Source: http://www.google.com/patents/US7888342?ie=ISO-8859-1&dq=6,163,776
Timestamp: 2015-05-05 20:34:46
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Matched Legal Cases: ['Application No. 2003284005', 'Application No. 02793880', 'Application No. 02793880', 'Application No. 02793880', 'Application No. 02793880', 'Application No. 02793880', 'Application No. 03748971', 'Application No. 496']

Patent US7888342 - Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe present invention provides a method of treating fibromyalgia syndrome (FMS), chronic fatigue syndrome (CFS), and pain in an animal subject. The method generally involves administering a therapeutically effective amount of a dual serotonin norepinephrine reuptake inhibitor compound or a pharmaceutically...http://www.google.com/patents/US7888342?utm_source=gb-gplus-sharePatent US7888342 - Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and painAdvanced Patent SearchPublication numberUS7888342 B2Publication typeGrantApplication numberUS 12/644,510Publication dateFeb 15, 2011Filing dateDec 22, 2009Priority dateNov 5, 2001Fee statusPaidAlso published asUS6602911, US6992110, US7820643, US7915246, US20030130353, US20040019116, US20040229956, US20070225375, US20080153919, US20100105778, US20100105779, US20100197796, WO2003053426A1Publication number12644510, 644510, US 7888342 B2, US 7888342B2, US-B2-7888342, US7888342 B2, US7888342B2InventorsJay D. Kranzler, Srinivas G. RaoOriginal AssigneeCypress Bioscience, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (99), Non-Patent Citations (229), Referenced by (1), Classifications (21), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetMethods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain
US 7888342 B2Abstract
1. A method of treating fibromyalgia, the method consisting essentially of administering to a patient in need thereof an effective amount of at least one compound selected from milnacipran, a pharmaceutically acceptable salt of milnacipran, or a combination thereof, with the proviso that the method excludes administering phenylalanine, tyrosine, or tryptophan.
2. A method of treating fibromyalgia, the method consisting essentially of administering to a patient in need thereof a daily dose of about 100 mg of active ingredient, wherein the active ingredient is at least one compound selected from milnacipran, a pharmaceutically acceptable salt of milnacipran, or a combination thereof, with the proviso that the method excludes administering phenylalanine, tyrosine, or tryptophan.
3. The method of claim 2, wherein the active ingredient is in tablet form.
4. The method of claim 2, wherein the daily dose of active ingredient is divided into multiple doses per day.
5. The method of claim 4, wherein the daily dose of active ingredient is administered as a 50 mg dose twice per day.
6. A method of treating fibromyalgia, the method consisting essentially of administering to a patient in need thereof a daily dose of about 200 mg of active ingredient, wherein the active ingredient is at least one compound selected from milnacipran, a pharmaceutically acceptable salt of milnacipran, or a combination thereof, with the proviso that the method excludes administering phenylalanine, tyrosine, or tryptophan.
7. The method of claim 6, wherein the active ingredient is in tablet form.
8. The method of claim 6, wherein the daily dose of active ingredient is divided into multiple doses per day.
9. The method of claim 8, wherein the daily dose of active ingredient is administered as a 100 mg dose twice per day.
10. The method of claim 9, wherein the daily dose of active ingredient is administered as two 50 mg doses in the morning and two 50 mg doses in the evening.
This application is a continuation of U.S. patent application Ser. No. 11/752,213, filed May 22, 2007, now abandoned which claims benefit to Ser. No. 10/623,431, filed Jul. 18, 2003, now U.S. Pat. No. 7,820,643 which claims the benefit of U.S. application Ser. No. 10/028,547, filed Dec. 19, 2001, now U.S. Pat. No. 6,602,911, which is a continuation-in-part of U.S. application Ser. No. 10/014,149, filed Nov. 5, 2001, now U.S. Pat. No. 6,635,675, all of which are incorporated herein by reference.
Fibromyalgia syndrome (FMS) is the most frequent cause of chronic, widespread pain, estimated to affect 2-4% of the population. EMS is characterized by a generalized heightened perception of sensory stimuli. Patients with FMS display abnormalities in pain perception in the form of both allodynia (pain with innocuous stimulation) and hyperalgesia (increased sensitivity to painful stimuli). The syndrome, as defined by the American College of Rheumatology's criteria, involves the presence of pain for over 3 months duration in all four quadrants of the body, as well as along the spine. In addition, pain is elicited at 11 out of 18 �tender points� upon palpation. Other associated symptoms include fatigue, nonrestorative sleep, and memory difficulties.
SSRJs
X is O or C; Y is N or C; R1 is H or Cl; R2 is selected from the group consisting of �(CH2)3N(CH3)2, �(CH2)3NHCH3, �CH2CH(CH3)CH2N(CH3)2, ═CH(CH2)NH(CH3)2, ═CH(CH2)2NHCH3 and �(CH2)3NHCH3; and the dotted line represents a single bond or a double bond. The NE≧5-HT SNRI compounds of the invention exclude compounds classified as tricyclic antidepressants, and thus exclude compounds characterized by the above-depicted fused tricyclic nuclei of structures (I), (II), (III), and (IV).
A specific example of a NE≧5-HT SNRI compound that can be used to practice the present invention is milnacipran. Additional NE≧5-HT SNRI compounds that can be used to practice the present invention include, by way of example and not limitation, any of the aminocyclopropane derivatives disclosed in the following references that inhibit norepinephrine reuptake to an equivalent or greater extent than serotonin reuptake (i.e., that have a NE:5-HT ratio that is ≧1:1): WO95/22521; U.S. Pat. No. 5,621,142; Shuto et al., 1995, J. Med. Chem. 38:2964-2968; Shuto et al., 1996, J. Med. Chem. 39:4844-4852; Shuto et al., 1998, J. Med. Chem. 41:3507-3514; Shuto et al., 2001, Jpn. Pharmacol. 85:207-213; Noguchi et al., 1999, Synapse 31:87-96; and U.S. Pat. No. 4,478,836. All of these references are hereby incorporated herein by reference in their entireties.
Those of skill in the art will recognize that NE≧5-HT SNRI compounds such as milnacipran may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. It should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the NE≧5-HT SNRI compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. For example, as is clear from the above structural diagram, milnacipran is optically active. It has been reported in the literature that the dextrogyral enantiomer of milnacipran is about twice as active in inhibiting norepinephrine and serotonin reuptake than the racemic mixture, and that the levrogyral enantiomer is much less potent (see, e.g., Spencer and Wilde, 1998, supra; Viazzo et al., 1996, Tetrahedron Lett. 37(26):4519-4522; Deprez et al., 1998, Eur. J. Drug Metab. Pharmacokinet. 23(2):166-171). Accordingly, milnacipran may be administered in entantiomerically pure form (e.g., the pure dextrogyral enantiomer) or as a mixture of dextogyral and levrogyral enantiomers, such as a racemic mixture. Unless specifically noted otherwise, the term �milancipran� as used herein refers to both enantiomerically pure forms of milnacipran as well as to mixtures of milnacipran enantiomers. Methods for separating and isolating the dextro- and levrogyral enantiomers of milnacipran and other NE≧5-HT SNRI compounds are well-known (see, e.g., Grard et al., 2000, Electrophoresis 2000 21:3028-3034).
It has recently been reported that compounds that inhibit reuptake of both NE and 5-HT, such as venlafaxine, duloxetine, milnacipran, and certain TCAs, are effective for the treatment of pain, CFS and FMS, among other maladies, when administered in combination with neurotransmitter precursors such as phenylalanine, tyrosine and/or tryptophan. See WO 01/26623. For example, according to one study reported in WO 01/26623, a patient experiencing, inter alia, fatigue and fibromyalgia, was administered many types of drugs, including many types of non-steroidal anti-inflammatories, both tricyclic and serotonin reuptake inhibiting and noradrenalin reuptake inhibiting antidepressants, and even steroids, without effect. When given a combination of lofepramine (70 mg�bd) and L-phenylalanine (500 mg�bd), the patient experienced a considerable improvement in fatigue and fibromyalgia, which persisted for more than six months. Thus, a compound that inhibits reuptake of both NE and 5-HT was effective only when administered in combination with a neurotransmitter precursor.
1. Patients meet the 1990 American College of Rheumatology criteria for fibromyalgia syndrome. 2. Male or female between the ages of 18 and 70 years. Females are either postmenopausal (no menses for at least 1 year) or status-post oophorectomy (bilateral) or have a negative pregnancy test and be using an accepted method of contraception. 3. Patients have a Gracely intensity pain scale recording (weekly recall) of at least 10 or more on a 20 point scale at baseline. 4. Patients may use non-prescription doses of NSAIDs, aspirin and acetaminophen on a PRN basis for acute pain unrelated to their underlying fibromyalgia. The patients are divided into 2 groups. The first group is administered 100 mg of milnacipran in a single-dose in the morning, while the second group is administered 50 mg twice a day (i.e., upon awakening and prior to going to sleep). Each patient is then followed for 6 weeks, with visits every two weeks, as follows: 4
20 patients with painful diabetic neuropathy (DN) are studied in a double-blind cross-over study. The inclusion criteria for the study are�age of between 18 and 85 years, daily pain of at least �moderate intensity� on the Gracely scale for greater than three months that was present more than 50% of the day, and adequate communication ability demonstrated during a telephone conversation and by completion of a pain diary. Additional inclusion criteria are a diagnosis of diabetes, and distal, symmetrical diabetic neuropathy as assessed by either an unequivocal decrease in pinprick, temperature, or vibration sense in both feet or ankles or decreased or absent ankle jerk reflexes. Exclusion criteria are the presence of another more painful condition, difficulty with ambulation, any unstable disease process, a history of significant substance abuse or alcoholism, liver or kidney disease, or concurrent use of a monoamine oxidase inhibitor.
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Monotherapy Study of Milnacipran for Treatment of Fibromyalgia
(ii) Secondary Efficacy Assessments: Time weighted average (AUC) of weekly average PED morning recall pain score; PGIC and SF-36 PCS administered to patients at visits Tx3 to Tx15.
The SF-36 is a brief, well-established, self-administered patient questionnaire for the assessment of health status, functional status, and quality of life. The SF-36 measures eight domains of health status: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations due to emotional problems, and mental health. An SF-36 PCS score and a mental component summary (MCS) score can be calculated by combining and weighting the various individual scales. The PCS and MCS scores have been standardized to have a mean=50, SD=10 in the general healthy US population (see, e.g., Ware, J., M. Kosinski, and J. Dewey, How to Score Version 2 of the SF-36 Health Survey (Standard & Acute Forms). 3rd ed. 2000, Lincoln, R1: QualityMetric).
Greater than or equal to 30% in pain reduction from baseline; PGIC rated as �much or very much improved,� (i.e., a score of 1 or 2 on the 1-7 scale at endpoint.) A patient was classified as a responder for the treatment of FMS if he or she satisfied the responder criteria for the treatment of pain of fibromyalgia and the following additional criterion (at visit Tx15):
Improvement on the SF-36 PCS score from baseline by an amount at least equivalent to the minimal clinically important difference, as defined in the Statistical Analysis Plan. Table 1 summarizes 3-month results for the Baseline Observation Carried Forward (BOCF), Last Observation Carried Forward (LOCF) and study completer (OC) populations. LOCF is an analysis in which observations are carried forward to the last time point for patients who dropped out. The LOCF analysis treats the carried-forward data as observed data at the last time point. BOCF is an analysis that requires that the patient remain active in the trial to be evaluated for response. If a patient withdrew from the trial for any reason, they were classified as a non-responder irregardless of their pain and global scores at the time of withdrawal.
# of patients included
101 124
119 115
101/263 124/237
119/217 Component
(39.90%)
p = 0.069 p = 0.125 p = 0.009
129 100
129/255 Component
p = 0.008 p = 0.002 p = 0.003
p = 0.063 p = 0.586 p = 0.029
*Nominal p-value.
All pair-wise comparisons to placebo for BOCF-based composite responder analyses are statistically significant (by the pre-specified multiple comparison procedure.)
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