TW200814989A - Milnacipran for the treatment of cognitive dysfunction associated with fibromyalgia - Google Patents

Abstract

Methods for treating cognitive dysfunction associated with fibromyalgia by administering high-dose milnacipran to a patient suffering from such cognitive dysfunction are provided. Also provided are methods for the long-term treatment of cognitive dysfunction associate with FMS by administering milnacipran to a patient suffering from such cognitive dysfunction.

Description

200814989 IX. Invention Description: c Invented the technical field of the households. References This application is the priority of the US Provisional Patent Application No. 60/836,705, which is filed on August 9, 2006. The entire disclosure is hereby incorporated by reference. FIELD OF THE INVENTION The field of the invention relates to the treatment of fibromyalgia-associated cognitive dysfunction by administering a high dose of milnacipran to a patient with a cognitive abnormality associated with fibromyalgia. .

L mr J BACKGROUND OF THE INVENTION Fibromyalgia, also known as fibromyalgia syndrome (FMS), is a common systemic rheumatic lesion estimated to affect 2%-4% of the population, which is second only to rheumatic lesions. The second highest penetration rate of osteoarthritis. Wolfe et al, Arthritis Rheum. 1990; 33(2): 160-172; Wolfe et al, Arthritis Rhernn 1995; 38(1): 19-28. Fibromyalgia is associated with a reduction in the threshold for pain, which can be identified by increased susceptibility to stress throughout the body, and is often accompanied by signs of fatigue, sleep disturbances 20 and morning joint stiffness. Other common symptoms include headache, migraine, changes in bowel habits, diffuse abdominal pain, and frequent urination. For the classification of fibromyalgia, it is not only necessary to have a history of extensivespread pain, but also the appearance of tenderness ("puncture point") in actual examination. In order to meet the American College of Rheumatology (American College) Of 200814989

Rheiimatology; ACR) The standard of fibromyalgia established in 1990. Individuals in the body must have extensive pain in the four quadrants and the central axis of the body, and π tender points should be diagnosed in the 18 tender points. . Et al, Arthritis Rheum· 1990; 33(2): 160-172· / 1995; 38(1): 5 19-28. w

Although there have been some claims that FMS may represent a form of physical illness, there is increasing evidence that FMS is a medical problem that reflects a broadening of the perception of stimuli. It is generally believed that this abnormality occurs in the central nervous system (CNS) rather than in the peripheral nervous system, and is a pathophysiological defect called "central sensitization." Clauw DJ and Chrousos GP, Neuroimmunomodulation 1997, 4(3) · 134-153, Bradley et al, Curr Rheumatol Rep. 2000; 2(2): 141-148; Simms RW9 Am J Med Sci. 1998; 315(6) : 1998 ; 315(6) : 346-350. The patient typically suffers from a painful touch 15 pain (even feeling pain in non-painful stimuli such as light contact) and hyperalgesia (a type of pain that stimulates higher than a normal volunteer) Intensity pain amplification phenomenon). Mountz et al, Arthritis & Rheumatism 1995; 38(7): 926-938; Arroyo JF and Cohen ML, J Rheumatol 1993; 20(11): 1925-1931. In this respect 20, there are many parallel theories in the clinical literature published there, and hypotheses such as diabetic neuropathy and the mechanism of neuropathic pain of trigeminal neuralgia. Sindrup SH and TS Jensen, Pain 1999; 83(3): 389-400; Woolf CJ9 Nature 1983; 306(5944): 686-688; Woolf CJ# RJ Mannion, Lancet 1999; 353(9168): 1959-1964. As a result, 6 200814989 FMS is primarily treated with this medical model. It is usually diagnosed in a primary care setting, and almost half of the formal cases of consultation are for medical and family care providers (1998 Domestic Action Medical Care Survey). FMS patients who have formal consultations with secrets are seeking help from rheumatologists. The remaining patients resorted to a variety of tertiary care providers including pain centers, physiotherapists and psychiatrists. Individuals with fibromyalgia suffer from a number of other symptoms, including recurrence of non-cardiac chest pain, heartburn, palpitations, and irritable bowel. Wolfe et al, Arthritis Rheum. 1990; 33(2): 10 160-172; Mukerji et al, Angiology 1995; 46(5): 425-430. Although the physiological basis of these symptoms remains unclear, increasing evidence suggests that functional disorders of the autonomic nervous system are often seen in fibromyalgia and related diseases. Clauw DJ and Chrousos GP, Neuroimmunomodulation 1997; 4(3): 134-153; Freeman R 15 and Komaroff AL, Am J Med 1997; 102(4): 357-364. In a prospective study of individuals with a randomized selection of fibromyalgia, objective evidence of dysfunction of the internal organs was found, including cardiac ultrasound evidence of a 75% incidence of sacral flap prolapse, 40-70% of abnormal esophageal activity and less static inspiratory and expiratory pressure in lung function tests. Lurie 20 et al., Scand J Rehab Med. 1990; 22(3): 151-155; Pellegrino et al., Arch Phys Med Rehab. 1989; 70(7): 541-543. Neuropathic Indirect hypotension and syncope often occur in individuals with fibromyalgia. Rowe et al, Lancet 1995; 345 (8950): 623-624. Fibromyalgia is associated with a relatively high proportion of disability, increased health care facilities, and more frequent psychotherapy consultations, as well as a large number of life-long psychotherapy diagnoses. Various different non-adapted therapies for patients with FMS have been successful to varying degrees. Buskila D, Baillieres Best Pract 5 Res Clin Rheumatol. 1999 ; 13(3) : 479-485 ; Leventhal LJ? Ann Intern Med. 1999 ; 131(11) : 850-858 ; Lautenschlager J, Scand J Rheumatol Suppl· 2000 : 113 : 32-36 Antidepressants are the basis of many treatment paradigms, but other agents such as anticonvulsants, antispasmodics, anxiolytics, sedatives and opiates have also been used. 10 non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are also used in many patients, even though they have not been proven to have peripheral inflammatory responses (Clauw DJ and Chrousos GP, Neuroimmunomodulation 1997; 4(3) ) : 134-153), and most studies still do not have the effect of being an analgesic for FMS (Wolfe et al, Arthritis Rheum. 15 1997, 40(9) · 1571-1579). Goldenberg et al, Arthritis Rheum 1986; 29(11): 1371-1377; Yunus et al, j Rheumatol 1989; 16(4): 527-532; Wolfe et al, Arthritis Rheum 2000; 43(2): 378-385; Russell et al, Arthritis Rheum· 1991; 34(5): 552_560; Quijada-Carrera et al., pain 1996; 65(2-3): 2〇221-225. However, these agents can provide protection against other sources of peripheral pain such as osteoarthritis. All types of antidepressants have a common form of treatment for many chronic pain conditions including FMS. Sindrup SH and Jensen TS, Pain 1999, 83(3) · 389-400, Busilla D, Baillieres Best Pract Res 200814989

Clin Rheumatol. 1999 ; 13(3) : 479^485 ; Leventhal LJ, Ann

Intern Med· 1999, 131(11) · 850-858 ; Lautenschlager J, Scand J Rheumatol Suppl. 2000 ; 113 : 32-36 ; Bennett RM? J Functional Syndromes 2001 ; 1(1) : 79_92. Most of the 5 antidepressants available can directly and/or indirectly increase the amount of 5-HT and/or NE in the CNS. The monoamine content can be released after it is released into the cell junction by inhibiting its reabsorption (by blocking the transport of proteins) and by interfering with the degradation of the monoamine (by inhibiting the action of the monoamine oxidase enzyme). increase. 10 Tricyclic antidepressants (TC As) • TCAs most commonly used in the treatment of FMS include amitriptyline, doxepin, and cyclobenzaprine. Buskila D, Baillieres Best Pract Res Clin Rheumatol. 1999 ; 13(3) : 479-485 ; Lautenschlager J? Scand 15 J Rheumatol Suppl. 2000 ; 113 : 32-36 ; Bennett RM, J Functional Syndromes 2001 ; 1(1) : 79-92. Although Cyclobenzaprine is typically classified as a muscle relaxant rather than an antidepressant, it has similar structural and pharmacological properties to TCAs, even though the sedative properties generally exceed those used in other applications. . Kobayashi et al., Eur J Pharmacol. 20 1996; 311(1): 29-35. TCAs block the reabsorption of 5-HT and NE, but they tend to block NE reabsorption, and the effectiveness of TCAs can be used to support the basis for explaining the analgesic activity motivated by NE. However, the additional anti-cholinergic, antihistaminergic and alpha-adrenergic receptor blocking activities of TCAs lead to many undesired effects of the secondary 9 200814989, which often jeopardize their Tolerance and clinical acceptance. Kent JM, Lancet 2000; 355 (9207): 911_918. TCAs have been shown to have a mild therapeutic effect on the treatment of neuropathic pain such as post-herpetic neuralgia and diabetes with aggravation of neuropathic pain. Max et al, Neurology 1988; 38(9): 1427-1432; Max et al, N Eng J Med 1992; 326(19): 1250-1256; Watson et al, Neurology 1982; 32(6): 671- 673 ; Watson et al., Pain 1992; 48(1): 29-36. Many studies on the treatment of FMS with TCAs also support the use of this in a syndrome, and TCAs are often used as a positive control group when they are often compared with newer agents. Max et al, N Eng J Med. 1992; 326(19) ·· 1250-1256; Watson et al., Pain 1992; 48(1) ·· 29-36; Hannonen et al., Br J Rheumatol· 1998; 37( 12): 1279-1286; Goldenberg et al, Arthritis &amp; Rheumatism 1996; 39(11): 1852-1859 〇15 Selective serotonin reuptake inhibitors (SSRIs). SS RI with more selective resorption inhibition The role of getting better side effects patterns, and completely change the treatment of depression. SSRI agents, such as fluoxetine, sertraline, and citolopram, were each evaluated in a randomized placebo-controlled trial of FMS. 20 Goldenberg et al., Arthritis &amp; Rheumatism 1996; 39(11): 1852-1859; Wolfe et al., Scand J Rheum 1994; 23(5) · 255-259; Anderberg et al., Eur J Pain 2000; (1): 27-35; Norregaard et al., Pain 1995; 61(3): 445-449. However, the results of these trials are inconsistent in some parts, and there is much debate about the relevance of SSRI, especially in terms of the effectiveness of TCAs. In two placebo-controlled trials of citolopram (see Table 2) for 5-HT most specific SSRIs, both showed significant negative responses in FMS patients. Anderberg et al., Eur J Pain, 2000; 5 4(1): 27-35; Norregaard et al., Pain 1995; 61(3) · 445-449. This means that only serotonin activity potentiation is not sufficient. Analgesic effects occur in conditions of chronic pain. In fact, based on the currently integrated evidence, this SSRI type of drug is generally not more effective than TCAs in chronic pain conditions (Max et al, N Engl J Med 1992; 326(19): 1250-1256; 10 Ansari A, Harv Rev Psych· 2000 ; 7(5) ·· 257-277 ; Atkinson et al., Pain 1999; 83(2): 137-145; Jung et al., J Gen Intern Med· 1997 &gt; 12(6 · 384-389) although there are some exceptions (Saper et al., Headache 2001; 41(5) · 465-474). The dual reuptake inhibitor 15 is called a dual resorption inhibitor of "snri" or "NSRI" and has pharmacological properties similar to TCAs such as amitriptyline and doxepin. It has a dual activity for the reabsorption of 5·ΗΤ and NE. Sanchez C and Hytell J, Cell Mol Neurobiol. 1999; 19(4): 467-489. However, these newer agents generally lack significant activity in other 2〇 receptor systems and thus produce fewer side effects and higher tolerance. Therefore, these types of antidepressants may have significant potential for treatment of 1?1^1§ and/or other chronic pain conditions. Commercially available SNRIs in the United States include Venlafaxine and duloxetine. Some of these agents developed clinically include 11 200814989 milnacipran, &©aS (bicifadine), (viloxazine), LY-113821, SEP-227162, AD-337, and succinic acid. Lafasin (desvenlafaxine succinate; DVS-233). EFFEXOR® showed promising results in a small type 5 open drug labeling study test in 15 patients with FMS. Dwight et al, Psychosomatics 1998; 39(1): 14-17. Six of the 11 completed trials had a positive response to viloxazacin, which was found in two different measurements for overall pain. Define a 50% or better improvement. Insomnia is the most frequently reported side effect, and 3 of the 10 11 patients who completed the trial required additional medical treatment. U.S. Patent No. 6,602,911 describes the use of milnacipran for the treatment of FMS and its symptoms, the entire disclosure of which is incorporated herein by reference. Opioids 15 Opiates can exert their anti-allodynic effects in a variety of different ways to augment pain and reduce pain. Duale et al, Neuroreport 2001; 12(10): 2091-2096; Besse et al, Brain Res. 1990; 521(1-2): 15-22; Fields et al, Nature 1983; 306(5944): 684- 686; Yaksh et al, Proc Natl Acad Sci USA 1999; 20 96(14): 7680-7686. The use of a dentine tablet drug in a condition of chronic pain states is gradually elevated. Bennett RM, J Functional Syndromes 2001; 1(1): 79-92. Especially when other analgesics still do not provide adequate relief. Bennett RM, Mayo Clin Proc· 1999; 74(4): 385-398. 12 200814989 There have been no reports of effective long-term treatment for fibromyalgia and its symptoms. Carette et al. presented a long-term (more than three months) clinical trial report of the results of amitriptyline (a tricyclic antidepressant), cyclobenzaprine (a structure similar to the tricyclic antidepressant muscle) The 5 agents of the relaxant and the placebo were administered to the target suffering from fibromyalgia syndrome (Carette et al., Arthritis &amp; Rheumatism 1994; 37(1): 32-40). After one month, 21% of the subjects given amitriptyline, 12% of the given Cyclobenzaprine, and 〇% of the placebo were given significant clinical progress. After three months, there was no difference between the treatment group and the 10 placebo group. After six months, the long-term efficacy of the placebo was not confirmed because the placebo response was higher than expected (19% progress with placebo). Suffering from fibromyalgia usually suffers from cognitive dysfunction, also known as "Fibro fog." Abnormal cognitive dysfunction associated with fibromyalgia causes short-term and 15-long-term memory loss and can lead to important disability disorders. In addition to memory loss, patients with this cognitive dysfunction often lose their mind and forget or confuse words. Most patients with this § ignorance function will continue this symptom for several years. A clinical study investigated FMS-related cognitive deficits 20 (Park et al., Arthritis &amp; Rheumatism 2001; 44(9): 5 2133) - eleven > pMS individuals with only depression (23 Elderly individuals whose age and education level are consistent with group (4) and 22 older adults who are consistent with the educational level of the control group are targeted at information processing, working memory function, free recall, cognitive memory, language fluency, and Word 13 200814989 Scoring test to measure. These FMS individuals performed worse than the age-matched control group in each measurement except for the rate of processing. In addition to the better speed of the secrets and the poor ability of the characters, the FMS individuals are close to the older control groups. These FMS individuals reported more memory problems than these older and younger control groups, which were associated with poor cognitive performance. Abnormal cognitive function associated with FMS ("Fibro fog") can be severe enough to affect a patient's ability to perform a life-threatening activity, get lost in a familiar environment, and lose the ability to communicate effectively. Therefore, there is currently a need for an effective treatment for cognitive dysfunction associated with fibromyalgia. SUMMARY OF THE INVENTION Summary of the Invention Until the discovery of the present invention, it is not known that patients suffering from cognitive dysfunction associated with fibromyalgia 15 may be administered by high doses (for example, more than about 125 mg/day). Milnacipran has a greater benefit than the typical milnacipran dose of 100 mg/day. This improvement benefit is unexpected, as high doses of milnacipran have been previously thought to have an adverse effect compared to typical milnacipran doses (for example, 50 mil 20 g/each) It is even worse for milnacipran or 100 mg/min milnacipran (see, for example, U.S. Patent Publication No. 2004/0106681). Therefore, prior to the present invention, physicians did not recommend any basis for high doses of milnacipran for patients with cognitive abnormalities associated with FMS. Furthermore, prior to the present invention, the physician did not have any need in patients with FMS to distinguish 14 200814989 from the need for patients with cognitive abnormalities associated with FMS, as it is not known that patients of this subtype usually benefit Different doses of milnacipran compared to patients with FMS. In one aspect of the invention, the high dose of milnacipran can provide an effective long-term treatment for 5 cognitive abnormalities associated with FMS for at least 3 months. In another aspect of the invention, the high dose of milnacipran can provide cognitive dysfunction associated with 1?]^18 for at least 6 months of effective long-term treatment. In a particular embodiment of the invention, the south dose of milnacipran may be a dose of from about 125 ng/mother to about 400 gram per day. In other specific embodiments of the invention, the high dose of milnacipran may be a dose of from about 15 mg/twist to about 350 mg/day. In still other embodiments of the invention, the strontium dose of milnacipran may be from about 200 mg/day to about 3 Torr. In a further embodiment of the invention, the dosage of milnacipran is about 200 mg/day. 15 The square horse of the present invention comprises administering a high dose of milnacipran at a dose of once per dose or in divided doses. The invention further provides for the administration of a second active compound, optionally in combination with milnacipran, for the treatment of cognitive dysfunction associated with 1 </ RTI> wherein the first active compound is selected from the group consisting of Group··20 antidepressants, an analgesic, a muscle relaxant, anorexia, a stimulant, an antiepileptic drug, a beta blocker, and a sedative/hypnotic. In a more specific embodiment, the first active compound for treating fatigue which is the main symptom of FMS is selected from the group consisting of: modafinil, gabapentin, pregabalin ((iv), pu Laxo 15 200814989 (pramipexole), 1-DOPA, amphetamine, tizanidine, clonidine, tramadol, morphine, tricyclic antidepressants, codeine, dysentery, west Sibutraniine, Wuning (^仙111), trazodone, caffeine, nicerg〇line, blfemelane, propranolol In combination with Atenolol, and the like. The simple illustration of the screening reveals that it is surprising to find that a high dose of milapril is given to a FMS patient with cognitive dysfunction ( For example, more than about 10 I25 mg/day) can provide a more effective treatment for this cognitive dysfunction than the dose of 1 mg/day. This improvement is expected. Other than the one that is the main symptom of the pain In particular, it can achieve a similar efficacy to a high dose of milnacipran from a typical dose (for example, about 5 mg/d to about 100 dg/day). Double-blind, randomized, placebo-controlled clinical trials (see Specific Examples 1 and 2 below) unexpectedly show that administration of high doses of milnacipran can provide for patients with cognitive dysfunction associated with fibromyalgia. Long-term treatment (ie, at least three months) that is effective for this cognitive function. 20 Figure 1 depicts the timeline of the clinical study in Specific Example 1. Figure 2 is an illustration of the third Months and 6 months, placebo, milnacipran 100 mg/day, and milnacipran 2 mg/day FMS patients responded to treatment for FMS-related pain Percentage histogram. 16 200814989 Figure 3 shows the efficacy of FMS-related cognitive dysfunction in the treatment of patients with MASQ total score and its baseline MASQ total score, milnacipran 200 mg / Daily group ("200") is better than Minap The 100 mg/daily group ("100") round table. The 200 and 100 groups were superior to placebo ("Pbo") in the treatment of abnormalities associated with 1^^. The evaluation was performed at 3, 7, 11, 15, 19, 23, and 27 weeks of treatment. Figure 4 is an illustration of the BDI of patients from TxO to Txl5 in the clinical study described in Specific Example 1. The Bayesian Depression Scale (OC) is a graphical representation of the percentage change in the “hesitant 10 indefinite” state. Fig. 5 is a graphical representation showing the percentage change in the "concentration" state of BDI (OC) of patients from TxO to Tx 15 in the clinical study described in the specific example 1. Figure 6 is a flow chart of the increasing dose of the clinical study described in Example 2. Figure 7 is a timeline depicting the clinical study in Specific Example 2. Figure 8 is a graphical representation of the "hesitant, "state of the state of BDI (OC) from TxO to Txl5 patients in the clinical study described in Specific Example 2. 20 Figure 9 is a An illustration of the "concentration, percentage of state" of BDI (0C) from TxO to Txl5 patients in the clinical study described in Example 2. I: Embodiment j Detailed Description of the Preferred Embodiments 17 200814989 As used herein, "subject," or "patient", these terms encompass both human and non-human mammals. As used herein, "treatment,", "medical," or "healing, on behalf of avoiding or delaying the discomfort of such symptoms and/or signs; alleviating such symptoms and/or signs; or inhibiting or Prevents further development of cognitive dysfunction associated with fibromyalgia. The treatment may be prophylactic or therapeutically inhibiting or ameliorating cognitive dysfunction associated with fibromyalgia. Treatment of dysfunction associated with related cognition The effectiveness can be measured by the subjective improvement of the symptoms of a patient's cognitive dysfunction (for example, the patient report is less amicious than 10), or objectively with, for example, the patient's MASQ total score. The relative improvement in baseline MASQ total score is measured. "The two inhibitors of serotonin serotonin reuptake dual inhibitor, (NSRI) and "serotonin norepinephrine reuptake inhibitor" (SNRI) are Synonym, and refers to a type of antidepressant that has been well understood to selectively inhibit the reuptake of normal adrenaline and serotonin. Common NSRI and SNRI compounds include, but are not limited to, Venlafaxine, duloxetine, bicifdine, and milnacipran. "NE &gt; 5-HT NSRI" and "ground" _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Absorption The subtype of the iNSRI compound. Both milnacipran and bisectin are specific examples.

NSRI 18 200814989 compounds of NSRI (SNRI) and ΝΕ&gt;5-Ητ(ΝΕ&gt; 5-HT SNRI) are described in detail in U.S. Patent No. 6,602,911, the entire disclosure of which is incorporated herein. reference. As used herein, the term "high dose" is a dose that is at least about 125 milligrams (mg) per day. For example, in one embodiment, the high dose 5 means from about 125 mg to about 400 mg per ounce. In another embodiment, the high dose means from about 150 mg to about 3 mg per ounce. In another embodiment, the high dose means from about 200 mg to about 300 mg per ounce. In a more particular embodiment, high dose means about 200 mg per day. According to the present invention, a patient suffering from cognitive 10 dysfunction associated with fibromyalgia syndrome (FMS) can be used with FMS patients for up to &gt; 3 months for, for example, forgetfulness, unable to find the correct word or It is a word to remember, it is difficult to carry out daily work; or any MASQ sub-score is greater than or equal to 3 or the MASQ total score is greater than or equal to 15, and the medical unit is provided for diagnosis. 15 The MASQ is a simple self-reported questionnaire that includes five cognitive domains: language skills, visual perception, oral memory, visual memory, and attention/concentration (Seidenberg et al., J Clin &amp; Neuroρ Neuropsychology 1994 ; 16: 93-104). MASQ has been identified as effective in both the normal individual and the group of patients with cognitive impairment. Menapur is an NSRI, a dual inhibitor of norepinephrine serotonin reuptake, which has a novel chemical structure. The milnacipran is a CIS-(dl) racemic iso- 19 200814989 construct (Z form) consisting of two isomers (1- and d-). The chemical name of the hydrochlorinated salt of milnacipran is: Z-2-aminoethyl-1-phenyl-N,N-diethylcyclopropyl decylamine hydrochloride. The chemical formula of milnacipran is C15H23C1N20. Negative effects associated with administration of milnacipran include: nausea, vomiting, 5 headaches, trembling, anxiety, acute anxiety, palpitations, urinary retention, hypotension, sweating, chest pain, rash, weight gain, back Pain, constipation, venting, dizziness, increased perspiration, emotional agitation, hot flashes, fatigue, drowsiness, indigestion, difficulty urinating, dry mouth, abdominal pain and insomnia. Due to the high incidence of these negative effects, patients are often unable to tolerate high doses of 10 milapron. The present invention encompasses an unexpected benefit in the administration of high doses of milnacipran for a group of patients with particular FMS (i.e., patients with cognitive dysfunction associated with FMS). Therefore, for this group of patients, the benefits obtained by high doses of milnacipran will be more important than the potential damage of one or more of these negative effects. A single treatment trial of 15 milnacipran for the treatment of symptoms associated with fibromyalgia and/or fibromyalgia was first described in a Phase II clinical trial of 125 patients with fibromyalgia. See, for example, U.S. Patent Application Serial No. 10/678,767, the entire disclosure of which is incorporated herein by reference. In this study, milnacipran was administered once or twice per dose in a dose of up to 20 doses of 200 mg/d. Treatment with milnacipran can provide many different benefits for the signs and symptoms of FMS. Milaproren administered twice daily (BID) and once daily (QD) had approximately equal effects on fatigue, mood, overall health and function. Two doses per day had better tolerance than the daily dose of 20 200814989, and were more effective in treating pain than once a day. The global impression of change (PGIC) results showed that more than 70% of the completed treatments in the two treatment groups of minnacipran reported an improvement in overall status, compared to only 10%. Report 5 reported that the overall status has deteriorated. In contrast, 40% of patients who received placebo completed the trial treatment and assessed their status at the end of the trial. The difference in PGIC between placebo and milnacipran is statistically significant, both based on a comparison of the average end-point score and the improved/unimproved binary factor. . 10 milapron is well tolerated in this Phase II study. There were no deaths or serious negative effects (AEs) associated with the treatment of milnacipran, and most of the reported aes were assessed to be mild and mild in terms of severity. The most frequently reported AE is (one or more) reported by 33% of patients treated with milnacipran. Nausea; all other AEs were reported to 15 patients who were treated with less than 9% milnacipran. The higher incidence of nausea, abdominal pain, headache, and certain other AEs in the 200 mg qD-treated group represents a daily intake of a larger dose, which is not as good as giving two smaller divided doses a day. Tolerance. Reports of dizziness, postural dizziness, hot flashes (and blushing) and palpitations were also higher in the QD-treated group, suggesting that peak drug levels may be an important factor in producing adverse effects. Consistent with previous trials, 7% of patients experienced mild ALT and/or AST increases (twice the upper limit of $) and were accompanied by an increase in bilirubin 碱性 alkaline phosphatase. The increase in liver enzyme content is only 2% of the rice 21 200814989 Napalen treatment of patients will have a negative impact (that is, only 7 of the 7 enzymes with elevated sputum will report "SG 〇 T rise, , or the "negative effect of rising". In patients treated with milnacipran, 'the average heart rate increased by 5-8 beats per minute. The results were compared with the previous milnacipran test. He was treated with milnacipran. The average systolic blood pressure and diastolic blood pressure in the group, only in the supine

Up to 3.4 mm Hg (-1.1 to 2.7 mm Hg in the placebo control group), and the diastolic pressure in the supine heart appears in the range of 7 mm Hg (in the ampoule) In the control group, _3·5 to U mm Hg). Two (2%) patients treated with milnacipran ΒID reported a worsening of hypertension; both patients had high blood pressure before the trial and were receiving antihypertensive medication. - The patient withdrew from the trial early due to the deterioration of hypertension. The monthly b-characteristic of the erect posture effect associated with treatment was also confirmed during the previous trial and 6 of the patients treated with milnacipran (6%) reported upright during the FMS test/ The negative effects of postural dizziness, while one patient did not experiment early due to moderate postural dizziness. Significant symptoms showed that 4% of placebo patients and 7% of patients treated with mina, who experienced more than one systolic blood pressure reduction of 2 mm Hg after one minute of standing upright phenomenon. Therefore, this Phase II trial showed that treatment with 1 mg of BID of milapura was an effective rapid (short-term) treatment for FMS pain symptoms, and once or twice a day. The Pullen dose can be measurable for various types of FMS symptoms including fatigue (measured by FIQ), pain (multiple measurement methods), quality of life (multiple measurements 22 200814989) (Beck form). Beneficial effect. An effective dose is produced: 5. A pharmaceutical composition suitable for use in the present invention comprises a high dose of milnavir and a pharmaceutically acceptable carrier or excipient. "Pharmaceutical 舆 - 一 ^ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , It is also a cumbersome reaction that typically does not cause allergies or, for example, gastrointestinal discomfort or dizziness at the time of giving to humans. Preferably, as used herein, "pharmaceutically acceptable, This term is used on behalf of the regulatory agency of the federal or state government, or for use in animals 2 (and more particularly in humans) listed in the US Pharmacopoeia or other generally recognized pharmacopoeia. "Carrier," the term refers to a diluent, adjuvant, excipient or carrier containing the compound to be administered. This specialized 7K carrier may be a sterilized liquid such as water and oil (including stone 15). Oil, animal oil, vegetable oil or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like, water or aqueous solutions, salt solutions and aqueous glucose and glycerol solutions are preferably used As a carrier, 4 inches is used in an injection solution. Alternatively, the carrier may be a carrier of a solid dosage form including, but not limited to, one or more binders (using 20 for compression) Pills, a slip agent, an encapsulating agent, a flavoring agent, and a suitable coloring carrier are described in Remington's Pharmaceutical Sciences by H Martin, the overall disclosure of which is here Incorporated for reference. In some embodiments of the invention, milnacipran is administered at a dose of between about 125 23 2008 14,989 mg/day and about 400 mg/day. In other embodiments, milnacipran is administered at a dose of between about 15 gram per day and about 350 mg per day. In still other embodiments, milnacipran is administered at a dose of between about 200 mg/dip and about 300 mg/g 5 g/day. In some specific examples, the minaline is administered at a dose of about 200 oz/dai. For example, a pharmaceutical composition of the present invention can be administered by oral administration (4), enterally and intravenously, and via mucosal administration (for example, rectally). A preferred route of administration is oral. The pharmaceutical composition suitable for oral administration may be a troche, a sachet, a pill, a lozenge, a powder or a granule, or a solution or a dispersion in a liquid. Each such dosage form will contain a predetermined amount of a compound of the invention as an active ingredient. The composition in the form of a lozenge can be prepared by any of the pharmaceuticals known in the art for this purpose, and is generally used as an excipient for the preparation of a solid pharmaceutical composition. Specific examples of such excipients include starch, lactose, microcrystalline cellulose, magnesium stearate, and a binder such as polyvinyl naloxone. In addition, an active compound can be formulated into a controlled release dosage form, for example, a tablet containing a hydrophilic anionic or aqueous base. 20 A pharmaceutical composition of the present invention can be formulated into a capsule, for example, by a conventional process of incorporating a mixture of an active compound and an excipient into a rigid capsule. Alternatively, a semi-solid matrix of an active compound and a molecular weight polyethylene glycol can be formed and filled into a hard capsule, or a solution of the active compound in polyethylene glycol, or in edible oil 24 200814989 The dispersion can also be filled into soft capsules. Powdered dosage forms (for example, lyophilized powders) using a re-established structure have also been considered. Alternatively, an oily carrier for injection can be used. Liquid dosage forms for enteral administration can be formulated for administration by injection or continuous perfusion. Intravenous, intraperitoneal, intramuscular, and subcutaneous administration are generally recognized. The components for intravenous injection typically comprise a sterilized isotonic aqueous solution or dispersion comprising, for example, an active compound and glucose or sodium chloride. Other specific examples of suitable excipients are lactated lactate solutions for injection, lactated lactate for injection with glucose, Normosol-M with glucose, deuterated lactate for injection. Solution. The injectable formulation may optionally comprise a cosolvent (for example, polyethylene glycol), a chelating agent (for example, ethylenediaminetetraacetic acid); a stabilizer (for example, cyclodextrin); Antioxidant (for example, pyro 15 sodium sulfate). The high dose of milnacipran may be administered once daily or two or more times daily in divided doses. The dosage of milnacipran administered by the method of the present invention is determined based on the subject being treated, the severity of the pain, the manner of administration, and the judgment of the physician who opened the prescription. 20 Combination Therapy: According to the present invention, milnacipran can be administered in combination with other active compounds to treat the long-term fatigue of the main symptoms of FMS. Other active compounds according to the invention comprise, for example, antidepressants, analgesics, muscle relaxants, anorectic agents, stimulants, antiepileptics, substances, beta blockers, and sedatives/hypnotics. Specific specific examples of compounds that can be adjuvantly administered with the SNRI compound include, but are not limited to, phenoxine, gabapentin, pregabalin, pramipexole, 1-DOPA, amphetamine, tizanidine , clonidine, travertine, morphine, tricyclic antidepressant, codeine, dysentery, sibutramine, anesthesia, trazodone, caffeine, nigralin, diphenyl melamine, pu Naarrolol, in combination with Atnino, and the like. In one embodiment of the invention, milnacipran is administered in combination with an alpha-2-delta ligand such as pregabalin. As used herein, the mode of administration is carried out by simultaneously administering the compounds in the same dosage form, administering the compounds simultaneously in separate dosage forms, and administering the compounds separately. For example, milnacipran can be administered concurrently with irritability, in which milnacipran and cumin are formulated in the same lozenge. Alternatively, milnacipran can be administered concurrently with numbness, wherein milnacipran and cumin are present in two separate lozenges 15. In a further alternative, milnacipran can be administered first, or not, or vice versa. The following specific examples are merely examples of the invention and are not to be construed as limiting the scope of the invention in any way, and many variations of the invention are included in the disclosure of the present disclosure. And equivalents • 20 are obvious and easy to understand. Specific Example 1 Example of a multicenter, blind, randomized, placebo-controlled study of milnacipran for the treatment of fibromyalgia. The primary objective of this study was to demonstrate that milnacipran is in the treatment of fibromuscular 26 200814989 pain syndrome. Clinical and statistical safety and effectiveness. The primary outcomes were the assessment response rate for the composite responder analysis at 14 and 15 weeks and the secondary analysis for the assessment response rates at weeks 26 and 27. The other purposes of this study were: 5 L based on a comprehensive response analysis of each item S and some additional assessment points including fatigue, sleep and mood, and cognition, comparing 1 gram per ounce and 200 mg / Daily statistical and clinical efficacy of milnacipran in the treatment of fibromyalgia syndrome; and 2. establishment and comparison of 10 mg of naprolide administered daily in 100 mg and 200 mg in FMS patients Security features. Methodology ^ This is a multicenter, double-blind, randomized, placebo-controlled, three-group trial study that enrolled criteria that met the 199 ACR for fibromyalgia syndrome and more detailed selection criteria listed in the protocol. 888 people suffer from 15 people. These patients recorded baselines for various symptoms after the first two weeks of the initial elimination of antidepressants, nitric oxides, and other drugs that might interfere with the effectiveness measurement. These patients were randomized to receive a placebo, 20 100 mg/df of milnacipran, or 200 mg/df of milnacipran at a ratio of 1:1:2. All randomized drug regimens (placebo and milnacipran) were administered as a divided dose (BID). The doses are administered in a dose escalating regimen as follows: Stage 1: 12.5 mg 1 day (12.5 mg afternoon) 27 200814989 Phase 2 · 25 mg 2 days (I2·5 mg AM, I2 · 5 mg in the afternoon) Stage 3: 50 mg 4 days (25 mg in the morning, 25 mg in the afternoon) Stage 4: 100 mg in 7 days (50 mg in the morning, 50 mg in the afternoon) 5 Stage 5: 200 mg 7 days (100 Mg morning, 100 mg afternoon) After a three-week dose escalation step, all patients are scheduled to receive a total of 24 weeks of milnacipran or placebo, so they will experience a total of 27 weeks of milnacipran Or use of placebo. The patient is required to complete an electronic diary as described in the scheduled plan for the study evaluation and additional written assessments. Negative effects, physical examinations, accompanying medications, important signs, and clinical trial data are collected based on detailed instructions in the study's planned schedule. Patients who successfully completed this double-blind trial were eligible to participate in an additional 15 15-28 weeks of open drug labeling testing. The timeline for this study is provided in Figure 1. Outcome Assessment Safety: The safety of milnacipran was assessed by analyzing the frequency and severity of adverse effects collected during the trial study, changes in important disease signs, and clinical trial data. Validity: In addition to the daily electronic patient diary completed daily, the following assessments were obtained: 28 200814989 a·Main causes: overall change impression of patients (pgic) and fibromyalgia impact questionnaire (FIQ) . b. Baseline Psychology Screening: m.I.N.I. c. Assessment of various states: Periodically as described in the assessment plan 5: BDI, sleep quality assessment, and ASEX.

d· FMS status assessment: 24-hour and 7-day response to patient pain VAS scale, SF-36, multivariate self-report Questionnaire (MASQ, cognitive function), multidimensional fitness self-leveling assessment Questionnaire (Multidimensional Health Assessment 10 Questionnaire; MDHAQ) and Multidimensional Dimensional Tiredness Scale (MFI). The assessment includes the current intensity of pain (morning, daily randomization, and evening reports); daily response to pain intensity (reported in the morning); medication (reported at night); overall pain over the past week The degree (reported weekly), the overall level of fatigue in the past week (15 reported per week), and the extent to which the pain prevented the patient from caring for themselves (weekly reports). The SF-36 is a multi-purpose, short-term health survey. It will receive a functional health assessment and quality of life assessment with 8 levels, a physical and mental health summary measurement based on psychometric measurements, and a health utility index based on a health utility index (Ware JE). , Snow KK, Kosinski M, Gandek B. SF-36® Health Survey Manual and

Interpretation Guide· Boston, MA · New England Medical Center, The Health Institute, 1993). The SF-36 can provide a measure of the functional impairment of the patient due to fatigue (i.e., how fatigue affects the patient's activity). SF-36 has been shown to be used to survey in general and in specific populations to compare the relative importance of the disease and to distinguish the health benefits of different types of treatment. The MFI is a self-reporting form for measuring 20 items of fatigue, including general fatigue, physical fatigue, mental fatigue, vitality reduction, and reduced vitality (811^8 et al., 1?8&gt;^11〇) 8〇111 on 1995, 39: 315-325). The score on each face reflects the severity of fatigue (higher values represent greater fatigue). The MASQ is a simple self-reported questionnaire containing five 10 cognitive domains • language skills, visual perception, oral memory, visual memory and attention/concentration (Seidenberg et al., J Clin &amp; Exp Neuropsychology 1994 ; 16: 93-104). MASQ has been identified as effective in both the normal individual and the group of patients with cognitive impairment in the assessment area. 15 Validity of Statistical Analysis: The main test indicator for this study was a comprehensive analysis of the analysis of the three areas of interest in the 24th week as the primary analysis, and the second analysis was performed in the 12th week. To analyze. The areas in which measurement 20 is performed are: 1) Pain (measured by the daily assessment of the pain score of the electronic diary, which is calculated as the weekly average score) 2) Overall sensation of the patient (measured by pGIC, level) u) 3) Body function (measured by fiq-PF) 30 200814989 In the main test indicators, the score in the pain field was compared by comparing the average of the 14th and 15th treatment weeks with two baseline weeks. Decide

And compare the 26th and 27th treatment weeks to the baseline for analysis. The 14th week or the 15th week (or 26th/27th week) of the 5 patients with self-reported pain scores could not be compared with the baseline values for the final observation. The secondary response rate of the placebo group in this study (based on the integrated archaeological indicator) was expected to fall within the range of 10-13% on the basis of ITT/LOCF, while in the trial group The response rate of 10% to milnacipran is expected to fall within the range of 27-29%. Based on these response ratios, it is assumed that each group of 125 randomized patients (250 patients in the high-dose group) is calculated to be the largest sample size required (90% efficacy). Secondary analysis included total area under the curve of pain intensity, weekly pain response as reported by patients in the clinical visit, and assessment of the FMS status, and q〇l measurements. - 15 EXPERIMENTAL RESULTS 一| A response is defined as the degree to which an individual experiences a reduction in pain greater than 30% from baseline and an improvement in PGIC. In the three months, the percentage of responses was: 35.44% (56/158) in the placebo group and 2〇53.33% (72/135) in the 100 mg/df of the milnacipran group. ) (p = 0.001); and 55.00% (143/260) (ρ&lt;〇·〇〇1) in the 200 mg/df of the milnacipran group. The percentage of responses in the six months was: 32.86% (46/140) in the placebo group and 49.59% in the 100 mg/per guanaminarin group (60/121). ) (ρ = 0.002); and 51.74% 31 200814989 (119/230) (p&lt;0.001) in the 200 mg/min milnarin group. See Table 1 for a summary of the results in the intended treatment population and the final observations (LOCF), baseline observations (10), and study completion (OC) populations in Table 2. It is an analysis of the last time point when the observation of the patient is withdrawn. The L0CF analysis can use the data in the observation as the observation data at the last point. B 〇 C F is an analysis of a test that requires the patient to be undergoing the assessment of the response. If a patient withdraws from the trial for any reason, it should be considered as a non-responder regardless of the pain and overall rating.

Table 1 10 An analysis (observation case) of responders to the treatment of fibromyalgia pain during the 14-15 and 26-27 treatment weeks intended to be treated. Statistical item placebo group (N = 223) milnacipran 100 mg group (N = 224) 200 gram group (N = 441, pain baseline N mean SD SEM median minimum, maximum 223 68.37 11.98 0.80 66.5 50, 100 224 68.32 11.54 0.77 67.9 41,100 441 69.41 11.85 0.56 69.1 47, 99 Treatment 14-15 weeks N m (%=m/n) Winning ratio 95% CI ρ-value 158 56 (35.44) 135 72 (53.33) 2.1〇 (1.31, 3.36) 0.002 260 ^ 143 (55.00) 2.20 (1.46, 3·31) &lt;0.001 Treatment Week 26-27 N m (%=m/n) Winning ratio 95% CI P - Value 140 46 (32.86) 121 60 (49.59) 1.96 (1.18, 3.26) 0.009 230 119 (51.74) 2.20 (1·42,3·41) &lt;0.001 32 200814989 Table 2 Summary of comprehensive response ratios Pain comprehensive response 3 Month 6 months placebo N=223 100 mg N-224 200 Ν Ν 2 441 Placebo Ν = 223 100 mg Ν = 224 200 mg N = 441 Main analysis (LOCF) 27.8% 33.5% 34.9% 25.1% 30.8 % 32.2% P* 2 0.187 ρ*=0.058 ρ*=0·197 ap*=0.393 ρ*=0·053 ap*=0.105 Sensitivity analysis I (BOCF) 25.1% 32.1% 32.4% 20.6% 26.8% 27.0% P *=0.094 ρ*=0.048 p*=0.167 ap*=0.334 ρ*=0·067 ap* II 0.133 Sensitivity analysis II 25.56% 32.% 32.7% 21.5% 27.2% 28.6% Ρ*=0·113 ρ*=0.056 ρ*=0·197 ap*=0.394 p*=0.048 Ap*=0.095 Sensitivity analysis III 25.1% 32.1% 32.4% 22.9% 29.5% 29.9% Ρ*=0.094 ρ*=0·048 p*=0.120 ap*=0.241 p*=0.051 ap*=0.102 OC analysis n*= 158 Ν=135 η=260 η two 140 n=121 n=230 35.4% 53.3% 55.0% 32.9% 49.6% 51.7% Ρ*=0·002 ρ*&lt;0.001 ρ*=0·009 p*&lt;0.001 Individual project response ratio summary pain comprehensive response, 3 months pain comprehensive response, 6 months placebo 100 mg 200 mg placebo 100 mg 200 mg primary analysis (LOCF) 27.8% 33.5% 34.9% 25.1% 30.8% 32.2% Ρ* =0············ 321 ρ=0·068 p=0.110 ρ=0·072 PGIC (LOCF) 47.1% 54.0% 50.6% 46.2% 49.6% 49.9% ρ=0·143 ρ=0.397 ρ=0·476 ρ=0·368 *p - Value: nominal p-value. Ap = adjusted p-values performed in the Hochberg step in the second step (p-values for a 3 month pain test with 200 mg only compared to the placebo group in the first step = &lt; Effective at 0.05). n = number of patients with appropriate dates for OC analysis (completers with observations for the results of the respondents' assessments).

Surprisingly, these results demonstrate the continued administration of milnacipran (for example, at least three months of daily dosing) to the target of fibromyalgia, which can provide fibromyalgia and its symptoms on 33 200814989. Long-term relief (at least three months). Moreover, these results surprisingly confirm the continued administration of low doses of milnacipran (for example, mg/per sputum), for long-term treatment of fibromyalgia with some of its symptoms, almost continuously with high doses of minar Pullen (example 5, 200 mg/day) has the same effect. Figure 2. The results of the SF-36 body function analysis are summarized in Table 3: Table 3 Weeks of treatment placebo group N = 223 m male - 100 g / f day N = 2? 1 milnacipran 200 mg / per曰Ν = 441 3 4.32 6.31 丄, Hi 7.44 ^' 7 5.23 6.62 8.80 ^, 11 6.23 7.70 8.46 15 5.32 7.70 8.44 ' 19 4.63 7.71 8.37 ~^ 23 5.70 7.07 ^ 7.85 27 5.77 7.11 7.95 '^ by MASQ total score and The results of the baseline MASQ total score change (summarized in Table 4) show that for 10 treatments of cognitive dysfunction associated with !^^^, milnacipran 1 mg/day and rice Napron 200 mg/per sputum is superior to placebo. See Figure 3. Moreover, these results confirm that milnacipran 2 mg/per sputum is superior to milnacipran 1 mg/per guanidine for the treatment of FMS-related cognitive dysfunction. The Bayesian Depression Scale contains two items that assess subjective cognition; Ming 15 says, question 13 ("hesitate") and 19 (''not easy to focus"). Problem 13 is divided into 0-3 (0=I am as easy to decide as before, 1=I think it is more difficult to decide than usual, 2=I am more difficult to decide than usual, 3 I feel very troubled to make any decision). Question 19 has a rating of 34 200814989 0-3 (0 = I am as easy to focus as before, 1 = I feel more difficult to focus than usual, 2 = I am more difficult to focus than ever, 3 = I found out that I am Everything is difficult to focus on. In Figure 4, BDI (OC) is given at 100 mg/day of milnacipran, 5 200 mg/day of milnacipran or placebo. "hesitate

Percentage of patients who changed the score. In Figure 5, BDI (OC) was given at 100 mg/day of milnacipran, 200 mg/day of milnacipran or placebo. The percentage of patients who are "not easy to focus on" with a change in score. Table 4 MASQ total score - change from baseline amount of treatment weeks placebo N = 223 100 mg N = 224 200 mg N = 441 3 -0.50 -0.39 -1.60 p = 0.922 p = 0.181 7 0.26 -0.34 -1.77 p = 0.259 p =0.024 11 0.60 -1.33 -1.73 p =0.116 ρ=0·014 15 0.39 -1.18 -1.76 p =0.095 ρ =0.025 19 0.73 -1.60 -1.63 p =0.026 ρ = 0.019 23 0.92 -0.89 -1.52 p = 0.065 ρ = 0.015 27 0.66 -1.07 -1.89 p = 0.098 ρ = 0.016 10 Example 2: Single central double-blind randomized, placebo-controlled monotherapy study of milnacipran for the treatment of fibroin It is demonstrated that milnacipran is clinically and statistically safe and effective in the treatment of fibrosis 35 200814989 Pain Syndrome (FMS) or pain associated with fibromyalgia. The primary outcome was the estimated response rate of two doses (100 mg/d) versus 200 mg/dil in the Ding Yi 15 (15th week) compared to the placebo comprehensive responder analysis. 5 The other purposes of this study were (1) based on a time-weighted average of the results of each item of the comprehensive response analysis from D. to Txl5, to 1 〇〇t/day and 2003⁄4 g/day of rice Napalen is statistically and clinically effective in treating fibromyalgia syndrome compared with placebo; and (ii) establishing and comparing 1 mg/t and 2 〇〇 in FMS patients 10 g / daily milnacipran safety features. Methodology This is a multicenter, double-blind, randomized, placebo-controlled, three-group trial that is eligible for the 1990 ACR criteria for fibromyalgia syndrome (a history of extensive pain and 18 tender points on digital palpation). The η 15 has painful appearances and more 1196 patients listed in more detailed selection criteria in the protocol. These patients recorded baselines for various symptoms after the first two weeks of the initial elimination of antidepressants, benzodiazepines, and other drugs that might interfere with the effectiveness measurement. 20 These patients were randomized to receive placebo, W0 mg/per milnacipran, or 200 mg/per milnaplanone (placebo = 401) at a ratio of 1 · 1 : 1 One patient, 100 mg / day = 399 patients, 200 mg / 曰 = 396 patients). These patients assigned to the two active treatment groups will receive a stable dose of milnacipran illuminating two active group assignments for a total of 12 stars 36 200814989 after receiving a three-week dose escalation phase. Therefore, the total use of milnacipran for 15 weeks. During the dose escalation phase (visit BL2/TxO-Tx3), three drug blister packs are provided, each of which is available for one week. On the first day of the evening, 5 of the three groups in the study received a large one with a small capsule. In the case of the two active treatment groups, the dose contained 12.5 grams of active ingredient plus placebo. In the case of the placebo group, the dose package contained a small and large placebo capsule. On the second and third days, the active treatment group received a capsule containing ΐ2.5mg10 of active ingredient and placebo in the morning and evening, and the placebo group received each morning and evening. To two placebo capsules. On day 4-7, these two active treatments will be received in the morning and evening – containing 25 mg of active ingredient and feminine capsules, and the placebo group will receive two comforts each morning and evening. Capsules. 15 During the second week of the dose escalation phase (ie, Days 8-14), all three groups of patients received only a larger capsule of 5 mg in size. Patients in the placebo group receive two larger placebo capsules each time they receive the drug. Actively treated patients with milligrams and milligrams of medication will receive a placebo and a 50 gram capsule in the morning and evening. 20 The third in the incremental phase, the placebo group will continue to receive two larger placebo capsules in the morning and evening. The touch of the mg group: ~ The day continues to receive - 5G mg of active ingredient with a homeopathic placebo capsule at early morning and evening. At this time, the patients in the milligram group will start to receive two riding gram (four) sex sacs in the morning and evening. 37 200814989 The gradual increase of private graphs in the 5th agent was revealed in the picture. A timeline for this study is provided in Figure 7. The patient is required to complete a dedicated electronic diary of the self-reported pain data as described in the study plan's scheduled plan and an additional 5 written assessments. Negative shirting, physical examination, accompanying music therapy, important signs, electrocardiogram (ECG), and clinical trial data are collected based on detailed instructions in the study's planned schedule. Outcome Assessment 10 Safety: The safety of milnacipran is analyzed by analyzing the frequency and severity of adverse effects (AEs) collected during the trial study, changes in important disease signs, physical examination results, ECG, and clinical trials. The data is evaluated. Validity: 15 In addition to the electronic diary system completed on the parent's day, the following assessments were obtained: (i) Primary effectiveness assessment: overall patient impression changes at Tx3, Tx7, Txll and Txl5/ET visits ( PGIC) assessment; physiologic partial 20 sum assessment of SF-36 (SF-36 PCS) at BL2/TxO, Tx3, Tx7, Txll and Txl5/ET visits; (ii) Secondary efficacy assessment: per Weekly mean PED morning response pain scores (AUC); PGIC and SF-36 PCS assessments at Tx3 to Txl5 visits. (iii) Additional effectiveness measures · Fibromyalgia impact questionnaire (FIQ) 38 200814989 Total score and physiological function items, Bayesian depression scale (BDI), MOS-SleepIndexScale, Arizona Sexual Experience Scale, 24-hour and 7-day response to patient pain VAS scale; personal area of SF-36, overall disease status of patients, overall treatment benefit for patients, multi-five self-reported survey Table (MASQ, cognitive function), multidimensional dimension health assessment questionnaire (MDHAQ), multidimensional dimension fatigue scale (MFI), and daily assessment including current pain status (morning, daily random, and evening) Report), overall pain in the past week (weekly report), overall fatigue in the last week (weekly report), and the extent to which the pain prevented the patient from being able to care for themselves (weekly report). The primary efficacy parameter for the indication of pain management for fibromyalgia is the morning response pain assessment recorded in the PED and recorded during the Txl5 visit. (31〇: The overall status of the overall condition of the patient as a basis for comprehensive response. 15 The primary efficacy parameter for the indication of fibromyalgia treatment is a comprehensive responder based on both the pain and the overall condition of the patient. Status (as described above for the primary efficacy signature for indicators of pain management for fibromyalgia), plus additional areas of physiological function assessed by SF-36 PCS in the Txl5 visit. The secondary efficacy parameter is the weighted average (AUC) of the weekly average PED inter-announced pain scores at weeks 4 to 15; and the PGIC and SF-36 PCS assessments performed at Tx3 to 1x15 visits. ^ The physiological functional field used for response analysis is measured by the SF-36 (SF-36 PCS) physiological project summary. The π% is a simple, developmental 39 200814989 comprehensive assessment of health status, functional status and life. Quality Self-Evaluation Patient Questionnaire. SF_36 will assess the health status of eight areas: physiological function, limitations on roles due to physiological problems, physical pain, general health perception, vitality/dynamics, social function, due to The limitations of emotional problems on roles, as well as mental health. The SF_36PCS score and the psychological partial sum (mcs) score can be calculated by combining and weighting various individual scales.

The PCS and MCS scores have been digitized to have an average of 50 in the generally healthy US population, SD = 10 (for example, see Ware, J, M Kosinski, and J. Dewey? How to Score Version 2 of The SF-36 10 Health Survey (Standard &amp; Acute Forms). 3rd ed. 2000 Lincoln, RI · QualityMetric). RESULTS • If a patient completes a T x 15 visit and meets the following criteria, he or she will be classified as a pain treatment for fibromyalgia: • One is greater than or from baseline A degree of pain reduction equal to 30%; a PGIC assessment evaluated as "many or very many improvements" (ie, the final assessment scored 1 or 2 in grades 1-7). If one meets the criteria for responders to pain treatment for fibromyalgia 20 and the following additional criteria (visit at Tx 15), he or she will be classified as a responder to the treatment of fibromyalgia: • The magnitude of improvement from baseline in the SF-36 PCS assessment is at least equivalent to the minimum clinically important difference value defined in the statistical analysis 0+ 0 40 200814989 shown in Figure 8 at 100 mg/ Daily milnacipran, 200 mg/day milnacipran or placebo, BDI (OC) is “hesitant, the percentage of patients with a change in score. It is shown in Figure 9 Percentage of patients with BDI (OC) "difficult to focus" scores given 100 mg/day of milnacipran, 2 mg/day of milnacipran or 5 doses of supine. Table 5 shows the amount of change in the MASQ total score from baseline for the treatment population during the three-month treatment period (LOCF).

Placebo group Table 5 milnacipran 100 mg milnacipran 200 mg actual value change amount actual value change amount actual value change amount

N

N 401 401 399 399 396 395 401 401 399 399 396 395 Average 90.02 -2.49 88.86 -3.34 89.63 -3.75

SD 20.22 11.98 20.55 12.63 18.80 12.64

SEM median minimum, maximum 1.01 89.0 42, 151 0.60 -1.0 -49, 46 L03 0.63 0.94 0.64 89.0 -3.0 90.5 -3.0

Geometric minimum mean (SE)* versus placebo 43,149 -63, 38 43,146 -3.39 (0.773) -60, 51 -3.93 (0.786) -1.13 -4.51 (0.797) • 1.12

95 % CI temperature, 0.181 T2776: 0.52) 10

Standard deviation, SEM 0.179 * and minimum value, max = maximum value; although ',,,: handle has been described with reference to a typical embodiment of the present invention and Peng Yue, this - tea test does not represent a limitation of the present invention, And derive these limitations. As f + 7 α should be called to understand the content of the disclosure of the case in the relevant device - can be clearly from the 'this is the day of the day and the Wei and the Wei on the 41 41 200814989 modification, change and its equivalent changes . The specific examples described and illustrated herein are merely exemplary and are not a limitation of the scope of the invention. Accordingly, the invention should be limited to the spirit and scope of the claims and the equivalents thereof. All references cited herein are hereby incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a time line describing the clinical study in Specific Example 1. Figure 2 is an illustration of 10 FMS patients in the 3rd and 6th months with placebo, milnacipran 100 mg/per guanidine, and milnacipran 2 mg/per group. A histogram of the percentage of response to treatment for pain associated with FMS. Figure 3 shows the milnacipran 200 mg/daily group ("200") when measuring the efficacy of FMS-related cognitive dysfunction with changes in the patient's MASQ total score and its baseline MASQ total score. The system is superior to the meter 15 napulen 1 〇〇 mg/daily group ("100") chart. Of the treatment outcomes associated with FMS-related cognitive dysfunction, both groups 200 and 100 were superior to placebo ("Pbo"). Assessments were performed on days 3, 7, 11, 15, 19, 23 and 27 of treatment. Fig. 4 is a graph showing the percentage of BDI (Bayesian Depression Scale) (the "hesitant indecision" state change of patients from TxO to Τ·χ15 in the clinical study 20 described in the specific example 1. Figure 5 is a graphical representation of the percentage change in the "concentration" state of BDI (OC) from patients with TxO to Tx 15 in the clinical study described in Example 1. 42 200814989 Fig. 6 is a dose increasing flowchart of the clinical study described in the specific example 2. Fig. 7 is a time line describing the clinical study in the specific example 2. Fig. 8 is an example of a specific example 2 is a graphical representation of the percentage of the "hesitant" status of BDI (OC) from TxO to Txl5 patients in Clinical Study 5 described. Figure 9 is an illustration of the clinical study described in Example 2. A graphical representation of the percentage of the BDI (OC) “concentration” status of patients from ΤχΟ to 。 15 10 [Main component symbol description] (none) 43

Claims (1)

200814989 X. Patent application scope: 1. A use of milnacipran for the manufacture of a medicament for the treatment of cognitive dysfunction associated with fibromyalgia syndrome (FMS), wherein the use comprises more than about 125 per sputum The milligram of naprolide is given to patients who need it. 2. For the use of the scope of claim 1, wherein the milnacipran is administered once per sputum. 3. The use of claim 1 wherein the milnacipran is administered in divided doses. 4. For the use of the scope of patent application 1, the milnacipran is administered for at least 3 months. 5. For the use of the scope of patent application 1, the milnacipran is administered for at least 6 months. 6. The use of claim 1 of the invention, comprising the auxiliary administration of a second active compound to treat a cognitive dysfunction associated with FMS, wherein the second active compound is selected from the group consisting of: An antidepressant, an analgesic, a muscle relaxant, an appetite reducing agent, a stimulant, an antiepileptic drug, a beta blocker, a sedative, a sleeping pill, and combinations thereof. 7. The use of claim 6 wherein the second active compound is selected from the group consisting of phenoxine, gabapentin, pregabalin, pramipexole, 1-DOPA, amphetamine, tizanidine , clonidine, travertine, morphine, tricyclic antidepressant, codeine, dysentery, sibutramine, anesthesia, trazodone, caffeine, nigralin, diphenylmethanol, 44 200814989 Propranolol, Artino, and combinations of them. 8. For the use of the first application of the patent scope, the milnacipran between about 125 mg per day and about 400 mg per day is administered to the patient. 9. For the use of paragraph 1 of the patent application, the milnacipran between about 150 mg per day and about 350 mg per day is administered to the patient. 10. For the use of claim 1 of the patent, in which between about 200 mg per day and about 300 mg per tad, milnacipran is administered to the patient. 11. For the use of the scope of claim 1, wherein approximately 200 mg of milnacipran per day is administered to the patient. 45