduced by at least 20% compared to those who were treated with cetine.

The method according to embodiment 45, 46, 47, 48 or 49, wherein after daily administration of oxepoxetine for six weeks, the human's VAS score for fibromyalgia pain is comparable to that immediately following administration of the first dose. VAS scores for fibromyalgia pain were reduced by at least 50% compared with those taking oxepoxetine.

A method of treating fibromyalgia, said method comprising administering oxepoxetine to a human in need thereof, wherein the administration of oxexetine in a daily dose of about 2 mg to about 4 mg continues for at least six weeks, wherein during the course of treatment, as The reduction in pain experienced by the human is greater than the reduction in pain experienced by the human by administration of a placebo, as measured by Visual Analog Scale (VAS) scores.

The method according to embodiment 51, wherein about 1 mg to about 2 mg of oxetine is administered once daily.

The method according to embodiment 51, wherein about 0.5 mg to about 1 mg of oxexetine is administered twice daily.

The method according to embodiment 51, 52 or 53, wherein the human is selected to have a Global Fatigue Index score of at least about 8.

The method according to embodiment 51, 52, 53, or 54, wherein after daily administration of oxepoxetine for six weeks, the human's VAS score for fibromyalgia pain is comparable to that immediately following administration of the first dose of oxepoxetine VAS scores for fibromyalgia pain were reduced by at least 20% compared to those who were treated with cetine.

The method according to embodiment 51, 52, 53, 54 or 55, wherein after daily administration of oxepoxetine for six weeks, the human's VAS score for fibromyalgia pain is comparable to that of the VAS score immediately following administration of the first dose. VAS scores for fibromyalgia pain were reduced by at least 50% compared with those taking oxepoxetine.

A method of treating fibromyalgia, said method comprising administering oxetine to a human in need thereof, wherein administering oxetine in a daily dose of about 0.5 mg to about 1 mg for at least six weeks, wherein during the course of treatment, The reduction in pain experienced by the human is greater than the reduction in pain experienced by the human by administration of a placebo, as measured by Visual Analog Scale (VAS) scores.

The method according to embodiment 57, wherein about 1 mg to about 2 mg of oxetine is administered once daily.

The method according to embodiment 57, wherein about 0.5 mg to about 1 mg of oxexetine is administered twice daily.

The method according to embodiment 57, 58 or 59, wherein the human is selected to have a Global Fatigue Index score of at least about 8.

The method according to embodiment 57, 58, 59, or 60, wherein after daily administration of oxepoxetine for six weeks, the VAS score for fibromyalgia pain in the human is comparable to that immediately following the administration of the first dose of oxepoxetine VAS scores for fibromyalgia pain were reduced by at least 20% compared to those who were treated with cetine.

The method of embodiment 61, wherein after daily administration of oxepoxetine for six weeks, the human has a VAS score for fibromyalgia pain that is comparable to the human's VAS score for fibromyalgia pain immediately prior to administration of the first dose of oxetine VAS scores for fibromyalgia pain were reduced by at least 50%.

Example

Example 1

A 40-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. Cataplexy episodes decreased after one week of treatment 10-30%.

Example 2

A 20-year-old female was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, cataplexy attacks were reduced by 30-60%.

Example 3

A 60-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, cataplexy attacks were reduced by 60-100%.

Example 4

A 50-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, ESS scores decreased by 10-30%.

Example 5

A 25-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, the ESS score has decreased 30-60%.

Example 6

A 47-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, ESS scores decreased by 60-100%.

Example 7

A 19-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, MWT scores decreased by 10-30%.

Example 8

A 42-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, MWT scores decreased by 30-60%.

Example 9

A 33-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After one week of treatment, MWT scores decreased 60-100%.

Example 10

A 54-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, cataplexy attacks were reduced by 10-30%.

Example 11

A 27-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, cataplexy attacks were reduced by 30-60%.

Example 12

A 52-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, cataplexy attacks were reduced by 60-100%.

Example 13

A 66-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, the ESS score decreased by 10- 30%.

Example 14

A 34-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, ESS scores decreased by 30-60%.

Example 15

A 35-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, ESS scores decreased by 60-100%.

Example 16

A 19-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, MWT scores decreased by 10-30%.

Example 17

A 70-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, MWT scores decreased 30-60%.

Example 18

A 57-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, MWT scores decreased by 60-100%.

Example 19

A 20-year-old female was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, HAM-D scores decreased by 10-30%.

Example 20

A 69-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, HAM-D scores decreased by 30-60%.

Example 21

A 56-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Patients were assessed before treatment and weekly to determine MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on the NSAQ. After three weeks of treatment, HAM-D scores decreased up 60-100%.

Example 22

A phase 2, double-blind, randomized, placebo-controlled, crossover, multicentre trial of reboxetine in patients with narcolepsy. A total of 21 patients diagnosed with cataplexy-type narcolepsy were treated with reboxetine or placebo for 2 weeks, then crossed over to another treatment after a 1-week taper and washout period. Reboxetine was administered orally twice daily, with a total daily dose of 8 mg in the first week and increased to 10 mg in the second week. Patients were randomized in a 1:1 ratio to treatment with reboxetine followed by placebo (sequence 1 ), or placebo followed by reboxetine (sequence 2). The mean number of cataplexy episodes at baseline was 30. Use the electronic diary for critical assessments every day. The prespecified primary endpoint was the change in the number of cataplexy episodes per week averaged over the 2-week treatment period (overall treatment effect). Secondary endpoints included change in the number of unplanned naps, cognition, and the Epworth Sleepiness Scale. Cognition was assessed using the Attention Ability item of the Narcolepsy Symptom Rating Questionnaire, a patient-reported outcome measure. The item is rated on a 5-point scale (1=very good to 5=very poor). All analyzes were performed on an intention-to-treat basis.

As shown in Figure 1, reboxetine demonstrated a highly statistically significant reduction from baseline in mean weekly cataplexy episodes averaged over the 2-week treatment period (overall treatment effect) compared to placebo ( p<0.001) while meeting the pre-specified primary endpoint. At week 2, reboxetine demonstrated a mean 14.6 weekly reduction in cataplexy attacks compared to placebo's 2.6 weekly reduction (p=0.002), representing 48.7% and 8.7% relative to baseline, respectively average reduction (Figure 1). Furthermore, reboxetine treatment resulted in a rapid reduction in cataplexy episodes. After 1 week of treatment, reboxetine demonstrated a mean reduction in cataplexy attacks of 13.0 compared to placebo's reduction of 0.3 attacks (p<0.001), representing mean reductions from baseline of 43.3% and 1.0%, respectively (figure 1). At week 2, the proportion of patients achieving a 50% or greater reduction in the number of weekly cataplexy episodes was 76.2% for reboxetine compared with 50% or greater for placebo The proportion of patients with fewer seizures was 30.0% (p=0.003) (Fig. 2). At week 2, the proportion of patients achieving a 75% or greater reduction in weekly cataplexy episodes was 42.9% for reboxetine compared with 75% or greater for placebo The proportion of patients with fewer seizures was 10.0% (p=0.018) (Fig. 3). Reboxetine improved cataplexy as early as week 1 was rapid, showing a significant benefit over placebo (p<0.001).

Reboxetine significantly improved EDS (excessive daytime sleepiness) symptoms compared to placebo as measured by the Epworth Sleepiness Scale (ESS) and by frequency of unexpected naps. As shown in Figure 4, treatment with reboxetine improved ESS twice as much as that observed with placebo, with reductions in ESS scores from baseline of 6.0 and 3.1 for reboxetine and placebo, respectively (p= 0.003). At week 2, reboxetine treatment resulted in a mean reduction from baseline in mean weekly accidental naps of 31.8%, compared with a mean reduction of 5.3% for placebo (p<0.001) (Figure 5). As shown in Figure 6, reboxetine treatment resulted in a greater number of patients having a 50% or greater reduction in accidental dozing (38.1%) compared to placebo (10.0%) (p=0.036). Improvement in accidental nap frequency with reboxetine was rapid as early as week 1, showing a significant benefit over placebo.

Over the 2-week treatment period, reboxetine significantly improved cognitive function compared to placebo as measured by the attentional ability item of the Narcolepsy Symptom Assessment Questionnaire (NSAQ), which was assessed daily (p <0.01) (Figure 7 to Figure 8). For this rating, patients rate their ability to concentrate on a 5-point scale (1=very good, 2=good, 3=average, 4=poor, and 5=very poor). At the end of the 2-week treatment period, 42.9% of patients treated with reboxetine had a "good" to "very good" ability to concentrate, compared with 25.0% of patients who received a placebo with "good" to Concentration was "very good" and at baseline 0% of patients had "good" to "very good" concentration. The improvement in concentration ability with reboxetine was rapid as early as week 1, showing a significant improvement over placebo (38.1% vs. 15.0%) (p=0.007).

Compared with placebo, reboxetine significantly improved sleep quality, as measured by overall improvement and number of nocturnal awakenings, and reduced sleep-related symptoms. As shown in Figure 9, reboxetine treatment resulted in 45.0% of patients reporting improved sleep quality compared to placebo resulting in 5.3% of patients reporting improved sleep quality (p=0.007). Treatment with reboxetine resulted in 30.0% of patients reporting a reduction in nighttime awakenings compared to 5.3% of patients reporting a decrease in nighttime awakenings when receiving placebo (p=0.044). Reboxetine treatment also resulted in a greater proportion of patients having fewer sleep paralysis episodes and fewer hypnagogic hallucinations than placebo.

Reboxetine was safe and well tolerated. No serious adverse events were reported in the trial, and there were no discontinuations due to adverse events. The overall percentage of patients who experienced adverse events was 42.9% on reboxetine and 40.0% on placebo, with the most commonly reported adverse events on reboxetine being anxiety, constipation and insomnia. The completion rate was 91% for patients randomized to treatment sequence 1 (reboxetine followed by placebo) and 100% for patients randomized to treatment sequence 2 (reboxetine followed by placebo).

Unless otherwise indicated, all numbers expressing amounts, properties (e.g. amounts, percentages), etc. "Retouch. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claimed scope, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

When used in the context of describing an embodiment (especially in the context of the claims of the appended claims), the terms "a", "an", "the" and similar designations and without modifiers of numerals shall be understood to cover both the singular and the plural unless The text states otherwise or is clearly contradicted by the context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claimed claims. No language in the specification should be construed as indicating that any non-claimed element is essential to the practice of what is claimed.

Groupings of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified, thus completing the written description of all Markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out claimed embodiments. Of course, variations of these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such modifications as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described in the claims as permitted by applicable law. Moreover, any combination of all possible variations of the above-described elements is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claimed claims. Other modifications that may be employed are within the scope of the patent application. Thus, by way of example and not limitation, alternative embodiments may be utilized in light of the teachings herein. Accordingly, the claim is not limited to the embodiment exactly as shown and described.

Claims (16)

A use of reboxetine in the manufacture of a medicament for rapidly reducing the number of cataplexy attacks in a person suffering from cataplexy narcolepsy, the administration of which comprises administering from about 8 mg to about Reboxetine 10 mg for at least two weeks, where the person had at least 7 cataplexy episodes per week prior to receiving reboxetine, and the person had at least 30% fewer cataplexy episodes compared to baseline one week after the start of treatment . The use according to claim 1, wherein the reduction in the number of cataplexy episodes is statistically significant, wherein p<0.01, compared with administration of a placebo. Use of reboxetine in the manufacture of a medicament for improving the ability to concentrate in a person suffering from cataplexy narcolepsy, the administration of which comprises administering from about 8 mg to about 10 mg per day to a person in need thereof Reboxetine for at least two weeks, where the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, and the person had "average," "poor," or "very poor" attention before treatment began ability to concentrate, and two weeks after the start of the treatment, the person had "good" or "very good" ability to concentrate, as determined by the ability to concentrate item of the Narcolepsy Symptom Rating Questionnaire . A use of reboxetine for the manufacture of a medicament for reducing the number of unintended dozes in a person suffering from cataplexy narcolepsy, the administration of which comprises administering about 8 mg to about 10 mg of reboxetine per day to a person in need thereof Reboxetine for at least two weeks, where the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, two weeks after the start of treatment, compared to the week before the patient first received reboxetine Said person has at least 20% fewer weekly accidental naps. A use of reboxetine in the manufacture of a medicament for improving the sleep quality of a person suffering from cataplexy narcolepsy, the administration of which comprises administering about 8 mg to about 10 mg of reboxetine to a person in need thereof per day At least two weeks of cataplexy in which the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, and two weeks after initiation of treatment, the person reported having the same compared to improved sleep quality. Use of reboxetine in the manufacture of a medicament for reducing nocturnal awakenings in a person suffering from cataplexy narcolepsy, the administration of which comprises administering about 8 mg per day to a person in need thereof to about 10 mg of reboxetine for at least two weeks, where the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, and two weeks after initiation of treatment, said person reported having Fewer nocturnal awakenings than the week before Ting. A use of reboxetine in the manufacture of a medicament for reducing sleep paralysis in a person suffering from cataplexy narcolepsy, the administration of which comprises administering about 8 mg to about 10 mg of reboxetine to a person in need thereof per day Reboxetine for at least two weeks, where the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, and two weeks after initiation of treatment, the person reported having the same symptoms as before the patient first received reboxetine Fewer sleep paralysis episodes than weekly. Use of reboxetine in the manufacture of a medicament for reducing hypnagogic hallucinations in a person suffering from cataplexy narcolepsy, the administration of which comprises administering about 8 mg to about 10 mg of reboxetine per day to a person in need thereof Reboxetine for at least two weeks, where the person had at least 7 episodes of cataplexy per week prior to receiving reboxetine, and two weeks after initiation of treatment, the person reported having the same symptoms as before the patient first received reboxetine Fewer hypnagogic hallucinations compared to week. A use of reboxetine for the manufacture of a medicament for improving the ability to concentrate in a person suffering from narcolepsy, the administration of said medicament comprising administering reboxetine to a person in need thereof, the person receiving narcolepsy Prior to cetine, there were at least 7 episodes of cataplexy per week. The use according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein about 4 mg of reboxetine is administered to the human twice a day for at least the first week. The use of claim 10, wherein about 4 mg of reboxetine is administered to the human in the morning and about 4 mg of reboxetine is administered to the human in the afternoon for at least a second week. The use of claim 10, wherein about 6 mg of reboxetine is administered to the human in the morning and about 4 mg of reboxetine is administered to the human in the afternoon for at least a second week. Use as described in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the person is diagnosed with cataplexy-type seizures that meet the criteria of the third edition of the International Classification of Sleep Disorders sleeping sickness. The use as described in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the Epworth sleepiness scale score of the person is greater than 10 before receiving reboxetine. Use as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the person is selected as needing improved ability to concentrate or having difficulty concentrating. Use as described in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein compared with before administering any reboxetine, the attention concentration ability item of the NSAQ of the people is reduced to at least About 0.1.

Images