TW202128179A - Use of reboxetine to treat nervous system disorders - Google Patents

Abstract

Described herein are methods of treating narcolepsy with cataplexy, comprising administering reboxetine (including esreboxetine) to a human being in need thereof. Reboxetine (including esreboxetine) may also be used in the manufacture of a medicament for the treatment of narcolepsy with cataplexy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine (including esreboxetine) and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

Description

Use of Reboxetine in the treatment of neurological disorders

The present invention requires the US patent application serial number 16/740,329 filed on January 10, 2020; the US patent application serial number 16/740,409 filed on January 11, 2020; the US patent application serial number filed on January 11, 2020 16/740,410; US patent application serial number 16/740,411 filed on January 11, 2020; US patent application serial number 62/943,077 filed on December 3, 2019; and US patent filed on December 10, 2019 The priority of application serial number 62/946,295; the entire contents of all these documents are incorporated herein by reference.

Narcolepsy is a serious and debilitating neurological disorder that can cause disturbances in the sleep-wake cycle and is clinically characterized by Excessive Daytime Sleepiness (EDS), cataplexy, hallucinations before going to bed, sleep paralysis, and Disrupted nocturnal sleep. It is estimated that narcolepsy afflicts 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 when the patient is awake, usually triggered by strong emotions (such as laughter, fear, anger, tension, or excitement). Type 1 narcolepsy includes cataplexy, while type 2 narcolepsy does not include cataplexy. Narcolepsy interferes with cognitive, psychological, and social functions, increases the risk of work and driving-related accidents, and is associated with a mortality rate that is 1.5 times higher. According to reports, up to 57% of patients suffer from depression. Unfortunately, currently approved treatments are rarely used for this underdiagnosed orphan condition, and are subject to differences in efficacy between patients, tolerability issues, and scheduling by the Drug Enforcement Administration (DEA). The need for restrictions.

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

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

Some embodiments include antidepressants (e.g., selective norepinephrine inhibitors, such as atomoxetine, addixetine, or reboxetine (including S,S-reboxetine)) in the treatment of cataplexy In the manufacture of drugs for narcolepsy.

Some embodiments include a kit containing an antidepressant (e.g., selective norepinephrine inhibitor, such as atomoxetine, addixetine, or reboxetine (including S, S-Ripoxetine) The pharmaceutical composition of oxetine)), and instructions for the use of the pharmaceutical composition to treat human cataplexy narcolepsy.

In some embodiments, antidepressants (e.g., selective norepinephrine inhibitors, such as atomoxetine, addixetine, or reboxetine (including S,S-reboxetine)) are administered at least once a day Lasts more than two weeks. In some embodiments, as a result of the treatment, the person has experienced a decrease in the number of cataplexy episodes, a decrease in the Epworth Sleepiness Scale (ESS), and a Maintenance of Wakefulness Test (Maintenance of Wakefulness Test) within a week. MWT) score decreases, Narcolepsy Symptom Assessment Score (NSAQ) decreases, patient Global Impression of Severity (PGI-S) score decreases, and patient’s overall change impression (Patient The Global Impression of Change (PGI-C) score is lower than 4, or the Hamilton Depression Rating Scale (HAM-D) is reduced, or the ability to concentrate is improved (for example, on the NSAQ).

Some embodiments include a method for rapidly reducing the number of cataplexy episodes in a person with cataplexy-type narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks, Among them, one week after the start of treatment, the person had at least 30% fewer cataplexy episodes compared to baseline, and the reduction in the number of cataplexy episodes compared to placebo administration was statistically significant, with p<0.01. In some embodiments, the The reduction in the number of cataplexy episodes was statistically significant compared with the drug, with p<0.001.

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

Some embodiments include a method for improving the concentration ability of a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks, wherein Before the start of treatment, the person had "average", "poor" or "very poor" concentration ability, and two weeks after the start of the treatment, the person had "good" or "very good" The concentration ability, as determined by the concentration ability item of the narcolepsy symptom assessment questionnaire. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is esreboxetine.

Some embodiments include a method of reducing the number of accidental naps in a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks, wherein Two weeks after the start of treatment, the person had at least 20% fewer accidental naps per week compared to the week before the patient received reboxetine for the first time. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

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

Some embodiments include a method of reducing nighttime awakening in a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need every day for at least two weeks, wherein Two weeks after the start of the treatment, the person reported having fewer nocturnal awakenings than the week before the patient first received reboxetine. In some implementation In the method, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

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

Some embodiments include a method of reducing pre-sleep hallucinations in a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need daily for at least two weeks, wherein Two weeks after the start of the treatment, the person reported having fewer hallucinations before going to bed than the week before the patient first received reboxetine. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

Some embodiments include a method of improving the concentration ability of a person suffering from narcolepsy, the method comprising administering reboxetine to a person in need. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

Some embodiments include a method of treating cataplexy-type narcolepsy, the method comprising administering reboxetine to a person in need, wherein reboxetine is administered at least once a day for more than two weeks, wherein as a result of the treatment, Two weeks after the start of treatment, the person experienced a decrease in the number of cataplexy episodes within a week, a decrease in the Epworth Sleepiness Scale score, a decrease in the cataplexy score of the Ullanlinna Narcolepsy Scale (UNS), or Keep awake test score decreases.

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 a day for at least three weeks. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

Some embodiments include a kit comprising a pharmaceutical composition containing reboxetine and instructions for use of the pharmaceutical composition for treating human cataplexy narcolepsy, wherein reboxetine is administered at least once a day Last at least three weeks. In some embodiments, reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxepoxetine.

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

Some embodiments include a method of treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein oxprexetine is administered at a daily dose of about 2 mg to about 4 mg for at least six weeks, wherein During the course, as measured by the visual analog scale (VAS) score, the person experienced a greater pain reduction than the person experienced by administering a placebo.

Some embodiments include a method of treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein oxoprexetine is administered at a daily dose of about 0.5 mg to about 1 mg for at least six weeks, wherein During the course of treatment, as measured by the visual analog scale (VAS) score, the person experienced a greater pain reduction than the person experienced by administering a placebo.

Figure 1 depicts the weekly changes in cataplexy in a human patient receiving reboxetine and placebo as described in Example 22.

Figure 2 depicts the number of human patients with 50% or more reduction in cataplexy episodes per week, where the human patients received reboxetine or placebo as described in Example 22.

Figure 3 depicts the number of human patients with 75% or more reductions in cataplexy episodes per week, where the human patients received reboxetine or placebo as described in Example 22.

Figure 4 depicts the changes in Epworth Sleepiness Scale scores for human patients receiving reboxetine and placebo as described in Example 22.

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

Figure 6 depicts the number of human patients with a 50% or greater reduction in accidental naps, where the human patients received reboxetine or placebo as described in Example 22.

Figure 7 depicts the improvement in the concentration score of 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 who showed improvements in sleep quality, nocturnal wakes, sleep paralysis episodes, and hallucinations before going to bed.

Antidepressants, such as reboxetine or S,S-reboxetine, can be used to treat conditions such as neurological disorders, including addictive disorders (including those caused by alcohol, nicotine, and other psychoactive substances), abstinence Syndrome, adjustment disorder (including depressive mood, anxiety, mixed anxiety and depressive mood, conduct disorder, and mixed mood and conduct disorder), depression (including major depression 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 caused by general medical conditions, attention-deficit hyperactivity disorder (Attention-Deficit Hyperactivity) Disorder, ADHD), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, conduct disorder, circular mood disorder, depression (including youth depression and mild depression), mood disorders , Fibromyalgia and other somatoform disorders (including somatization disorder, transformation disorder, pain disorder, depressed affective disorder, somatomorphic disorder, undifferentiated somatization disorder, and somatization NOS), generalized anxiety disorder (Generalized Anxiety Disorder, GAD), urinary incontinence (ie, stress incontinence (stress incontinence), true stress urinary incontinence, and mixed urinary incontinence), stress urinary incontinence (stress urinary incontinence), inhalation disorder, poisoning disorder (alcohol Addiction), mania, migraine, obesity (for example, weight reduction in obese or overweight patients), obsessive-compulsive disorder or related spectrum disorders, oppositional defiant disorder, panic disorder, peripheral neuropathy, post-traumatic stress disorder, Premenstrual mood disorders (ie, premenstrual syndrome and late luteal phase anxiety), psychotic disorders (including schizophrenia, negative symptoms of schizophrenia, schizoaffective or schizophrenia-like disorders, either alone or As adjuvant therapy), seasonal affective disorder, sleep disorders (such as narcolepsy or enuresis), social phobia (including social anxiety disorder), specific developmental disorders, selective serotonin reuptake inhibition (Selective Serotonin Reuptake Inhibition) , SSRI) "Exhaustion" syndrome (ie, in which the patient fails to maintain a satisfactory response to SSRI therapy in the initial period), TIC disorder (eg, Tourette's disease), band 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) can lead to improvement of disease symptoms. For example, for painful conditions such as fibromyalgia, the patient may experience a pain reduction measured on a visual analog scale (VAS), such as 0-100 mm, which is greater than the pain reduction that would be experienced by administering 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 experienced by administering 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 improvement in the 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 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%, such as 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-chloromipramine, amitriptyline, amoxapine, norimipramine, protriptyline, trimimipramine, nortriptyline, maprotiline, phenelzine, Isoxazide, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindan, benatiazine, escitalopram, fluvoxamine, Lafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, busofensine, Moclobemide, Rasagiline, Nyaladide, Iprofeniazide, Isoprochloride, Toloxanone, Butiline, Dutiapine, Diphenzepine, Ipraindole, Lofepa Ming, opipramol, norfluoxetine, dapoxetine, ketamine, etc., including norepinephrine reuptake inhibitors (e.g. atomoxetine, addixetine or reboxetine (including S, S -Reboxetine)), has the potential to treat the symptoms of narcolepsy.

Many antidepressants, such as norepinephrine reuptake inhibitors (such as atomoxetine, addixetine, or reboxetine (including S,S-reboxetine)), lack DEA scheduling, which will indicate Significant benefits for patients suffering from this condition.

If the criteria A and B are met, the person may have type 1 narcolepsy:

A. The patient has daily uncontrollable sleep needs or falls into sleep during the day and lasts for at least 3 months

B. There is one or both of the following:

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, an average sleep latency of <8 minutes, and

Two sleeps started Rapid Eye Movement (REM) period (Sleep-Onset REM Periods, SOREMP). SOREMP (within 15 minutes of sleep start) on the previous laboratory-based polysomnography (PSG) can replace one of the SOREMP on MSLT

2. The concentration of CSF hyposecretin-1 measured by immunoreactivity <110pg/mL or <1/3 of the average value obtained in normal subjects using the same measurement

In young children, narcolepsy sometimes manifests as too long night sleep or restoring a previously interrupted daytime nap. If there is a strong clinical suspicion of type 1 narcolepsy, but the B2 criterion is not met, the possible strategy is to repeat 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 an uninhibited daily sleep requirement or The period of falling asleep during the day occurs and lasts 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, 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-years 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 , About 6 minutes, about 7 minutes, or about 8 minutes of average sleep latency.

Some patients treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) may have and/or may be selected to perform MSLT ( The average sleep latency test) has at least 2, at least 3, or at least 4 SOREMP. 15 minutes from the beginning of sleep on PSG that occurred during the previous night The SOREMP inside can replace one of the SOREMP 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 About 40pg/mL, less than about 50pg/mL, less than about 60pg/mL, less than about 70pg/mL, less than about 80pg/mL, less than about 90pg/mL, less than about 100pg/mL, less than about 110pg/mL CSF hypothalamus 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 immunoreactivity measured The CSF hypothalamic secretin-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 1/10 of the average value obtained in normal subjects using the same measurement. 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 be and/or may be selected to exhibit excessive night sleep Toddlers.

Some patients treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) may be and/or may be selected to appear as having a previous interrupted daytime nap 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 compliance with the International Classification of Sleep Disorders The third edition (ICSD-3) standard diagnosis of cataplexy narcolepsy.

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 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 use antidepressants (including norepinephrine inhibitors, such as Ripple Patients treated with oxetine (including S,S-reboxetine) may have and/or may be selected to have an Epworth Sleepiness Scale (ESS) score 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 times, 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 times, or about 49-70 episodes of cataplexy 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, before receiving antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)), the patient has Having 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, 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 older than 75 years old.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may be and/or may be selected as a female. In some embodiments, patients can be selected as non-lactating and non-pregnant women.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may be and/or may be selected as a male.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any accompanying sleep disorders. When using stable treatment, some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS) Type narcolepsy), may not have and/or may be selected as not having other than mild sleep apnea (<15 events/hour) or mild to moderate sleep apnea (<30 events/hour ) Any accompanying sleep disorders other than those. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any From the clinically significant disease of EDS. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any clinically significant mental disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any type of depression that is not caused by narcolepsy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any drowsiness caused by depression not caused by narcolepsy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having an emotional disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a mental disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having brain dysfunction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having dyskinesias. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having motor neuron disease.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type hair) Patients with narcolepsy) are not taking sodium oxybate at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking stimulants at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking anticonvulsants at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking clonidine at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking a selective serotonin reuptake inhibitor (SSRI) at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking serotonin and norepinephrine reuptake inhibitors (Serotonin and Norepinephrine Re-uptake Inhibitor, SNRI) at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking Monoamine Oxidase Inhibitor (MAOI) at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking Tricyclic Antidepressant (TCA) at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking hypnotics at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking anti-anxiety drugs at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) patient, It's not that I am taking sedative antihistamines at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking antipsychotic drugs at the same time. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient is not taking any other medications for narcolepsy or cataplexy at the same time.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a neurodegenerative disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having epilepsy disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a convulsive disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a diagnosis of cancer (other than possible basal cell carcinoma) within the last 5 years.

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

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have clinically significant hypertension. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have uncontrolled hypertension. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a history of cardiovascular disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a myocardial infarction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have angina. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a rhythm disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having heart failure.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a history of narrow-angle glaucoma. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Suffer Alternatively, it may not have and/or may be selected as not having gastric bypass. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have any conditions that are expected to affect drug absorption.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have headaches. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having major depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having treatment-resistant depression.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having treatment-resistant bipolar depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have bipolar disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have circulatory affective disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having seasonal affective disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Of patients may not have and/or may be selected as not having a mood disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having chronic depression (e.g., dysthymia). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having psychotic depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a history of psychotic episodes. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected not to have a significant risk of self-harm, suicide, or assault on others.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having postpartum depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Premenstrual Dysphoric Disorder (PMDD). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having situational depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have atypical depression. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have mania. Some use antidepressants (including norepinephrine suppression Agents, such as Reboxetine (including S,S-Reboxetine) for the treatment of patients with narcolepsy (such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected as not Has an anxiety disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having Attention Deficit Disorder (ADD).

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

Some use antidepressants (including norepinephrine inhibitors, such as Ripple Cetine (including S,S-reboxetine)) for the treatment of patients with narcolepsy (such as cataplexy and/or EDS narcolepsy), may not have and/or may be selected as not having premenstrual syndrome Levy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having substance addiction or abuse. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having nicotine addiction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having psycho-sexual dysfunction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have pseudobulbar affect. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having emotional instability.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having an anxiety disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a phobia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have generalized anxiety disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having social anxiety disorder. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S, S-Rui) Poxetine)) patients who treat narcolepsy (such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected as not having panic disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having agoraphobia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having OCD. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having Post-Traumatic Stress Disorder (PTSD). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have mania.

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

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having schizophrenia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have delusional disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have schizoaffective disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having schizophrenia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be chosen not to have aggressive behavior. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have the aggressive behavior in Alzheimer's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have agitation. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have the agitation in Alzheimer's disease.

Some use antidepressants (including norepinephrine inhibitors, such as Ripple Cetine (including S,S-reboxetine) in the treatment of patients with narcolepsy (such as cataplexy and/or EDS-type narcolepsy) may not have and/or may be selected as not having drug dependence. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having cocaine addiction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having psychostimulant addiction or dependence on psychostimulants. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having crack addiction or dependence on crack. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having cocaine addiction or dependence on cocaine. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having fast pill addiction or dependence on fast pill. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having methamphetamine addiction or dependence on methamphetamine. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having nicotine addiction or dependence on nicotine.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having alcohol addiction or dependence on alcohol. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Of patients may not have and/or may be selected as not having opioid addiction or dependence on opioids. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having an anxiolytic and/or hypnotics addiction or dependence on an anxiolytic and/or hypnotics. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having cannabis/marijuana addiction or dependence on cannabis. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having amphetamine addiction or dependence on amphetamine. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having hallucinogen addiction or dependence on hallucinogens. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having phencyclidine addiction or dependence on phencyclidine.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having volatile solvent addiction or dependence on volatile solvents. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having volatile nitrite addiction or dependence on volatile nitrite. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Alzheimer's. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Disease) may not have and/or may be selected as not having Alzheimer's dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have memory loss. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having amnesia/amnesia syndrome. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having epilepsy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have unconsciousness.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a coma. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a drop in attention. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having a speech disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have sound cramps. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Parkinson's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patient, may not have and/or may be selected as not Lennox-Gastaut syndrome.

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

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having dyskinesia. Some use Antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) treat patients with narcolepsy (such as cataplexy and/or EDS-type narcolepsy), May not have and/or may be selected as not to have athletes. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have ataxia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having ballismus. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have the throwing disorder. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have bradykinesia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have cerebral palsy.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having chorea. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Huntington's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have rheumatic chorea. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Sidenham's disease. one Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having dyskinesias. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have tardive dyskinesia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have dystonia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have blepharospasm.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having spastic torticollis. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have dopamine-responsive dystonia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have restless legs syndrome (RLS). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having tremor. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having primary tremor. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Tourette's syndrome. one Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Wilson's disease.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have vascular dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Lewy body dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have mixed dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have frontotemporal dementia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Creutzfeldt-Jakob disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having normal pressure hydrocephalus. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having Wernicke-Korsakov syndrome.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Pick's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patient, do you have Yes and/or can be selected as not having progressive bulbar palsy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Primary Lateral Sclerosis (Primary Lateral Sclerosis, PLS). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having progressive muscular dystrophy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having post-poliomyelitis syndrome (PPS). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having Spinal Muscular Atrophy (SMA).

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have spinal motor atrophy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Tay-Sach's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Sandhoff's disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected to not have hereditary spastic paraplegia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Alzheimer's disease. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-Reboxetine)) patients who treat narcolepsy (such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected to not have prion related diseases. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have cerebellar ataxia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having spinocerebellar disorder (Spinocerebellar Ataxia, SCA).

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having spinal muscular atrophy (SMA). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have bulbar muscular atrophy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Friedrich's ataxia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Lewy body disease. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Multiple Sclerosis (MS). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Suffer Alternatively, they may not have and/or may be selected to not have multiple system atrophy.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Shy-Drager syndrome. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have cortical basal ganglia degeneration. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have progressive supranuclear palsy.

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

Some use antidepressants (including norepinephrine inhibitors, such as Ripple Cetine (including S,S-reboxetine)) for the treatment of patients with narcolepsy (such as cataplexy and/or EDS-type narcolepsy), may not have and/or may be selected as not having Chamadou Charcot-Marie-Tooth disease (CMT). Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected to not have familial spastic paraplegia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have neurofibromas. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have pontine cerebellar atrophy or degeneration. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have substantia nigra degeneration. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Guillain-Barré syndrome. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have spastic paraplegia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having non-seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having epilepsy. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) Patients who treat narcolepsy (such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected to not have febrile convulsions. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have partial seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a simple partial seizure. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having Jackson seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have complex partial seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a partial persistent epileptic state. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have generalized seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected to not have generalized tonic-clonic seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having absence seizures.

Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have atonic seizures. Some antidepressants (including norepinephrine inhibitors, such as reboxetine (including S, S-Rui) Poxetine)) patients who treat narcolepsy (such as cataplexy and/or EDS narcolepsy) may not have and/or may be selected to not have myoclonic seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have juvenile myoclonic seizures. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having infantile spasms. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having status epilepticus. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have Reiter's syndrome. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have tinnitus. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a disorder of consciousness. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having sexual dysfunction. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have a sound disorder due to uncontrolled spasm of the larynx muscles. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have abduction spastic dysphonia. Some are treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) Patients with narcolepsy (such as cataplexy and/or EDS-type narcolepsy) may not have and/or may be selected as not having adduction spastic dysphonia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have muscle tone dysphonia. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have voice tremor. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having diabetic neuropathy. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having chemotherapy-induced neurotoxicity. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) Patients may not have and/or may be selected as not having methotrexate neurotoxicity. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have stress urinary incontinence. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have urge incontinence. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected to not have fecal incontinence. Some use antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) to treat narcolepsy (such as cataplexy and/or EDS-type narcolepsy) The patient may not have and/or may be selected as not having erectile dysfunction.

Cataplexy involves a sudden decrease or loss of muscle tone when the patient is awake, which can Affects specific parts of the body or the entire body, such as eyelids, drooping head, drooping face and/or twitching, slurred speech, jaw weakness, weakness of arms, shoulders or hands, and/or knee flexion. Cataplexy can be specific to narcolepsy. Cataplexy can be triggered by strong emotions, such as laughter, triumph, surprise, or anger. Cataplexy can be partial or local (about 75% of cases) and usually has a short duration. The frequency of damping can vary widely. Cataplexy narcolepsy can be socially disabling and socially isolated.

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-type narcolepsy Disease (type 1), which is an autoimmune disorder that causes the loss of neurons that produce hypothalamic secretin (orexins) in the CNS. Hypothalamic secretin (orexin) is a hypothalamic-specific trait with neurostimulatory activity. Patients who are being treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) for cataplexy narcolepsy, and can be selected as having specific genetic markers The specific genetic markers include human leukocyte antigen (HLA DQB1-06:02) and/or T cell receptor alpha variants. Some patients who are being treated with antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) may not have and may be selected as not having the secretory neurons associated with hypothalamus Loss of 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 a genetically susceptible individual by season Narcolepsy caused by sexual streptococcal infection, H1N1 influenza and/or H1N1 vaccination.

Conventional narcolepsy treatments only resolve some of the symptoms of narcolepsy, provide variable efficacy, and have significant side effects. In addition, all conventional therapeutic substances 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.” (The Voice of the Patient, A series of reports from the USFood and Drug Administration's(FDA's) Patient-Focused Drug Development Initiative, Narcolepsy , June 2014, page 25)

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (such as methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, selective serotonin Compared with uptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI)), daytime sleepiness is reduced by 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Cataplexy is reduced by 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The number of partial cataplexy episodes 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 Per week, at least about 8 times per week, at least about 9 times per week, at least about 10 times per week, at least about 12 times per week, at least about 13 times per week, at least about 14 times per week, at least about 15 times per week 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, 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, 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 humans 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The frequency of complete cataplexy 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 Per week, at least about 8 times per week, at least about 9 times per week, at least about 10 times per week, at least about 12 times per week, at least about 13 times per week, at least about 14 times per week, at least about 15 times per week 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, 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, 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 humans 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , 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, 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, 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, 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 humans 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 antidepressants (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 controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The proportion of patients achieving a 50% or greater reduction in the number of cataplexy attacks per week 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%. This improvement of reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant compared to placebo administration (p

0.05).

0.05)。 In some embodiments, administration of antidepressants (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 controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The proportion of patients achieving a 75% or greater reduction in the number of cataplexy attacks per week 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%. This improvement of reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant compared to placebo administration (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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in comparison with baseline, placebo, or some other suitable control, for example. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , Epworth Sleepiness Scale (ESS) score decreased 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Compared with the administration of placebo, this improvement of reboxetine treatment can be statistically significant, 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The number of accidental naps per week 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%, about 20-40%, about 30- 35%, or about 30-33%, at least about 1 nap per week, at least about 2 naps per week, at least about 3 naps per week, at least about 4 naps per week, at least about 5 naps per 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 times Snooze/week. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Compared with the administration of placebo, this improvement of reboxetine treatment can be statistically significant, 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 accidental naps, such as accidental naps associated with narcolepsy (with or without cataplexy).

0.05)。 In some embodiments, administration of antidepressants (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 controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The proportion of patients achieving a 50% or greater reduction in the number of accidental naps per week 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (p

0.05).

In some embodiments, the administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in comparison with baseline, placebo, or some other suitable control, for example. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , Keep awake test (MWT) score 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 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 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 -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 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 of reboxetine treatment can Observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 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)) can improve cognitive function, for example, over a period of 1 week or a period of 2 weeks, such as Measured by the NSAQ's Attention Ability Program. For example, the improvement of the attentional 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 with baseline, placebo, or some other suitable Controls (including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI ) 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, where "-" represents a decrease in the concentration score. In some embodiments, the number of patients with "very good" or "good" attention ability can be, for example, compared to baseline, placebo, or some other suitable control (including active control substances, such as stimulants ( For example, methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) compared to 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 reduced cognitive function associated with narcolepsy (with or without cataplexy).

In some embodiments, the person has "average", "poor" or "very poor" ability to concentrate before the start of treatment, and one week after the start of treatment, the person Have "good" or "very good" concentration skills.

In some embodiments, the person has an "average" concentration ability before the start of treatment, and one week after the start of treatment, the person has a "good" concentration ability.

In some embodiments, the person has an "average" concentration ability before the start of the treatment, and one week after the start of the treatment, the person has a "very good" concentration ability.

In some embodiments, the person has "poor" concentration ability before the start of treatment, and one week after the start of treatment, the person has "good" concentration ability.

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

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

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

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

In some embodiments, the person has an "average" concentration ability before the start of treatment, and two weeks after the start of treatment, the person has a "good" concentration ability.

In some embodiments, the person has an "average" concentration ability before the start of the treatment, and two weeks after the start of the treatment, the person has a "very good" concentration ability.

In some embodiments, the person has "poor" concentration ability before the start of treatment, and two weeks after the start of treatment, the person has "good" concentration ability.

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

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

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

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)) can improve sleep quality. For example, patients can report improved sleep quality. In some embodiments, the number of patients reporting improved sleep quality can be, for example, compared with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine) Ming), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) 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 sleep quality improvement that the patient may have is, for example, compared with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), Modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 sleep quality problems 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can reduce the number of nocturnal awakenings, for example, as reported by patients. For example, the number of patients reporting a reduction in the number of nighttime awakenings can be compared with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), Mo Dalfinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) 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 nighttime awakenings that the patient has can be, for example, compared with baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine) , Modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant compared to placebo administration (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 arousal problems, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can reduce the number of episodes of sleep paralysis, for example, as reported by patients. For example, the number of patients with reduced number of sleep paralysis episodes can be, for example, with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine) , Modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), 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 episodes of sleep paralysis that the patient has can be, for example, compared to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine) Ming), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) 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 50-70%, about 52-57%, or about 55%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on having sleep paralysis problems, such as sleep paralysis problems associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can reduce the number of hallucinations before going to bed, for example, as reported by patients. For example, the number of patients with reduced number of hallucinations before going to bed can be compared with baseline, placebo, or some other suitable controls (including active controls, such as Compared with 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 hallucinations that the patient has before going to bed can be, for example, compared with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g., 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 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with hallucinations before going to bed, such as hallucinations related to narcolepsy (with or without cataplexy).

In some embodiments, the administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in comparison with baseline, placebo, or some other suitable control, for example. (Including active controls, such as stimulants (such as methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The cataplexy score on 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 of reboxetine treatment It can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, the administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in comparison with baseline, placebo, or some other suitable control, for example. (Including active controls, such as stimulants (such as methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , The sleep latency on MSLT is extended 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%, at least about 1 minute, at least about 2 minutes, at least About 3 minutes, more 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 -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 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 be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , The patient’s overall severity impression (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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in a patient’s overall change of impression (PGI-C) score of about 1- 2. About 2-3, or about 3-4, or for example with baseline, placebo, or some other suitable controls (including active controls, such as stimulants (e.g. methylphenidate, amphetamine), Modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) are 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 0.5, 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, the administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can result in comparison with baseline, placebo, or some other suitable control, for example. (Including active controls, such as stimulants (e.g. methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI) , 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. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Nightmares or unpleasant dreams (such as frequent nightmares or frequent unpleasant dreams) 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be based on having nightmares or unpleasant dreams (e.g. frequent nightmares or frequent unpleasant dreams) including nightmares or unpleasant dreams associated with narcolepsy (with or without cataplexy) Problems with dreams (such as frequent nightmares or frequent unpleasant dreams) are selected for treatment.

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Hallucinations 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with hallucinations, such as hallucinations related to narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 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 antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with baseline, placebo, or some other suitable control. (Including active controls, such as stimulants (e.g. methylphenidate, Compared with amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), nocturnal sleep disorders 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with nocturnal sleep disorders, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Narcolepsy-related accidents 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with accidents related to narcolepsy (with or without cataplexy).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Narcolepsy-related damage 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of antidepressants (including norepinephrine inhibitors, such as reboxetine (including S,S-reboxetine)) can, for example, be compared with 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) , Narcolepsy-related fatalities 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%. This improvement in reboxetine treatment can be observed at, for example, 1 week, 2 weeks, overall, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on the risk of narcolepsy-related fatalities (for narcolepsy patients with or without cataplexy).

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

Unless otherwise stated, any reference to a compound (such as reboxetine) herein by structure, name, or any other means includes pharmaceutically acceptable salts; free acids or bases; alternating solid forms, such as polymorphs Forms, solvates, hydrates, etc.; tautomers; enantiomers; deuterium-modified compounds, such as deuterium-modified reboxetine; or under the conditions of using the compound as described herein Any chemical substance that quickly converts to the compounds 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%). %) (+)-reboxetine (also known as S,S-reboxetine or oxepoxetine); or excessive (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at least 95 %, at least 97%, or at least 99%) (-)-reboxetine.

For the treatment of narcolepsy, it 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) is administered as the second local maximum of the concentration.

There are many methods that can cause the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine) and the second local maximum of the plasma concentration of reboxetine (including S,S-reboxetine). Potential pathways of reboxetine (including S,S-reboxetine). Local maxima in the maximum value described herein are of interest in vivo plasma concentration time period of the individual patient, the maximum value is not necessarily _{the largest} C. The local maximum can be lower than or equal to _Cmax . A method for administering Rebox in a manner that results in the first local maximum of the plasma concentration of Reboxetine (including S,S-Reboxetine) and the second local maximum of the plasma concentration of Reboxetine (including S,S-Reboxetine) The potential route for oxetine (including S,S-reboxetine) is to administer the first dosage form containing reboxetine (including reboxetine), and to administer reboxetine (including S,S-reboxetine) at a later time. Xetine) the second dosage form. The administration is administered at a time that results in the first local maximum of reboxetine (including S,S-reboxetine) plasma concentration and the second local maximum of reboxetine (including S,S-reboxetine) plasma concentration dose. For example, it can be less than half a day after the first dosage form, for example, 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 The second dosage form is administered for hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or any time period within the range defined by any of these values.

Another method involves the administration of a single dosage form containing 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 during the day (is the only dosage form administered during the day, or the first dosage form of the two or more dosage forms administered during the day) is on waking Soon thereafter, for example, 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 containing a first release component and a second release component administered in one 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 defined by any of these values, the first release component can release reboxetine (including S,S-reboxetine), and can start to release reboxetine (including S,S-reboxetine), or can cause reboxetine (including S,S-reboxetine) Poxetine) the first local maximum of plasma concentration. The second release component can release reboxetine (including S,S-reboxetine) after the first release component releases reboxetine (including S,S-reboxetine); or it can be used in reboxetine (including S,S-reboxetine). S,S-Reboxetine) is about 1-10 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 3-4 hours after the first release from the first release component 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- After 8 hours, or about 7-10 hours, or after the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine), or any value within the limits of any of these values Time causes an increase in the plasma concentration of reboxetine (including S,S-reboxetine) or the second local maximum of the plasma concentration of reboxetine (including S,S-reboxetine).

The first release component and the second release component can be incorporated into a single dosage form (e.g., pill, tablet, capsule, caplet, or chewing gum). In one embodiment, the first release component will be located in one of the outer layers of the dosage form, and the second release component will be located in one of the inner layers of the same dosage form.

In another embodiment, the first release component is located in the first layer of the dosage form, and the second release component is located in the second layer of the same dosage form. The two layers are different, and may or may not be in contact with each other. In some embodiments, the two layers are stacked on each other and physically combined in a two-layer structure (for example, the largest surfaces of the two layers are in contact with each other, or the layers are thinner than other dimensions of the layers). In some embodiments, the two layers are placed adjacent to each other and physically combined in a two-layer structure (e.g., where the layer is thicker than the other dimensions of the layer).

In another embodiment, the first release component and the second release component can be separately constructed in the form of their own specific particles, particles, etc., wherein the first release component particles are formulated to be released on the second release component particles. Reboxetine (including S,S-Reboxetine) was previously released from Reboxetine (including S,S-Reboxetine), and wherein both the first release component particles and the second release component particles were combined together to form A single dosage form, such as capsules, pills, tablets, caplets, chewing gum, etc., and these two release components may or may not be physically combined with each other.

In some embodiments, the first local maximum plasma concentration of reboxetine (including S,S-reboxetine) occurs about 1-30 minutes after administration of the single dosage form or the first dosage form, About 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4 hours, or at any time within the range defined by any of these values. Generally, the second local maximum 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), for example 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 -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 in these Any time period within the range defined by any value in the value.

For the dosage form containing the first release component and the second release component, the first release component is related to the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine) because the first release group Separately released reboxetine (including S,S-reboxetine) contributed to the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine). For example, the first release component can release reboxetine (including S,S-reboxetine) faster or faster than the second release component, so that it contributes to reboxetine (including S,S-reboxetine) 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 the first release component and the second release component, the second release component is related to the second local maximum of the plasma concentration of reboxetine (including S,S-reboxetine) because the second release group Separately released reboxetine (including S,S-reboxetine) contributes to the second local maximum of the plasma concentration of reboxetine (including S,S-reboxetine). For example, the second release component can delay the release of reboxetine (including S,S-reboxetine), so that when the plasma concentration of reboxetine (including S,S-reboxetine) is after the first local maximum When it is decreasing, the second release component releases a sufficient amount of reboxetine (including S,S-reboxetine) to increase the plasma concentration of reboxetine (including S,S-reboxetine) again in order to reach reboxetine (Including S,S-reboxetine) the second local maximum of plasma concentration.

For a dosage form 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 defined by any of these values.

For a dosage form containing 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 -1.5mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 2-4mg, about 3-5mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 4-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 5-7 mg, 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 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within the range defined 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, More about 20-30%, or more than about 30-40% reboxetine (including S,S-reboxetine).

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

In some embodiments, the daily dose of reboxetine (including S,S-reboxetine) may 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 can 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 the 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 daily (for example, a 10 mg maintenance dose may be a 10 mg dose once a day, a 6 mg dose in the morning and a 4 mg dose in the afternoon, or a 5 mg dose given twice a day 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 8-11 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 (e.g., the first dose administered in the morning) may contain more reboxetine (including S, S-Reboxetine). For example, the first dose of the day (for example, the first dose administered in the morning) may have about 10-20% more and about 20-30% more than the second dose of the day (for example, the second dose administered in the afternoon). %, or about 30-40% reboxetine (including S,S-reboxetine). The maintenance dose can 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 period of two weeks.

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 For the 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 immediate 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 immediate release of reboxetine (including S,S-reboxetine). Slow release.

Regarding the administration of Reboxetine (including S,S-Reboxetine) in the first dosage form containing Reboxetine (including S,S-Reboxetine) and the second dosage form containing Reboxetine (including S,S-Reboxetine) In the method of reboxetine), any suitable amount of reboxetine (including S,S-reboxetine) may be present in the first dosage form, for example, 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 -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 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within the range defined by any of these values.

Regarding the administration of Reboxetine (including S,S-Reboxetine) in the first dosage form containing Reboxetine (including S,S-Reboxetine) and the second dosage form containing Reboxetine (including S,S-Reboxetine) Reboxetine), any suitable amount of reboxetine (including S,S-reboxetine) may be present in the second dosage form, for example, 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 7-10mg, 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 amount within the range defined 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 and about 20-30% more than the second dosage form. , Or 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 a first release component and a second release component, in some embodiments, a single dose is administered within two hours of waking up from overnight sleep.

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

There are many factors that can affect the total time required for a drug (eg Reboxetine (including S,S-Reboxetine)) to be completely absorbed in the human body and/or to reach the maximum plasma concentration. Some of these factors include the age, weight, sex, stress level, gastric content, gastric pH level of the human patient, and the presence of other drugs. The time required to reach the maximum plasma concentration of a drug (e.g. Reboxetine (including S,S-Reboxetine)) may also be affected by taking the drug during the day (e.g. Reboxetine (including S,S-Reboxetine)) ) Time and the physical activity level of human patients. Another can affect the maximum blood that reaches the drug (e.g. Reboxetine (including S,S-Reboxetine)) The factor of the time required for the slurry concentration is whether there is a controlled release coating on the drug (eg Reboxetine (including S,S-Reboxetine)).

Controlled release includes: immediate release of drugs (such as reboxetine (including S,S-reboxetine)) at a certain time or in a certain area of the body; delayed release of drugs; The sustained release of the drug at a certain time or at a certain position in the body; or the extended release of the drug (for example, Reboxetine (including S,S-Reboxetine)).

Reboxetine (including S,S-reboxetine) is usually rapidly absorbed in human patients, reaching a maximum plasma concentration in about 2-4 hours. In order to achieve a delay in the time required to reach the maximum plasma concentration, a controlled release coating or mixture can be used.

Delayed release is a general drug delivery term that describes an oral drug form that does not immediately release its active drug component in the patient's mouth or stomach. Although there may be many ways to achieve delayed release, the delayed release of reboxetine (including S,S-reboxetine) can be completely or completely by using a coating or layer that does not dissolve immediately when swallowed (such as an internal controlled release coating). This is achieved by partially surrounding reboxetine (including S,S-reboxetine) (for example in the second release component). For example, the material of the coating or layer can slowly dissolve in the stomach, and/or slowly disintegrate in the stomach through a chemical reaction (e.g., by hydrolysis), until the layer can no longer prevent reboxetine (including S, S-Ripoxetine). Xetine) is 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 decompose and begin to 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 partly in the duodenum and partly 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) can be released partly in the jejunum and partly 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, for example, 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 Use materials that more or less slowly dissolve or disintegrate in the digestive system, adjust the thickness of the coating layer or coating material (for example, a thicker layer will provide a longer time) and/or use characteristics that are sensitive to pH Material to adjust. For example, materials that are less stable to acidic pH or more soluble at acidic pH can dissolve or disintegrate more quickly in the stomach because the gastric pH is lower than the pH in the intestine. Conversely, due to the time it takes for the dosage form to travel through the gastrointestinal tract, materials that are stable at low pH but less stable at higher pH may dissolve or disintegrate later.

The controlled release formulation containing reboxetine (including S,S-reboxetine) can 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-proof coatings, enteric polymer coatings, and the like.

Depending on the structure of the dosage form, controlled release polymers can be used for sustained or delayed release. For example, dispersing reboxetine (including S,S-reboxetine) throughout the 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 (such as a coating) that is intended to last for a short period of time (such as less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) so that when the barrier is penetrated At that time, 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 can be used, such as acrylic acid and methacrylic acid copolymers and various esters thereof, such as methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methyl methacrylate Amino alkyl acrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkyl amine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), poly(methacrylic acid) Copolymer of acrylamide, poly(methacrylic anhydride) and glycidyl methacrylate.

Other suitable controlled release polymers include polymerizable quaternary ammonium compounds, such as quaternized aminoalkyl esters of acrylic and methacrylic acid and aminoalkyl amides, such as β-methyl propyl Enoxoethyltrimethylammonium methylsulfate, β-acryloxypropyltrimethylammonium chloride and trimethylaminomethacrylamide methylsulfate. The quaternary ammonium atom can also be part of a heterocyclic ring, such as in methacryloxyethylmethylmorpholine chloride or the corresponding piperidinium salt, or it can be passed through a group containing a heteroatom (such as polyethylene The glycol ether group) is connected to the acrylic group or the methacrylic group. Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles, such as methyl-vinyl pyridinium salts, vinyl esters of quaternized amino carboxylic acids, styryl trialkylammonium salts Wait. Other polymerizable quaternary ammonium compounds include benzyl dimethyl ammonium ethyl-methacrylate chloride, diethyl methyl ammonium ethyl-acrylate and methacrylate methyl sulfate, N-trimethyl ammonium Propylmethacrylamide chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

Delayed release can also be achieved by using a controlled release polymer for a specific pH, wherein it should be understood that with appropriate fasting or eating, a specific pH can correspond to a specific time after administration.

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

In other embodiments, the controlled release coating further includes a polymer whose permeability is pH-dependent, such as an anionic polymer 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. It is known that the ratio of free carboxyl group to ester is 1:1 in EUDRAGIT® L, and And it is 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acid and pure water, but becomes more and more permeable above pH 5.0. This makes EUDRAGIT® L suitable for targeted release of coated drugs in the duodenum and jejunum of the small intestine, such as coated reboxetine (including S,S-reboxetine). Therefore, EUDRAGIT® L-coated drugs can achieve about 30 minutes to about A maximum plasma concentration delay of 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 more and more 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 and in the colon. Therefore, EUDRAGIT® S-coated drugs can achieve about 1-2 hours compared to uncoated or immediate-release drugs (such as reboxetine in the first release component (including S,S-reboxetine)). , 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 Maximum plasma concentration is delayed.

The hydrophobic acrylic polymer coating may also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylate (eg EUDRAGIT® E, commercially available from Evonik). EUDRAGIT® E is insoluble in saliva (making it useful for masking taste and odor), but it is soluble in gastric juice with a pH of 5 or lower, which provides immediate release of the drug in the stomach. Approximately 0-30 minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after the oral administration of the dosage form, or any time within the range defined by any of these values, is EUDRAGIT® E 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 it can lead to the first local maximum of the plasma concentration of reboxetine (including S,S-reboxetine).

The hydrophobic acrylic polymer coating may comprise a neutral copolymer based on polymethacrylate, such as EUDRAGIT® NE (NE=neutral ester) commercially available from Evonik. 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 pH-independent sustained-release effect, which can release drugs (such as reboxetine (including S,S-reboxetine)) within a period of time, or can delay the release for a period of time, wherein the release or delay 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 a polymer (KOLLICOAT® EMM 30 D, BASF) containing ethyl acrylate and methyl methacrylate in a 2:1 ratio. KOLLICOAT® EMM 30 D has a pH-independent sustained-release effect, which can release drugs (such as reboxetine (including S,S-reboxetine)) over a period of time, or can delay the release for a period of time, wherein the release Or the delay 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 changed by changing the relative amounts of different acrylic resin paints contained in the coating. In addition, by changing the molar ratio of the polymerizable penetration enhancer (for example, a quaternary ammonium compound) to the neutral methacrylate, the penetration characteristics of the resulting coating (which affects the dissolution characteristics) can be changed. KOLLICOAT® SR30D is another coating with a pH-independent sustained-release effect, which can release drugs (such as reboxetine (including S,S-reboxetine)) over a period of time, or delay the release for a period of time Time, wherein the time of release or delay 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 Hour.

In some embodiments, the controlled release coating contains ethyl cellulose, which can be used as a dry polymer solubilized in an organic solvent before use (eg ETHOCELTM, Dow Chemical Company), or as an aqueous dispersion body. A suitable commercially available aqueous dispersion of ethyl cellulose is Aquacoat® (Danisco). Aquacoat® ECD (Aqueous Ethyl Cellulose Dispersion), Aquacoat® ARC (Aqueous Alcohol Resistant Ethyl Cellulose Dispersion) and Aquacoat® CPD (Aqueous Cellulose Acetate Phthalate Dispersion) are all commercially available Available controlled release coatings. Another suitable aqueous dispersion of ethyl cellulose is commercially available as Surelease® (Colorcon, Inc.). The product can be manufactured by During the process, a plasticizer is incorporated into the dispersion to prepare it. The hot melt of polymer, plasticizer (e.g. dibutyl sebacate) and stabilizer (e.g. oleic acid) can be mixed and prepared into a homogeneous mixture, and then the mixture can be diluted with an alkaline solution to obtain direct application Aqueous dispersion onto the substrate. These coatings have a pH-independent sustained-release effect, which can release drugs (such as reboxetine (including S,S-reboxetine)) over a period of time, or can delay the release for a period of time, wherein the release or delay The 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, hydroxypropyl methylcellulose phthalate, hydroxypropyl Acetate methyl cellulose succinate, polyvinyl alcohol phthalate, shellac, hydrogel and gel forming materials, such as carboxyvinyl polymer, sodium alginate, sodium carboxymethyl cellulose, carboxy Calcium methyl cellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based cross-linked polymers (wherein the degree of cross-linking As low as to promote the adsorption of water and the expansion of the polymer matrix), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen Protein, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymer) poly(hydroxyalkyl methacrylate) (molecular weight 5k to 5000k), polyvinylpyrrolidone (molecular weight 10k) To 360k), anionic and cationic hydrogels, zein, polyamide, polyvinyl alcohol with low acetate residue, a swellable mixture of agar and carboxymethyl cellulose, 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 gum, polypropylene amide, POLYOX® polyoxyethylene ( The molecular weight is 100k to 5000k, Dow), AQUA KEEP® acrylate polymer (mainly composed of acrylic acid polymer and sodium salt), diester of polydextrose, cross-linked polyvinyl alcohol and polyN-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, Glycerin fatty acid ester, 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 gum, tragacanth, carrageenan, guar gum, xanthan gum, scleroglucan, and their mixtures and blends.

In some embodiments, the dosage form of reboxetine (including S,S-reboxetine) is coated with a polymer to promote mucosal adhesion in the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucosal adhesion include carboxymethyl cellulose, polyacrylic acid, Carbopol ^™ (Lubrizol), polycarbophil, gelatin, and other natural or synthetic polymers.

The polymer coating of the present invention may be any one of the coatings, or may be a combination of two or more of the coatings, to realize reboxetine (including S, S-Ripoxetine) Xetine) required release characteristics.

In addition to the improved release dosage forms described herein, other improved release techniques known to those skilled in the art can also be used to achieve the improved release formulations of the present invention, that is, when administered (for example, orally or by other modes of administration). in) formulation _maximum and / or other pharmacokinetic parameters provided herein, the patient's average human pharmaceutical T. Such formulations can be formulated into 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 include a controlled release carrier, which is incorporated into a matrix with the drug, 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 adhesives) can be added to the drug-filler mixture to increase the mechanical strength of the granules and tablets during formation. The binder can be added to the formulation in the following different ways: (1) as a dry powder, which is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as agglomeration liquid during wet agglomeration and is called As a solution binder, and (3) as a dry powder, which is mixed with other ingredients before compaction. In this form, the adhesive is called a dry adhesive. Solution binders are a common way to incorporate binders into particles. In some embodiments, the binder used in the tablet is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oil, 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, with a hydrocarbon backbone Of hydrophobic and hydrophilic polymers, and their mixtures. 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 Cellulose, HPC)). )), polyvinyl alcohol, and their mixtures. Any suitable amount of binder may be present, for example, about 0.5-5 wt%, about 5-10 wt%, about 10-15 wt%, about 15-20 wt%, about 20-25 wt% 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 the pharmaceutical formulation to reduce any friction that occurs between the solids and the mold wall during tablet manufacturing. High friction during tableting can cause a series of problems, including improper tablet quality (the tablet is capped or even broken during ejection, and vertical scratches on the edge of the tablet) and can even stop production. Therefore, lubricants can 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®). ® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol , Ethylene oxide polymers (for example, the registered trademark CARBOWAX® is available from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate , DL-leucine, colloidal silica, their mixtures, and other substances known in the art. In some embodiments, the lubricant is glyceryl behenate (for example, COMPRITOL® 888). Any A suitable amount of binder, for example, based on the dry weight of the tablet, about 0.5-5 wt%, about 5-10 wt%, about 10-15 wt%, about 15-20 wt%, about 20-25 wt%, 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, reboxetine (including S,S-reboxetine) is administered once a day or twice a day 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, 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, reboxetine (including S,S-reboxetine) 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. Years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

Examples of useful compositions for dosage forms containing about 5-10 mg of Reboxetine (including S,S-Reboxetine) (not intended to limit the scope of the invention) 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 same significant side effects as conventional treatment options. Treatment of cataplexy-type narcolepsy with reboxetine (including S,S-reboxetine) in the dosage form described herein can be well tolerated in mammals such as humans.

Some embodiments include a kit containing 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 the composition for the treatment of narcolepsy.

Some embodiments include a kit containing 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 form) pharmaceutical composition, wherein one unit dosage form contains about 5-10 mg of reboxetine (including S,S-reboxetine) Ting); and instructions for the use of the pharmaceutical composition for the treatment of narcolepsy.

Some embodiments include a kit containing 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 the composition for the treatment of narcolepsy.

Some embodiments include a kit containing 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 the composition for the treatment of narcolepsy.

Some embodiments include a kit containing 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 the composition for the treatment of narcolepsy.

The following embodiments are specifically considered.

A method of treating cataplexy-type narcolepsy, the method comprising administering reboxetine to a person in need, wherein reboxetine is administered at least once a day for more than two weeks, wherein as a result of the treatment, after treatment begins At two weeks, the person experienced a decrease in the number of cataplexy episodes within a week, a decrease in the Epworth Sleepiness Scale score, a decrease in the cataplexy score of the Ullanlinna Narcolepsy Scale (UNS), or a decrease in the keep-awake test score.

Use of reboxetine in 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 comprising a pharmaceutical composition containing reboxetine, and instructions for use of the pharmaceutical composition to treat human cataplexy narcolepsy, wherein Reboxetine should be administered at least once a day for at least three weeks.

The method, use or kit according to embodiment 1, 2 or 3, wherein reboxetine is administered twice a day, 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 according to 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 according to 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 according to 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 according to 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 every day, wherein the single dosage form contains a first release component containing reboxetine and a second release component containing reboxetine, wherein 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 The maximum occurs about 2 to about 6 hours before the second local maximum of the plasma concentration of reboxetine.

The method, use or kit according to 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 according to 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 according to 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 Ripple 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 the person is selected as not suffering 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.

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 dosage of reboxetine is Increase from 1 day to 7 days, and then keep 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 From 1 day to 7 days, then a total daily dose of about 0.02 mmol to about 0.03 mmol is kept constant.

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 From 1 day to 7 days, then a total daily dose of about 0.03 mmol to about 0.04 mmol is kept constant.

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 From 1 day to 7 days, then a total daily dose of about 0.04 mmol to about 0.05 mmol is kept constant.

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 From 1 day to 7 days, then a total daily dose of about 0.05 mmol to about 0.06 mmol is kept constant.

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 From 1 day to 7 days, then a total daily dose of about 0.06 mmol to about 0.07 mmol is kept constant.

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 From 1 day to 7 days, then a total daily dose of about 0.07 mmol to about 0.08 mmol is kept constant.

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 , Use or kit, wherein reboxetine is in a certain dosage form and the 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 , Use or kit, wherein reboxetine is in a certain dosage form and the dosage form contains about 10 mg of reboxetine.

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

According to embodiment 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, the method, use or kit, wherein the human experiences sleep latency prolongation on multiple sleep latency tests (MSLT).

The method, use or kit according to embodiment 27, wherein the human experiences at least a 10% prolongation of sleep latency on MSLT.

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

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

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

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

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

According to embodiment 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 the human experiences at least a 15% reduction in cataplexy score on UNS.

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

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

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

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

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

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

The method, use or kit according to embodiment 34, wherein the human cataplexy score is about 0.

A method for improving the concentration ability of a person suffering from narcolepsy, the method comprising administering reboxetine to a person in need.

The method according to embodiment 42, wherein the person is selected as needing to improve concentration ability or having difficulty concentrating.

The method according to embodiment 42 or 43, wherein the improvement of the person's concentration ability item on the NSAQ is at least about -0.1 compared to before any reboxetine administration.

A method of treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the daily dose of oxprexetine is administered from about 1 mg to about 2 mg for at least six weeks, wherein during the course of treatment, such as As measured by the visual analog scale (VAS) score, the person experienced fibromyalgia pain reduction greater than the pain experienced by the person by administering a placebo.

The method of embodiment 45, wherein about 1 mg to about 2 mg of oxprexetine is administered once a day.

The method of embodiment 45, wherein about 0.5 mg to about 1 mg of oxprexetine is administered twice a day.

The method of embodiment 45, 46, or 47, wherein the person 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 the VAS score of the person’s fibromyalgia pain is the same as the VAS score of the person’s fibromyalgia pain immediately after the administration of the first dose of malignant The VAS score for fibromyalgia pain of people before cetine was reduced by at least 20%.

The method according to embodiment 45, 46, 47, 48 or 49, wherein after daily administration of oxepoxetine for six weeks, the VAS score of the person’s fibromyalgia pain is the same as that immediately after the administration of the first dose The VAS score of fibromyalgia pain in people before oxepoxetine was reduced by at least 50%.

A method of treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the daily dose of oxprexetine is administered from about 2 mg to about 4 mg for at least six weeks, wherein during the course of treatment, such as As measured by the visual analog scale (VAS) score, the person experienced a greater reduction in pain than the person experienced by administering a placebo.

The method of embodiment 51, wherein about 1 mg to about 2 mg of oxprexetine is administered once a day.

The method of embodiment 51, wherein about 0.5 mg to about 1 mg of oxoproxetine is administered twice a day.

The method of embodiment 51, 52, or 53, wherein the person 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 moxetine for six weeks, the VAS score of the person’s fibromyalgia pain is the same as that of the first dose of malignant pain immediately after administration of the first dose. The VAS score for fibromyalgia pain of people before cetine was reduced by at least 20%.

The method according to embodiment 51, 52, 53, 54 or 55, wherein after daily administration of oxepoxetine for six weeks, the VAS score of the person’s fibromyalgia pain is the same as that immediately after administration of the first dose The VAS score of fibromyalgia pain in people before oxepoxetine was reduced by at least 50%.

A method of treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the daily dose of oxprexetine is administered at a daily dose of about 0.5 mg to about 1 mg for at least six weeks, wherein during the course of treatment, As measured by the visual analog scale (VAS) score, the person experienced a greater pain reduction than the person experienced by administering a placebo.

The method of embodiment 57, wherein about 1 mg to about 2 mg of oxprexetine is administered once a day.

The method of embodiment 57, wherein about 0.5 mg to about 1 mg of oxprexetine is administered twice a day.

The method of embodiment 57, 58 or 59, wherein the person 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 the VAS score of the person’s fibromyalgia pain is the same as the VAS score of the person’s fibromyalgia pain immediately after the administration of the first dose of malignant The VAS score for fibromyalgia pain of people before cetine was reduced by at least 20%.

The method according to embodiment 61, wherein after daily administration of oxprexetine for six weeks, the VAS score of the person’s fibromyalgia pain is comparable to that of the person immediately before the administration of the first dose of oxepoxetine. Compared with fibromyalgia pain, the VAS score is reduced by at least 50%.

Example

Example 1

A 40-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After a week of treatment, the number of cataplexy episodes decreased By 10-30%.

Example 2

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

Example 3

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

Example 4

A 50-year-old woman was diagnosed with cataplexy narcolepsy. Reboxetine was given to her and she was instructed to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After a week of treatment, the ESS score dropped by 10-30%.

Example 5

A 25-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After a week of treatment, the ESS score has dropped 30-60%.

Example 6

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

Example 7

A 19-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After one week of treatment, the MWT score dropped by 10-30%.

Example 8

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

Example 9

A 33-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After a week of treatment, the MWT score dropped 60-100%.

Example 10

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

Example 11

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

Example 12

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

Example 13

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

Example 14

A 34-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the ESS score dropped by 30-60%.

Example 15

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

Example 16

A 19-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the MWT score dropped by 10-30%.

Example 17

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

Example 18

A 57-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the MWT score dropped by 60-100%.

Example 19

A 20-year-old woman was diagnosed with cataplexy narcolepsy. Reboxetine was given to her and she was instructed to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the HAM-D score dropped by 10-30%.

Example 20

A 69-year-old man was diagnosed with cataplexy narcolepsy. Give him reboxetine and instruct him to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the HAM-D score dropped by 30-60%.

Example 21

A 56-year-old woman was diagnosed with cataplexy narcolepsy. Reboxetine was given to her and she was instructed to take 5mg reboxetine at 8 am and 5mg reboxetine at 1 pm for three weeks. The patients were evaluated before treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and concentration ability on NSAQ. After three weeks of treatment, the HAM-D score dropped Up 60-100%.

Example 22

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

As shown in Figure 1, Reboxetine exhibited a highly statistically significant reduction in the average weekly average number of cataplexy during the 2-week treatment period relative to baseline (overall treatment effect) compared to placebo ( p<0.001) and meet the pre-specified primary endpoint. In week 2, reboxetine showed an average of 14.6 weekly cataplexy reductions, compared to 2.6 weekly cataplexy reductions for placebo (p=0.002), representing 48.7% and 8.7% relative to baseline, respectively The average reduction (Figure 1). In addition, reboxetine treatment resulted in a rapid reduction in cataplexy episodes. After 1 week of treatment, Reboxetine showed an average reduction of 13.0 cataplexy episodes, compared with 0.3 episodes reduction of placebo (p<0.001), representing an average reduction of 43.3% and 1.0% from baseline, respectively (figure 1). In week 2, for Reboxetine, the proportion of patients who achieved a 50% or greater reduction in the number of weekly cataplexy episodes was 76.2%, compared with placebo, which achieved a 50% or greater weekly cataplexy The proportion of patients with reduced number of attacks was 30.0% (p=0.003) (Figure 2). In week 2, for Reboxetine, the proportion of patients who achieved a 75% or greater reduction in the number of weekly cataplexy episodes was 42.9%, compared with placebo, which achieved a 75% or greater weekly cataplexy The proportion of patients with reduced number of episodes was 10.0% (p=0.018) (Figure 3). As early as the first week, the improvement of reboxetine on cataplexy was It was rapid and showed a significant benefit over placebo (p<0.001).

As measured by the Epworth Sleepiness Scale (ESS) and by the frequency of accidental naps, reboxetine significantly improved the symptoms of EDS (excessive daytime sleepiness) compared with placebo. As shown in Figure 4, the improvement of ESS with reboxetine treatment was twice that observed with placebo, and the ESS scores of reboxetine and placebo relative to baseline decreased by 6.0 and 3.1, respectively (p= 0.003). In the second week, reboxetine treatment resulted in an average decrease in the average number of accidental naps per week relative to baseline of 31.8%, while the average decrease in placebo was 5.3% (p<0.001) (Figure 5). As shown in Figure 6, compared with placebo (10.0%), reboxetine treatment resulted in a greater number of patients with a 50% or greater reduction in unexpected naps (38.1%) (p=0.036). As early as the first week, reboxetine's improvement in the frequency of accidental naps was rapid, showing a significant benefit over placebo.

Compared with placebo, reboxetine significantly improved cognitive function during the two-week treatment period, as measured by the narcolepsy symptom assessment questionnaire (NSAQ)'s concentration ability item, which is assessed daily (p <0.01) (Figure 7 to Figure 8). For this assessment, patients rated their concentration ability 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 "good" to "very good" concentration skills, compared to 25.0% of patients with placebo who had "good" to “Very good” concentration ability, and 0% of patients at baseline have “good” to “very good” concentration ability. As early as the first week, reboxetine's improvement in concentration was rapid, showing a significant improvement relative to placebo (38.1% vs. 15.0%) (p=0.007).

Compared with placebo, reboxetine significantly improved the quality of sleep, as measured by overall improvement and the number of night 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 causing 5.3% of patients to report improved sleep quality (p=0.007). Reboxetine treatment resulted in 30.0% of patients reporting a reduction in the number of night awakenings, compared with 5.3% of patients using a placebo who reported a reduction in the number of night awakenings (p=0.044). Compared with placebo, reboxetine treatment also resulted in a greater proportion of patients with reduced sleep paralysis episodes and reduced hallucinations before going to bed.

Reboxetine is safe and well tolerated. There were no serious adverse events reported in the trial, and no drug discontinuations due to adverse events. The total percentage of patients who experienced adverse events when using reboxetine was 42.9%, and the total percentage of patients who experienced adverse events when using placebo was 40.0%. Among them, the most frequently reported adverse events when using reboxetine were anxiety and constipation. And insomnia. The completion rate for patients randomized to treatment sequence 1 (reboxetine followed by placebo) was 91%, and the completion rate for patients randomized to treatment sequence 2 (reboxetine after placebo) was 100%.

Unless otherwise stated, all numbers used in the specification and the scope of the patent application that indicate the amounts and properties (such as amounts, percentages), etc. of the ingredients should be understood in all cases to indicate the precise values shown and are defined by the term "about "Modify. Therefore, unless there are instructions to the contrary, the numerical parameters listed in the specification and the appended patent scope are approximate values, and the approximate values may vary according to the desired properties sought to be obtained. At the very least, and it is not an attempt to limit the application of the principle of equivalence to the scope of the patent application, each numerical parameter should be understood at least in accordance with the reported significant number and the application of ordinary rounding.

In the context of describing the embodiments (especially in the context of the scope of the appended application), the use of the terms "a", "an", "the" and similar designations and the absence of quantifiers should be understood to cover the singular and plural, unless This article states otherwise or obviously contradicts the context. Unless otherwise stated herein or clearly contradicting the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (for example, "for example") provided herein is only intended to better clarify the embodiments, and does not limit the scope of any patent application. No language in the specification should be construed as indicating that any non-patentable element is necessary to implement the patented scope.

The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each group member can be mentioned and claimed individually or in any combination with other members of the group or other elements found in this document. It is foreseen that for reasons of convenience and/or patentability, one or more members of the group may be included in or deleted from the group. When any such inclusion or deletion occurs, the specification is regarded as including the modified group, and the drafting description of all Markush groups used in the scope of the appended application is completed.

Certain embodiments are described herein, including the best way known to the inventors for implementing the claimed embodiments. Of course, for a person of ordinary skill in the art, after reading the foregoing description, variations of the described implementation manners will become apparent. The inventor expects that the skilled person will adopt these changes according to the situation, and the inventor intends to implement the claimed embodiment in a manner different from that specifically described herein. Therefore, the scope of patent application includes all modifications and equivalents of the subject matter described in the scope of patent application permitted by applicable law. In addition, unless otherwise stated herein or clearly contradictory to the context, any combination of all possible variations of the aforementioned elements is contemplated.

Finally, it should be understood that the embodiments disclosed herein are illustrations of the principles of the scope of patent application. Other modifications that can be adopted are within the scope of the patent application. Therefore, by way of example and not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the scope of the patent application is not limited to the embodiments exactly as shown and described.

Claims (17)

A method for rapidly reducing the number of cataplexy episodes in a person suffering from cataplexy-type narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need every day for at least two weeks, wherein at the beginning of treatment The following week, the person had at least 30% fewer cataplexy episodes compared to baseline. The method of claim 1, wherein the reduction in the number of cataplexy episodes is statistically significant as compared with the administration of a placebo, wherein p<0.01. A method for improving the concentration ability of a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks before the start of treatment , The person has an "average", "poor" or "very poor" concentration ability, and two weeks after the start of the treatment, the person has a "good" or "very good" concentration ability , As determined by the concentration ability item of the Narcolepsy Symptom Rating Questionnaire. A method for reducing the number of accidental naps in a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks, wherein two weeks after the start of treatment Week, compared to the week before the patient first received reboxetine, the person had at least 20% fewer accidental naps per week. A method for improving the sleep quality of a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need every day for at least two weeks, wherein two weeks after the start of treatment , The person reported having improved sleep quality compared to the week before the patient received reboxetine for the first time. A method for reducing nighttime awakening of a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need every day for at least two weeks, wherein two weeks after the start of treatment The person reported having fewer nocturnal awakenings than the week before the patient first received reboxetine. A method for reducing sleep paralysis in a person suffering from cataplexy-type narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine to a person in need every day for at least two weeks, which In two weeks after the start of treatment, the person reported having fewer episodes of sleep paralysis compared to the week before the patient received reboxetine for the first time. A method for reducing pre-sleep hallucinations in a person suffering from cataplexy narcolepsy, the method comprising administering about 8 mg to about 10 mg of reboxetine daily to a person in need for at least two weeks, wherein two weeks after the start of treatment Week, the person reported having fewer hallucinations before going to bed than the week before the patient received reboxetine for the first time. A method for improving the concentration ability of a person suffering from narcolepsy, the method comprising administering reboxetine to a person in need. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein about 4 mg of reboxetine is administered to the person twice a day for at least the first week. The method of claim 10, wherein about 4 mg of reboxetine is administered to the person in the morning and about 4 mg of reboxetine is administered to the person in the afternoon for at least the second week. The method of claim 10, wherein about 6 mg of reboxetine is administered to the person in the morning and about 4 mg of reboxetine is administered to the person in the afternoon for at least the second week. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the person is diagnosed with cataplexy type paroxysmal that meets the standards of the third edition of the International Classification of Sleep Disorders Sleep sickness. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the person has a minimum of 7 cataplexy episodes per week before receiving reboxetine. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the person has an Epworth Sleepiness Scale score greater than 10 before receiving reboxetine. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the person is selected as needing to improve concentration ability or having difficulty concentrating. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the person’s NSAQ concentration ability item is reduced to at least About 0.1.

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