Source: http://www.google.fr/patents/US7915246
Timestamp: 2013-05-20 19:15:27
Document Index: 299848428

Matched Legal Cases: ['Application No. 02793880', 'Application No. 02793880', 'Application No. 02793880', 'Application No. 03748971', 'Application No. 2003284005', 'Application No. 496', 'arty 13', 'Application No. 02793880', 'Application No. 02793880']

Brevet US7915246 - Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain - Google�BrevetsRecherche Images Maps Play YouTube Actualit�s Gmail Drive Plus » Recherche avanc�e dans les brevets | Historique Web | Connexion Recherche avanc�e dans les brevets BrevetsThe 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.fr/patents/US7915246?utm_source=gb-gplus-shareBrevet US7915246 - Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and pain Num�ro de publicationUS7915246 B2Type de publicationOctroi Num�ro de demande12/035,820 Date de publication29 mars 2011 Date de d�p�t22 f�vr. 2008 Date de priorit�5 nov. 2001Autre r�f�rence de publicationUS7888342US20080153919US20100197796 InventeursJay D. KranzlerSrinivas G. Rao Cessionnaire d'origineCypress Bioscience, Inc. Classification aux �tats-Unis514/183514/385514/252.1514/210.12514/579 Classification internationaleA61K31/33A61K31/165A61K31/135A61P25/00A61K31/00 Classification coop�rativeA61K31/165A61K31/135A61K31/00 Classification europ�enneA61K 31/165A61K 31/00A61K 31/135R�f�rencesCitations de brevets (103)Citations hors brevets (207)Liens externesUSPTO Cession USPTO EspacenetMethods of treating fibromyalgia syndrome, chronic fatigue syndrome and painUS 7915246 B2 R�sum� The 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 acceptable salt thereof, wherein said dual serotonin norepinephrine reuptake inhibitor compound is characterized by a non-tricyclic structure and an equal or greater inhibition of norepinephrine reuptake than serotonin reuptake. In particular, the use of milnacipran to treat FMS, CFS, and pain is disclosed.
1. A method of treating diabetic peripheral neuropathic pain, the method consisting essentially of orally administering to a patient in need thereof an effective amount of an 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.
2. The method of claim 1, wherein the active ingredient is in a tablet form.
3. The method of claim 1, wherein the effective amount of the active ingredient is an amount between about 25 mg and about 400 mg per day.
4. The method of claim 1, wherein the effective amount of the active ingredient is an amount between about 100 mg and about 250 mg per day.
5. The method of claim 1, wherein the effective amount of the active ingredient is about 100 mg per day.
6. The method of claim 1, wherein the effective amount of the active ingredient is about 200 mg per day.
7. The method of claim 5, wherein the effective amount of the active ingredient is administered as a 50 mg dose twice per day.
8. The method of claim 6, wherein the effective amount of the active ingredient is administered as a 100 mg dose twice per day.
9. The method of claim 8, wherein the effective amount of the 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. 10/623,431, filed Jul. 18, 2003, which is a continuation of U.S. patent 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. patent application Ser. No. 10/014,149, filed Nov. 5, 2001 (now U.S. Pat. No. 6,635,675).
1. FIELD OF THE INVENTION The present invention relates to methods for the treatment of fibromyalgia syndrome, chronic fatigue syndrome, and pain. In particular, the present invention relates to methods of treating fibromyalgia syndrome, chronic fatigue syndrome, and pain with a sub-class of dual serotonin norepinephrine reuptake inhibitors characterized by a non-tricyclic structure and inhibit the reuptake of norepinephrine to an equal or greater extent than they inhibit the reuptake of serotonin.
2. BACKGROUND OF THE INVENTION Fibromyalgia syndrome (FMS) is the most frequent cause of chronic, widespread pain, estimated to affect 2-4% of the population. FMS 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.
Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by profound tiredness or fatigue. Patients with CFS may become exhausted with only light physical exertion, and must often function at a level of activity substantially lower than their capacity before the onset of illness. In addition to the key defining characteristic of fatigue, CFS patients generally report various nonspecific symptoms, including weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, and depression. Like patients with FMS, patients with CFS suffer from disordered sleep, localized tenderness, and complaints of diffuse pain and fatigue.
There are two widely used criteria for diagnosing CFS. The criteria established by the U.S. Centers for Disease Control and Prevention include medically unexplained fatigue of at least six months duration that is of new onset, not a result of ongoing exertion and not substantially alleviated by rest, and a substantial reduction in previous levels of activity. In addition, the diagnosis involves the determination of the presence of four or more of the following symptoms�subjective memory impairment, tender lymph nodes, muscle pain, joint pain, headache, unrefreshing sleep, and postexertional malaise (>24 hours). Reid et al., 2000, British Medical Journal 320: 292-296. The diagnostic criteria from Oxford includes severe, disabling fatigue of at least six months duration that affects both physical and mental functioning and the fatigue being present for more than 50% of the time. In addition, the diagnosis involves the determination of the presence of other symptoms, particularly myalgia and sleep and mood disturbance. Reid et al., 2000, British Medical Journal 320: 292-296.
Owing to their common symptomology, FMS and CFS are thought to be related. However, they manifest different major symptoms. Whereas pain is the major symptom reported by patients with FMS, fatigue is the major symptom reported by patients with CFS. Given their relatedness, these two indications have been treated with the same medications. Some of the common medications currently employed to treat CFS and/or FMS include, but are not limited to, analgesics, hypnotics, immune suppressants, various other prescribed medications, and an array of non-prescription medications. Although a broad array of medications are used in FMS and CFS patients, no single pharmacological agent or combination of agents is effective in the treatment of either of these disorders. Thus, due to the lack of effective treatment regimens for FMS and/or CFS, there is a need to develop effective treatments.
Pain is associated with a variety of different underlying illnesses or injuries. Pain may be either acute or chronic. Chronic or intractable pain is often endured over many years or decades. Patients suffering from chronic pain often develop emotional problems which can lead to depression and in the worst case, attempted suicide. Long lasting pain often occurs particularly in joints, in muscles, connective tissue and in the back. In the United States alone, chronic pain causes a loss of more than 250 million working days per year. A patient is considered to have chronic pain when complaints thereof last longer than six months. In the course of time, chronic pain may form an independent clinical syndrome.
Most analgesic agents in use today are not always effective, may produce serious side effects and can be addictive. Hence, there is a demand for more active analgesic agents with diminished side effects and toxicity, and which are non-addictive. The ideal analgesic would reduce the awareness of pain, produce analgesia over a wide range of pain types, act satisfactorily whether given orally or parenterally, produce minimal or no side effects, and be free from the tendency to produce tolerance and drug dependence.
3. SUMMARY OF THE INVENTION In one aspect, the invention provides a method of treating fibromyalgia syndrome (FMS) and/or the symptoms associated therewith in an animal subject, including a human. The method generally involves administering to an animal subject suffering from FMS an effective amount of a dual serotonin norepinephrine reuptake inhibitor (�SNRI�) compound of a specific type, or a pharmaceutically acceptable salt thereof. The SNRI compounds that are useful to treat FMS and/or symptoms associated therewith are characterized by a non-tricyclic structure and inhibit the reuptake of norepinephrine to an equal or greater extent than they inhibit the reuptake of serotonin (referred to hereinafter as �NE≧5-HT SNRI compounds�). In one embodiment of the invention, the NE≧5-HT SNRI compound administered inhibits norepinephrine reuptake to a greater degree than it inhibits serotonin reuptake (referred to hereinafter as a �NE>5-HT SNRI compound�). One particular example of such a NE>5-HT SNRI compound is milnacipran, or a pharmaceutically acceptable salt thereof. In another embodiment, the NE≧5-HT SNRI compound is not administered adjunctively with phenylalanine, tyrosine and/or tryptophan.
In another aspect, the invention provides a method of treating pain in an animal subject, including a human. The method generally involves administering to an animal subject suffering from pain an effective amount of a NE≧5-HT SNRI compound, or a pharmaceutically acceptable salt thereof. In one embodiment, a NE>5-HT SNRI compound is administered. One particular example of a NE>5-HT SNRI compound is milnacipran or a pharmaceutically acceptable salt thereof. In another embodiment, the NE≧5-HT SNRI compound is not administered adjunctively with phenylalanine, tyrosine and/or tryptophan.
In still another aspect, the invention provides a method of treating CFS and/or symptoms associated therewith. The method generally involves administering to a patient suffering from CFS an effective amount of a NE≧5-HT SNRI compound, or a pharmaceutically acceptable salt thereof. In one embodiment, a NE>5-HT SNRI compound is administered. One particular example of a NE>5-HT SNRI compound is milnacipran or a pharmaceutically acceptable salt thereof. In another embodiment, the NE≧5-HT SNRI compound is not administered adjunctively with phenylalanine, tyrosine and/or tryptophan.
In yet another aspect, the invention provides a kit comprising a N≧5-HT SNRI compound packaged in association with instructions teaching a method of using the compound according to one or more of the above-described methods. The kit can contain the NE≧5-HT SNRI compound packaged in unit dosage form. In one embodiment, a NE>5-HT compound can be included in the kit. One particular example of a NE>5-HT SNRI compound is milnacipran or a pharmaceutically acceptable salt thereof.
4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 4.1 Abbreviations CFS chronic fatigue syndrome
FMS fibromyalgia syndrome
5-HT serotonin
NARIs norepinephrine specific reuptake inhibitors
NSAIDs non-steroidal anti-inflammatory drugs
SSRIs selective serotonin reuptake inhibitors
SNRIs dual serotonin norepinephrine reuptake inhibitors
4.2 Definitions The term �dual serotonin norepinephrine reuptake inhibitor compound� or SNRI refers to the well-recognized class of anti-depressant compounds that selectively inhibit reuptake of both serotonin and norepinephrine. Common SNRI compounds include, but are not limited to, venlafaxine, duloxetine, and milnacipran.
The terms �NE≧5-HT SNRI� and �NE>5-HT SNRI� refer to particular subclasses of SNRI compounds that are useful in the methods and kits of the present invention, as will be described in more detail herein.
4.3 Treatment of FMS, CFS and/or Pain The present invention provides methods and kits for treating FMS, CFS, and pain. A particular subclass of SNRI compounds is useful for practicing the present invention. Compounds in this SNRI subclass, referred to as �NE≧5-HT SNRI compounds,� inhibit norepinephrine reuptake more than or equal to serotonin reuptake. Moreover, the NE≧5-HT compounds of the invention exclude compounds that belong to the distinct class of antidepressant compounds commonly referred to in the art as tricyclic antidepressants or TCAs. In particular, compounds useful for practicing the present invention inhibit norepinephrine reuptake more than serotonin reuptake, referred to as �NE>5-HT SNRI compounds.�
Tricyclic antidepressants (TCAs) are a well-recognized class of antidepressant compounds that are characterized by a dibenz[b,e]azepine (structure I), dibenz[b,e]oxepine (structure II), dibenz[a,d]cycloheptane (structure III) or dibenz[a,d]cycloheptene (structure IV) tricyclic ring structure. These various rings are depicted below:
The TCAs are typically substituted at position 1 of the tricyclic ring with alkylamines or alkylidenamines, and may include additional substituents (typically on the benzo groups). Many common TCAs, including imipramine, desipramine, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, cyclobenzaprine and protriptyline are characterized by the general formula (V), below:
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)N(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), (I), (III), and (IV).
As mentioned above, the NE≧5-HT SNRI compounds useful in the methods and kits of the invention include compounds that inhibit norepinephrine reuptake to a greater extent than serotonin reuptake, as well as compounds that inhibit the reuptake of these two monoamines to an equivalent extent. In one embodiment of the invention, the NE≧5-HT SNRI compounds have a ratio of inhibition of norepinephrine reuptake to serotonin reuptake (�NE:5-HT�) in the range of about 1-100:1. In a particular embodiment, the compounds are NE>5-HT SNRI compounds, i.e., compounds that inhibit norepinephrine reuptake to a greater extent than serotonin reuptake. Such NE>5-HT SNRI compounds generally have a NE:5-HT in the range of about 1.1-100:1. That is, such NE>5-HT SNRI compounds are at least about 1.1 to about 100 times more effective at inhibiting norepinephrine reuptake than serotonin reuptake. NE>5-HT SNRI compounds having a NE:5-HT ratio in the range of about 2:1 to about 10:1 may be particularly effective.
Various techniques are known in the art to determine the NE:5-HT of a particular SNRI. In one embodiment, the ratio can be calculated from IC50 data for NE and 5-HT reuptake inhibition. For example, it has been reported that for milnacipran the IC50 of norepinephrine reuptake is 100 nM, whereas the IC50 serotonin reuptake inhibition is 200 nM. See Moret et al., 1985, Neuropharmacology 24(12):1211-1219; Palmier et al., 1989, Eur J Clin Pharmacol 37:235-238. Therefore, the NE:5-HT reuptake inhibition ratio for milnacipran based on this data is 2:1. Of course, other IC values such as IC25, IC75, etc. could be used, so long as the same IC value is being compared for both norepinephrine and serotonin. The concentrations necessary to achieve the desired degree of inhibition (i.e., IC value) can be calculated using known techniques either in vivo or in vitro. See Sanchez et al., 1999, Cellular and Molecular Neurobiology 19(4):467-489; Turcotte et al., 2001, Neuropsychopharmacology 24(5):511-521; Moret et al., 1985, Neuropharmacology 24(12):1211-1219; Moret et al., 1997, J. Neurochem. 69(2): 815-822; Bel et al., 1999, Neuropsychopharmacology 21(6):745-754; and Palmier et al., 1989, Eur J Clin Pharmacol 37:235-238.
The NE:5-HT of a particular SNRI also can be calculated using equilibrium dissociation constants (KD'S) for norepinephrine and serotonin transporters as described in Tatsumi et al., 1997, European Journal of Pharmacology 340:249-258. For example, a NE>5-HT SNRI compound with a KD of 2 nM for the norepinephrine transporter and a KD of 8 nM for the serotonin transporter has an NE:5-HT of 4:1.
Yet another means for determining the NE:5-HT of a particular SNRI involves measuring the affinity (Ki) of the SNRI for the norepinephrine and serotonin transporters as described in Owens et al., 1997, JPET 283:1305-1322. For example, a NE>5-HT SNRI compound with a Ki of 1 nM for the norepinephrine transporter and a Ki of 20 nM for the serotonin transporter has an NE:5-HT of 20:1.
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. J. 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.
In a specific embodiment of the invention, the NE>5-HT SNRI compound is milnacipran. The chemical structure of milnacipran, cis-(�)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropanecarboxamide, is as follows:
Milnacipran is also known in the art as F2207, TN-912, dalcipran, midalcipran, and midalipran. The NE:5-HT of milnacipran is 2:1. See Moret et al., 1985, Neuropharmacology 24(12):1211-1219; Palmier et al., 1989, Eur J Clin Pharmacol 37:235-238. Milnacipran and methods for its synthesis are described in U.S. Pat. No. 4,478,836, which is hereby incorporated by reference in its entirety. Additional information regarding milnacipran may be found in the Merck Index, 12th Edition, at entry 6281. Quite significantly, milnacipran has been used as an antidepressant in approximately 400,000 patients, and is known to be non-toxic in humans. In clinical trials at dosages of 100 mg/day or 200 mg/day, milnacipran was well tolerated and usually produced no more adverse effects than placebo (Spencer and Wilde, 1998, Drugs 56(3):405-427).
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 enantiomerically 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 will also be appreciated that in many instances the NE≧5-HT SNRI compounds may metabolize to produce active NE≧5-HT SNRI compounds. The use of active metabolites is also within the scope of the present invention.
It has been reported that milnacipran and its derivatives have antagonistic properties at the NMDA receptor. See 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; and Shuto et al., 2001, Jpn. J. Pharmacol. 85:207-213. As a consequence, one particularly useful embodiment of the invention includes NE≧5-HT SNRI compounds that also have NMDA antagonistic properties. The NE≧5-HT SNRI compounds with NMDA receptor antagonistic properties can have IC50 values from about 1 nM-100 μM. For example, milnacipran has been reported to have an IC50 value of about 6.3 μM. The NMDA receptor antagonistic properties of milnacipran and its derivatives are described in 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; and Shuto et al., 2001, Jpn. J. Pharmacol. 85:207-213. Methods for determining the antagonism and affinity for antagonism are disclosed in 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; Noguchi et al., 1999, Synapse 31:87-96; and Shuto et al., 2001, Jpn. J. Pharmacol. 85:207-213. Aminocyclopropane derivatives disclosed in 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; Noguchi et al., 1999, Synapse 31:87-96; and Shuto et al., 2001, Jpn. J. Pharmacol. 85:207-213 that inhibit NE reuptake equal to or greater than 5-HT reuptake and have NMDA antagonistic properties can be used to practice the present invention. These references are hereby incorporated by reference in their entirety.
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 noradrenaline 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.
Quite surprisingly, the present inventors have discovered that the NE≧5-HT SNRI subclass of SNRI compounds are effective in treating CFS, FMS and pain when administered alone (or in combination with other compounds that are not neurotransmitter precursors such as phenylalanine, tyrosine and/or tryptophan, as will be discussed in more detail, below). Thus, in one embodiment of the invention, the NE≧5-HT SNRI compound is administered alone, or in combination with a compound other than a neurotransmitter precursor such as phenylalanine, tyrosine and/or tryptophan.
The NE≧5-HT SNRI compounds, such as, for example, milnacipran, can be administered adjunctively with other active compounds such as antidepressants, analgesics, muscle relaxants, anorectics, stimulants, antiepileptic drugs, and sedative/hypnotics. Specific examples of compounds that can be adjunctively administered with the NE≧5-HT SNRI compounds include, but are not limited to, gabapentin, pregabalin, pramipexole, I-DOPA, amphetamine, tizanidine, clonidine, tramadol, morphine, tricyclic antidepressants, codeine, cambamazepine, sibutramine, amphetamine, valium, trazodone and combinations thereof. Typically for FMS patients the NE≧5-HT SNRI compounds may be adjunctively administered with antidepressants, anorectics, analgesics, antiepileptic drugs, muscle relaxants, and sedative/hypnotics. For CFS patients, the NE≧5-HT SNRI compounds may be adjunctively administered with antidepressants, anorectics, stimulants, and sedative/hypnotics. For patients suffering from pain the NE≧5-HT SNRI compounds may be adjunctively administered with antidepressants, analgesics, antiepileptic drugs. By adjunctive administration is meant simultaneous administration of the compounds, in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of the compounds. For example, milnacipran can be simultaneously administered with valium, wherein both milnacipran and valium are formulated together in the same tablet. Alternatively, milnacipran could be simultaneously administered with valium, wherein both the milnacipran and valium are present in two separate tablets. In another alternative, milnacipran could be administered first followed by the administration of valium, or vice versa.
The NE≧5-HT SNRI compounds can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated, e.g., eradication or amelioration of the underlying FMS, CFS or pain disorder, and/or eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of milnacipran to a patient suffering from FMS provides therapeutic benefit not only when the underlying FMS indication is eradicated or ameliorated, but also when the patient reports decreased fatigue, improvements in sleep patterns, and/or a decrease in the severity or duration of pain.
Although depression is often comorbid in patients suffering from FMS and CFS, and could therefore be characterized as a symptom associated with these disorders, it is well-recognized in the art that NE≧5-HT SNRI compounds such as milnacipran are useful in the treatment of depression. Accordingly, while successful treatment regimens of the invention contemplate providing an improvement in at least one symptom associated with FMS or CFS, treatment regimens that cause an improvement only in depression are considered ineffective for purposes of the present invention. While improvements in associated psychological symptoms such as depression may be reported, for purposes of the present invention, an improvement in the underlying disorder and/or in at least one of the physiological symptoms associated with the disorder must be reported. Thus, the present invention does not contemplate the treatment of depression alone.
For therapeutic administration, the NE≧5-HT SNRI compound typically will be administered to a patient already diagnosed with the particular indication being treated.
For prophylactic administration, the NE≧5-HT SNRI compound may be administered to a patient at risk of developing FMS, CFS, or pain or to a patient reporting one or more of the physiological symptoms of FMS or CFS, even though a diagnosis of FMS or CFS may not have yet been made. Alternatively, prophylactic administration may be applied to avoid the onset of the physiological symptoms of the underlying disorder, particularly if the symptom manifests cyclically. In this latter embodiment, the therapy is prophylactic with respect to the associated physiological symptoms instead of the underlying indication. For example, the NE≧5-HT SNRI compound could be prophylactically administered prior to bedtime to avoid the sleep disturbances associated with FMS or CFS. Alternatively, the NE≧5-HT SNRI compound could be administered prior to recurrence of pain, or prior to onset of fatigue.
While the invention has been described so far with respect to NE≧5-HT SNRI compounds, the present invention can also be practiced with norepinephrine specific reuptake inhibitors (NARIs). NARIs are a well-recognized class of compounds that specifically inhibit the reuptake of only norepinephrine. An example of a compound that is classified as a NARI is reboxetine.
4.4 Formulation and Routes of Administration The NE≧5-HT SNRI compounds useful in the present invention, or pharmaceutically acceptable salts thereof, can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
The term �pharmaceutically acceptable salt� means those salts which retain the biological effectiveness and properties of the compounds used in the present invention, and which are not biologically or otherwise undesirable. Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, if the compounds used in the present invention contain a carboxy group or other acidic group, it may be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine and triethanolamine.
The compounds, or pharmaceutically acceptable salts thereof, may be administered singly, in combination with other NE≧5-HT SNRI compounds, and/or in cocktails combined with other therapeutic agents. Of course, the choice of therapeutic agents that can be co-administered with the compounds of the invention will depend, in part, on the condition being treated.
The active NE≧5-HT SNRI compounds (or pharmaceutically acceptable salts thereof) may be administered per se or in the form of a pharmaceutical composition wherein the active compound(s) is in admixture or mixture with one or more pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the NE≧5-HT SNRI compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
For administration orally, the compounds may be formulated as a sustained release preparation. Numerous techniques for formulating sustained release preparations are described in the following references�U.S. Pat. Nos. 4,891,223; 6,004,582; 5,397,574; 5,419,917; 5,458,005; 5,458,887; 5,458,888; 5,472,708; 6,106,862; 6,103,263; 6,099,862; 6,099,859; 6,096,340; 6,077,541; 5,916,595; 5,837,379; 5,834,023; 5,885,616; 5,456,921; 5,603,956; 5,512,297; 5,399,362; 5,399,359; 5,399,358; 5,725,883; 5,773,025; 6,110,498; 5,952,004; 5,912,013; 5,897,876; 5,824,638; 5,464,633; 5,422,123; and 4,839,177; and WO 98/47491. Specifically, sustained release formulations of milnacipran are described in WO 98/08495. These references are hereby incorporated herein by reference in their entireties.
Alternatively, the active compound(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
in addition to the formulations described previously, the compounds may also be, formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
4.5 Effective Dosages Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredient is contained in a therapeutically or prophylactically effective amount, i.e., in an amount effective to achieve therapeutic or prophylactic benefit, as previously discussed. Of course, the actual amount effective for a particular application will depend, inter alia, on the condition being treated and the route of administration. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the disclosure herein.
Therapeutically effective amounts for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve circulating concentration that has been found to be effective in animals. Useful animal models of pain are well known in the art. Models of neuropathic pain are described in Zeltser et al., 2000, Pain 89:19-24; Bennett et al., 1988, Pain 33:87-107; Seltzer et al., 1990, Pain 43:205-218; Kim et al., 1992, Pain 50:355-363; and Decosterd et al., 2000, Pain 87:149-158. An animal model of inflammatory pain using complete Freund's adjuvant is described in Jasmin et al., 1998, Pain 75: 367-382. The stress-induced hyperalgesia model described in Quintero et al., 2000, Pharmacology, Biochemistry and Behavior 67:449-458 may be used as an animal model of FMS and CFS.
Effective amounts for use in humans can be also be determined from human data for the NE≧5-HT SNRI compounds used to treat depression. The amount administered can be the same amount administered to treat depression or can be an amount lower than the amount administered to treat depression. For example, the amount of milnacipran administered to treat depression is in the range of about 50 mg-400 mg/day. Thus, either 50 mg-400 mg/day or a lower dose can be administered for practicing the present invention.
Patient doses for oral administration of the NE≧5-HT SNRI compound typically range from about 1 μg-1 gm/day. For example, for the treatment of FMS, CFS, or pain with milnacipran the dosage range is typically from 25 mg-400 mg/day, more typically from 100 mg-250 mg/day. The dosage may be administered once per day or several or multiple times per day. The amount of the NE≧5-HT SNRI compound administered to practice methods of the present invention will of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. The dose used to practice the invention can produce the desired therapeutic or prophylactic effects, without producing serious side effects.
5. EXAMPLES 5.1 Example 1 Assessment of the Analgesic Properties of Milnacipran in a Rat Pain Model The rats used in this study are divided into two groups. One group of rats receive a spinal ligation as described in Kim et al., 1992, Pain 50(3):355-63 and the other group of rats receive a sham surgery. Each group of rats is further divided into 5 subgroups. Each subgroup receives subcutaneous injection of the vehicle or one of the 4 test doses of milnacipran (5, 10, 25, and 50 mg/kg). The vehicle or milnacipran are administered at a pre-determined time point following the surgeries. Allodynia and thermal hyperalgesia are respectively measured with Von Frey filaments and tail- or paw-flick with a radiant heat source. The allodynia and thermal hyperalgesia measurements are performed at the following time points�prior to surgery, following surgery but prior to the administration of vehicle or milnacipran, and following surgery after the administration of vehicle or milnacipran. The allodynia and thermal hyperalgesia measurements will provide information on the ability of milnacipran to block the development of mechanical allodynia and thermal hyperalgesia.
5.2 Example 2 Assessment of the Efficacy of Milnacipran in an FMS Animal Model This study is performed on rats or mice that have undergone stress-induced hyperalgesia as described in Quintero et al., 2000, Pharmacology, Biochemistry and Behavior 67:449-458. The study consists of 3 groups: placebo, milnacipran subcutaneous pretreatment, and milnacipran treatment. The milnacipran groups are further divided to 4 subgroups and each subgroup is administered 5, 10, 25, or 50 mg/kg of milnacipran. In the milnacipran subcutaneous pretreatment group, the milnacipran is administered prior to the inducement of the stress-induced hyperalgesia. In the milnacipran treatment group, the milnacipran is administered following the inducement of the stress-induced hyperalgesia. Allodynia and thermal hyperalgesia are respectively measured with Von Frey filaments and tail- or paw-flick with a radiant heat source. The allodynia and thermal hyperalgesia measurements are performed at the following time points�prior to both the inducement of stress-induced hyperalgesia and the administration of the milnacipran, prior to the inducement of stress-induced hyperalgesia but following the administration of the milnacipran, following the inducement of stress-induced hyperalgesia but prior to administration of the milnacipran, following both the inducement of stress-induced hyperalgesia and the administration of the milnacipran. The allodynia and thermal hyperalgesia measurements provide information on whether pretreatment or treatment with milnacipran will be effective in the treatment of stress-induced thermal and mechanical hyperalgesia.
5.3 Example 3 Assessment of the Efficacy of Milnacipran in FMS Patients Approximately 40 subjects are studied for a total of 6 weeks, after being weaned from their previous analgesic or antidepressant medications.
The inclusion criteria for this study is as follows:
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:
As indicated above, global patient (Pt) and physician (MD) assessments are taken at the beginning and end of the trial. In addition, a total of 4 sets of pain and sleep measures are also performed at 2-week intervals. The pain measure consists of the patient's recall of overall pain over the previous 2-week period as indicated by a 110 cm visual analog scale. The sleep instrument consists of 4 questions taken from the Jenkin's sleep questionnaire. It is expected that milnacipran will produce an improvement in a majority of the patients.
5.4 Example 4 Assessment of the Efficacy of Milnacipran in Patients with Painful Diabetic Neuropathy 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.
Milnacipran is compared to placebo in a randomized, double-blind, two-period, crossover study. After discontinuing other medication for pain for two weeks, patients enter a one-week baseline period, followed by two six-week drug treatment periods, separated and concluded by a one-week washout period. The treatments, given in random order, are milnacipran titrated up to maximum-tolerated dose or placebo. A nurse calls the patients every three days to titrate medication dosage and to assess pain, side effects, and study compliance. During the first four weeks of each period (titration phase) the medication is increased by 25 mg/day every three days unless the patient reports complete pain relief, side effects that interfere with daily activities, or unless the maximum dose of 200 mg daily is reached. During weeks 5 and 6 (maintenance phase), the highest well-tolerated dose is maintained at a constant level.
Prior to randomization, a general physical exam and laboratory tests (complete blood count, liver function tests, blood glucose, hemoglobin A1c, blood urea nitrogen, creatinine, electrolytes and urinalysis) is obtained. Diabetics are examined to assure they had adequate blood sugar control before and during the trial. They are instructed to perform daily blood sugar monitoring using a fingerstick and a home glucometer. In addition, a neurologic examination is performed at baseline to identify any area of increased pain to pinprick (hyperalgesia), decreased sensation to pinprick, or pain with stimulation by cotton gauze (allodynia); these studies are conducted every 2 weeks during the trial. In addition, patients record their pain intensity in a diary 3 times daily using the Gracely scale. It is expected that milnacipran will produce an improvement in the majority of patients, as measured by both physician neurological exam and patient diary.
Citations de brevets Brevet cit� Date de d�p�t Date de publication D�posant TitreUS447883622 juin 198223 oct. 1984Pierre Fabre S.A.1-Aryl 2-aminomethyl cyclopropane carboxyamide (Z) derivatives and their use as useful drugs in the treatment of disturbances of the central nervous systemUS47088341 mai 198624 nov. 1987Pharmacaps, Inc.Preparation of gelatin-encapsulated controlled release compositionUS471038428 juil. 19861 d�c. 1987Rotman; AvnerSustained release tablets made from microcapsulesUS473428528 oct. 198529 mars 1988The Dow Chemical CompanySustained release compositionsUS474019815 f�vr. 198526 avr. 1988Alza CorporationMethod of administering intravenous drug using rate-controlled dosage formUS475691116 avr. 198612 juil. 1988E. R. Squibb & Sons, Inc.Controlled release formulationUS476150122 mai 19852 ao�t 1988American Home Products CorporationSubstituted phenylacetamidesUS47755354 avr. 19864 oct. 1988Lowey; HansMethod of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristicsUS478191914 nov. 19871 nov. 1988Schering CorporationSustained release dosage formUS478485822 ao�t 198615 nov. 1988Zyma SaControlled release tabletUS479244811 juin 198720 d�c. 1988Pfizer Inc.Generic zero order controlled drug delivery systemUS479532726 mars 19843 janv. 1989Forest Laboratories, Inc.Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactantsUS479564217 ao�t 19873 janv. 1989Pharmacaps, Inc.Gelatin-encapsulated controlled-release compositionUS479564525 nov. 19863 janv. 1989Yissum Research And DevelopmentSustained release tablets of theophyllineUS479872516 juin 198617 janv. 1989Norwich Eaton Pharmaceuticals, Inc.Sustained release capsuleUS480008320 oct. 198624 janv. 1989R. P. Scherer CorporationSustained release method and productUS48030764 sept. 19867 f�vr. 1989Pfizer Inc.Controlled release device for an active substanceUS480307920 d�c. 19857 f�vr. 1989Syntex (U.S.A.) Inc.Controlled release naproxen and naproxen sodium tabletsUS480635922 avr. 198721 f�vr. 1989Mcneilab, Inc.Iburprofen sustained release matrix and processUS481626228 ao�t 198628 mars 1989Universite De MontrealControlled release tabletUS482052227 juil. 198711 avr. 1989Mcneilab, Inc.Oral sustained release acetaminophen formulation and processUS482261918 f�vr. 198718 avr. 1989Ionor, Inc.Controlled release pharmaceutical preparation containing a gastrointestinal irritant drugUS48246785 sept. 198525 avr. 1989Aktiebolaget LeoControlled-release medical preparationsUS483295725 juil. 198823 mai 1989Merck & Co., Inc.Controlled release combination of carbidopa/levodopaUS48370324 f�vr. 19866 juin 1989Farval AgTheophylline sustained release tabletUS48391779 d�c. 198613 juin 1989Jagotec AgSystem for the controlled-rate release of active substancesUS484286614 d�c. 198727 juin 1989Abbott Laboratories Ltd.Slow release solid preparationUS48492295 janv. 198818 juil. 1989Forest Laboratories, Inc.Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactantsUS486159025 sept. 198629 ao�t 1989Colgate-Palmolive CompanySustained release fluoride and calcium compositionUS486374319 f�vr. 19865 sept. 1989Key Pharmaceuticals, Inc.Controlled release potassium chlorideUS487154817 avr. 19873 oct. 1989Alza CorporationControlled release dosage form comprising different cellulose ethersUS488216724 nov. 198721 nov. 1989Jang; Choong-GookDry direct compression compositions for controlled release dosage formsUS48912334 oct. 19882 janv. 1990The Procter & Gamble CompanyFlakes of baking shortening or lardUS489274218 nov. 19859 janv. 1990Hoffmann-La Roche Inc.Controlled release compositions with zero order releaseUS495638812 janv. 199011 sept. 1990Eli Lilly And Company3-aryloxy-3-substituted propanaminesUS503454127 d�c. 198923 juil. 1991Pierre Fabre MedicamentMethod of preparing 1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl-cyclopropane-zUS53975744 oct. 199314 mars 1995Andrx Pharmaceuticals, Inc.Controlled release potassium dosage formUS53993594 mars 199421 mars 1995Edward Mendell Co., Inc.Controlled release oxybutynin formulationsUS539936225 avr. 199421 mars 1995Edward Mendell Co., Inc.Once-a-day metoprolol oral dosage formUS541991714 f�vr. 199430 mai 1995Andrx Pharmaceuticals, Inc.Controlled release hydrogel formulationUS542212321 sept. 19936 juin 1995Jagotec AgTablets with controlled-rate release of active substancesUS54569219 f�vr. 199410 oct. 1995Labopharm, Inc.Use of cross-linked amylose as a matrix for the slow release of biologically active compoundsUS545800515 juil. 199317 oct. 1995Abbk-Flow Inc.Fluid mass flow metersUS54588872 mars 199417 oct. 1995Andrx Pharmaceuticals, Inc.Controlled release tablet formulationUS54588882 mars 199417 oct. 1995Andrx Pharmaceuticals, Inc.Controlled release tablet formulationUS546463324 mai 19947 nov. 1995Jagotec AgPharmaceutical tablets releasing the active substance after a definite period of timeUS54727082 nov. 19935 d�c. 1995Andrx Pharmaceuticals Inc.Pulsatile particles drug delivery systemUS551229722 mai 199530 avr. 1996Edward Mendell Co., Inc.Sustained release heterodisperse hydrogel systems for insoluble drugsUS553224417 mai 19952 juil. 1996Eli Lilly And CompanyPotentiation of drug responseUS553225017 mai 19952 juil. 1996Eli Lilly And CompanyPotentiation of drug responseUS553226817 mai 19952 juil. 1996Eli Lilly And CompanyPotentiation of drug responseUS560395616 juin 199418 f�vr. 1997Labopharm Inc.Cross-linked enzymatically controlled drug releaseUS562114222 f�vr. 199515 avr. 1997Asahi Kasei Kogyo Kabushiki KaishaAminoalkylcyclopropane derivativesUS56589551 nov. 199519 ao�t 1997Hitzig; PietrCombined use of dopamine and serotonin agonists in the treatment of immune disordersUS57258837 juin 199510 mars 1998Edward Mendell Co., Inc.Pharmaceutical excipient having improved compressibilityUS574447420 avr. 199528 avr. 1998Eli Lilly And CompanyTreatment of incontinenceUS577302518 avr. 199630 juin 1998Edward Mendell Co., Inc.Sustained release heterodisperse hydrogel systems--amorphous drugsUS577696927 f�vr. 19977 juil. 1998Eli Lilly And CompanyTreatment of sleep disordersUS57927966 juin 199511 ao�t 1998Warner-Lambert CompanyMethods for treating anxiety and panicUS582463822 mai 199520 oct. 1998Shire Laboratories, Inc.Oral insulin deliveryUS58340239 juil. 199610 nov. 1998Andrx Pharmaceuticals, Inc.Diltiazem controlled release formulationUS583737931 janv. 199717 nov. 1998Andrx Pharmaceuticals, Inc.Once daily pharmaceutical tablet having a unitary coreUS588561618 ao�t 199723 mars 1999Impax Pharmaceuticals, Inc.Sustained release drug delivery system suitable for oral administrationUS589787620 juin 199727 avr. 1999Shire Laboratories Inc.Emulsified drug delivery systemUS591201321 avr. 199515 juin 1999Shire Laboratories, Inc.Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepineUS591225622 mai 199715 juin 1999Eli Lilly And CompanyCompounds having effects on serotonin-related systemsUS591659512 d�c. 199729 juin 1999Andrx Pharmaceutials, Inc.HMG co-reductase inhibitorUS59425494 mars 199724 ao�t 1999Knoll Pharmaceutical CompanyImproving glucose toleranceUS594541624 mars 199731 ao�t 1999Eli Lilly And CompanyMethod for treating painUS595200417 mars 199514 sept. 1999Shire Laboratories Inc.Emulsified drug delivery systemsUS600458229 mai 199821 d�c. 1999Laboratorios Phoenix U.S.A, Inc.Multi-layered osmotic deviceUS602807017 sept. 199822 f�vr. 2000Eli Lilly And CompanyTreatment of oppositional defiant disorderUS60666439 oct. 199823 mai 2000Eli Lilly And CompanyPotentiation of pharmaceuticalsUS607754118 juin 199920 juin 2000Andrx Pharmaceuticals, Inc.Omeprazole formulationUS609634014 nov. 19971 ao�t 2000Andrx Pharmaceuticals, Inc.Omeprazole formulationUS609985920 mars 19988 ao�t 2000Andrx Pharmaceuticals, Inc.Controlled release oral tablet having a unitary coreUS609986231 ao�t 19988 ao�t 2000Andrx CorporationOral dosage form for the controlled release of a biguanide and sulfonylureaUS610326317 nov. 199415 ao�t 2000Andrx Pharmaceuticals, Inc.Delayed pulse release hydrogel matrix tabletUS610686213 ao�t 199822 ao�t 2000Andrx CorporationOnce daily analgesic tabletUS611049822 oct. 199729 ao�t 2000Shire Laboratories, Inc.Osmotic drug delivery systemUS618422217 sept. 19986 f�vr. 2001Eli Lilly And CompanyTreatment of conduct disorderUS63802001 d�c. 200030 avr. 2002Pfizer, Inc.Combination of aldose reductase inhibitors and selective serotonin reuptake inhibitors for the treatment of diabetic complicationsUS639578811 ao�t 200028 mai 2002Vela Pharmaceuticals, Inc.Methods and compositions for treating or preventing sleep disturbances and associated illnesses using very low doses of cyclobenzaprineUS64329895 juin 200013 ao�t 2002Pfizer IncUse of CRF antagonists to treat circadian rhythm disordersUS644103812 oct. 200027 ao�t 2002Laxdale LimitedTreatment of fatigue, head injury and strokeUS645178827 ao�t 199717 sept. 2002The Wwk Trust Of 225-235 High StreetTreatment of painUS648934130 mai 20003 d�c. 2002Sepracor Inc.Methods for the treatment of neuroleptic and related disorders using sertindole derivativesUS650085311 oct. 200031 d�c. 2002Genetics Institute, LlcInhibitors of phospholipase enzymesUS659690016 avr. 200222 juil. 2003Pfizer IncFused bicyclic or tricyclic amino acidsUS660291119 d�c. 20015 ao�t 2003Cypress Bioscience, Inc.Methods of treating fibromyalgiaUS66356755 nov. 200121 oct. 2003Cypress Bioscience, Inc.Method of treating chronic fatigue syndromeUS696496228 d�c. 200115 nov. 2005Pharmacia & Upjohn CompanyCombinations of reboxetine and neuroleptic agentsUS699211018 juil. 200331 janv. 2006Cypress Bioscience, Inc.Methods of treating fibromyalgia syndrome, chronic fatigue syndrome and painUS70054523 juin 200328 f�vr. 2006Pierre Fabre MedicamentUse of the dextrogyral enantiomer of milnacipran for the preparation of a drugUS2001003694318 d�c. 20001 nov. 2001Pfizer Products Inc.Pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migrainesUS2002000696329 janv. 200117 janv. 2002SepracorMethod of using and compositions comprising (-) sibutramine optionally in combination with other pharmacologically active compoundsUS2002001021623 f�vr. 200124 janv. 2002Rogosky KarenNew drug combinationsUS200200868644 janv. 20024 juil. 2002Pharmacia & Upjohn CompanyMethod of treating or preventing fibromyalgia and other somatoform disordersUS200200949865 d�c. 200118 juil. 2002Pfizer IncCombination treatment for depression, anxiety and psychosisUS200201471963 avr. 200210 oct. 2002Glaxo Group LimitedComposition and method for treating neuropathic painUS2002015606728 d�c. 200124 oct. 2002Wong Erik Ho FongNew drug combinationsUS200201879587 ao�t 200212 d�c. 2002Amarin Neuroscience LimitedTreatment of painUS2003001368915 ao�t 200216 janv. 2003Helton David ReedMethod for treating painCitations hors brevetsR�f�rence1Aaron et al., "A review of the evidence for overlap among unexplained clinical conditions", Ann. Intern. Med. , vol. 134, No. 9.2, (2001), pp. 868-881.2Aaron et al., "Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder," Arch. Intern. Med., 160: 221-227 (2000).3Advisory Action dated Dec. 24, 2008, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.4Advisory Action dated May 12, 2008, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.5Alagiri et al., "Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes," Urology, 49(Suppl. 5A): 52-57 (1997).6Amendment Accompanying Request for Continued Examination dated May 24, 2007, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.7Amendment and Response dated Apr. 6, 2009, in U.S. Appl. No. 11/835,620, filed Aug. 8, 2007.8Amendment and Response dated Mar. 18, 2009, in U.S. Appl. No. 11/835,590, filed Aug. 8, 2007.9Amendment and Response to Office Action dated Jun. 17, 2009, in U.S. Appl. No. 11/752,213, filed May 22, 2007.10Amendment dated May 7, 2004, in European Application No. 02793880.2.11Anderberg et al., "Citalopram in patients with fibromyalgia-a randomized, double-blind, placebo-controlled study," Eur. J. Pain, 4: 27-35 (2000).12Anderberg et al., "Citalopram in patients with fibromyalgia�a randomized, double-blind, placebo-controlled study," Eur. J. Pain, 4: 27-35 (2000).13Ansari, "The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature," Harv. Rev. Psychiatry, 7: 257-277 (2000).14Applicant Statement of Interview Summary dated May 7, 2009, in U.S. Appl. No. 11/752,213, filed May 22, 2007.15Ardid, et al., "Antidepressants and pain," La Lettre De Parmacologue, 13:8, Oct. 1993, 191-195.16Atkinson et al., "Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intesnity," Pain, 83:137-145 (1999).17Barkin, "The management challenges of chronic pain: the roll of antidepressants," Am. J. Ther., 7: 31-47 (2000).18Bel et al., 1999, Nerophychopharmacology 21 (6):745-754.19Bennett et al., 1988 Pain 33:87-107.20Bennett, "Pharmacological treatment of fibromyalgia," J. Functional Syndromes, 1: 79-92 (2001).21Boissevain et al., "Toward an integrated understanding of fibromyalgia syndrome. I. Medical and pathophysiological aspects", Pain, vol. 45, No. 3, (1991), pp. 227-238.22Briley M., "Milnacipran, A Double Noradrenaline and Serotonin Reuptake Inhibiting Antidepressant," European Neuropsychopharmacology, vol. 6, Supplement 4, p. S4 (Sep. 1996).23Briley, "New hope in the treatment of painful symptoms in depression," Curr. Opin. Invest. Drugs (2003) 4(1): 42-45. Abstract.24Buskila, "Drug therapy," Baillieres Best Pract. Res. Clin. Rheumatol., 13: 479-485 (1999).25Caccia, "Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetics implications," Clin. Pharmacokinet., 34: 281-302 (1998).26Carette et al., "Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial," Arthritis Rheum., 37: 32-40 (1994).27Clauw et al., "Chronic Pain and Fatigue Syndromes: Overlapping Clinical and Neuroendocrind Features and Potential Pathogenic Mechanisms," Neuroimmunomodulation, 4: 134-153 (1997).28Clauw, "The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia," Med. Hypotheses, 44: 369-378 (1995).29Communication pursuant to Article 94(3) EPC dated Dec. 17, 2007, in European Application No. 02793880.2.30Communication pursuant to Article 96(2) EPC dated Jun. 1, 2005, in European Application No. 02793880.2.31Communication pursuant to Article 96(2) EPC dated Oct. 25, 2006, in European Application No. 03748971.3.32Cypress Bioscience, Inc., Investor Fact Sheet, Aug. 2001.33Decosterd et al., 2000, Pain 87:149-158.34Deprez, et al., "Which bioequivalence study for a racemic drug? Application to milnacipran," Eur. J. Drug Metab. Pharmacokinet. 23(2): 166-171(1998).35Doyle & Hu, "A new enantioselective synthesis of milnacipran and an analogue by catalytic asymmetirc cyclopropanation," Adv. Synth. Catal. 343(3):299-302 (2001).36Drug Legend, "Toledomin Tablets 15, Toledomin Tablets 25", 5th Edition, Jan. 2002.37Drugu AN 1983-01770, Woerz zum Thema R, Muench.Med.Wochenschr. 124(40) 855-56, 1982, abstract.38Drugu AN 1992-39596, Monreau, G et al, Fundam.Clin.Pharmacol. 6(4-5) 226, 1992, abstract.39Dryson E., Venlafaxine and fibromyalgia, NZ Med J., Mar. 10, 2000, 87, 1134(1105): 87(2000).40Dwight, et al., "An open clinical trial of venafaxine treatment of fibromyalgia," Psychosomatics 39: 14-17 (1998).41Dworkin et al., "Clinical aspects of depression in chronic pain patients," Clin. J. Pain, 7: 79-94 (1991).42Eisen, "Venlafaxine therapy for vulvodynia," The Pain Clinic, 8: 365-367 (1995).43Emase AN 1998 129084, Prescrire Enternational, 1998, 7/34, 51-53, abstract.44Emase AN 90228858, Macher J et al Neuropsychobiology, 1989, 22/2,77-82, abstract.45Examiner's first report dated Mar. 5, 2008 in Australian Application No. 2003284005.46Farthing, "Irritable bowel syndrome: new pharmaceutical approaches to treatment," Baillieres Best Pract. Res. Clin. Gastroenterol., 13: 461-471 (1999).47Farthing, New Drugs in the Management of the Irritable Bowel Syndrome, Drugs, vol. 56, pp. 11-21, 1998.48Fennerty, Traditional Therapies for Irritable Bowel Syndrome: An Evidence-Based Appraisal, Rev. Gastroenterol. Disord., vol. 3, Suppl. 2, pp. 18-24, 2003.49Final Office Action dated Apr. 17, 2009, in U.S. Appl. No. 11/752,213, filed May 22, 2007.50Final Office Action dated Feb. 25, 2008, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.51Final Office Action dated Jun. 4, 2009, in U.S. Appl. No. 11/835,590, filed Aug. 8, 2007.52Final Office Action dated Mar. 4, 2009, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.53Final Office Action dated Nov. 29, 2006, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.54Final Office Action dated Sep. 5, 2008, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.55First Examination Report for Indian Application No. 496/DELNP/2005, dated Jun. 15, 2006.56Fishbain, "Evidence-based data on pain relief with antidepressants," Ann. Med., 32: 305-316 (2000).57Fuller, Clinical Applications of 5-HT Uptake Inhibitors, Advances in the Biosciences, vol. 85, pp. 255-270, 1992.58Gendreau et al., "Efficacy of Milnacipran in Patients with Fibromyalgia," The Journal of Rheumatology, vol. 32, No. 10 (2005), pp. 1975-1984.59Giamberardino, "Recent and forgotten aspects of visceral pain," Eur. J. Pain, 3: 7-92 (1999).60Goldenberg et al., "A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia," Arthritis Rheum., 29: 1371-1377 (1986).61Goldenberg et al., "A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia," Arthritis Rheum., 39: 1852-1859 (1996).62Goodnick, et al., "Psychotropic treatment of chronic fatigue syndrome and related disorders," J. Clin. Psychiarty 13-20 (1993).63Gruber et al., "The management of treatment-resistant depression in disorders on the interface of psychiatry and medicine," The Psychiatric Clinics of North America, 19: 351-369 (1996).64Hannonen et al., "A randomized, double-blind, placebo-controlled study of miclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder," Br. J. Rheumatol., 37: 1279-1286 (1998).65Higuchi et al., "Handling Milnacipran, Chapter 1, Pharmacokinetic Features, Appropriate Dosage Amount, and Adminstration Period of Milnacipran," Japanese Journal of Clinical Psychopharmacology, 5:903-909 (2002).66Interview Summary dated Jan. 10, 2008, in U.S. Appl. No. 11/752,213, filed May 22, 2007.67Jain, "Addressing both the emotional and physical symptoms in depression," Medscape CME program (2003).68Jasmin et al., 1998, Pain 75:367-382.69Jung et al., "The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain," J. Gen. Intern. Med., 12: 384-389 (1997).70Kasper et al., "A placebo-controlled study of pregabalin and venlafaxine treatment of GAD", European neuropsychopharmacology, vol. 12, Suppl. 3, (Oct. 2002), pp. S341-S342.71Kim et al., 1992, Pain 50:355-363.72Kranzler et al., "The psychopharmacology of fibromyalgia: a drug development perspective," Psychopharmacol Bull., 36: 165-213 (2002).73Lautenschlager, "Present state of medication therapy in fibromyalgia syndrome," Scand. J. Rheumatol. Suppl., 113: 32-36 (2000).74Lecrubier, Milnacipran: The Clinical Properties of a Selective Serotonin and Noradrenaline Reuptake Inhibitor (SNRI), Human Psychopharmacol. Clin., vol. 12, pp. S127-S134, 1997.75Leventhal, "Management of fibromyalgia," Ann. Intern. Med., 131: 850-858 (1999).76Martindale, Antidepressants, Pharmaceutical Press, London, 32nd ed., pp. 271, 284, 298, 1485 (1999).77Max et al., "Effects of disipramine, amitriptyline, and fluoxetine on pain diabetic neuropathy," N. Engl. J. Med., 326: 1250-1256 (1992).78Medline AN 2001240387, Enggaard et al, Clin pharmacol therapeutics, Apr. 2001, 69(4) 245-54, abstract.79Medline AN 2001337451, Barken et al, Am J Therapeutics, Jan. 2000, 7(1) 31-47, abstract.80Medline AN 97229930, Lewis et al, Am J health-system pharmacy, Mar. 15, 1997, 54(6) 643-52, abstract.81Medline AN 97363915, Aronson, Clin therapeutics, May-Jun. 1997, 19(3) 420-32, abstract.82Medline Embase 1998129084 1998. Milnacipran: New Preparation.83Medline, et al., "Treatment of chronic fatigue syndrome with sibutramine . . . "PCTInt'l Appl. 14 (Sep. 28, 2000).84Mertz, Irritable Bowel Syndrome, N. Engl. J. Med., vol. 349(22), pp. 2136-2146, 2003.85Montgomery, "Venlafaxine: a new dimension in antidepressant pharmacotherapy," J. Clin. Psychiatry, 54: 119-126 (1993).86Moret et al., "Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT", Neuropharmacology, vol. 27, No. 1, (1988), pp. 43-49.87Moret et al., 1985, Neuropharmacology 24 (12):1211-1219.88Moret et al., 1985, Neuropharmacology 24(12):1211-1219.89Moret et al., 1997, J. Neurochem. 69(2):815-822.90Murasaki et al., "Clinical Effect of Milnacipran Hydrochloride (TN-912) in Depression and Depressive States, a New Antidepressant-Dose Finding Study," Journal of Clinical Therapeutics & Medicine, 11:85-101 (1995).91Murasaki et al., "Clinical Evaluation of Milnacipran Hydrochloride (TN-912) in Depression and Depressive States, a New Antidepressant," Journal of Clinical Therapeutics & Medicine, 11:71-83 (1995).92Murasaki et al., "Clinical Effect of Milnacipran Hydrochloride (TN-912) in Depression and Depressive States, a New Antidepressant�Dose Finding Study," Journal of Clinical Therapeutics & Medicine, 11:85-101 (1995).93Nagaoka, et al., "Beneficial Effects of a Serotonin-Noradrenaline Reuptake Inhibitor of Fibromyalgia Syndrome: A Case Report," Medicine and Drug Journal, 37:10, Oct. 1, 2001, 238-240.94Nicolodi et al., "Fibromyalgia and headache. Failure of serotonergic analgesia and N-methyl-d-aspartate-mediated neuronal plasticity: their common clues," Cephalalgia, Supp.21: 41-44 (1998).95Ninan, M.D., Philip T., Use of Venlafacine in Other Pyschiartic Disorders, Depression and Anziety 12(1) (2000) 90-94.96Noguchi et al., Open Channel Block of NMDA Receptors by Conformationally Recpetors Restricted Analogs of Milnacipran and Their Protective Effect Against NMDA-Induced Neurotoxicity, Synapse, 1999, 87-96, 31.97Norregaard et al., "A randomized controlled trial of citalopram in the treatment of fibromyalgia," Pain, 61: 445-449 (1995).98Novick et al., "A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation," Aliment Pharmacol. Ther., 16: 1877-1888 (2002).99Nutt et al., "Potential applications of veniafaxine," Rev. Contemp. Pharmacother. 9:321-331 (1998).100Office Action dated Apr. 17, 2006, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.101Office Action dated Aug. 12, 2008, in U.S. Appl. No. 11/752,213, filed May 22, 2007.102Office Action dated Aug. 19, 2005, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.103Office Action dated Aug. 22, 2008, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.104Office Action dated Aug. 27, 2007, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.105Office Action dated Feb. 20, 2007, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.106Office Action dated Mar. 17, 2009, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.107Office Action dated Mar. 18, 2005, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.108Office Action dated Oct. 7, 2008, in U.S. Appl. No. 11/835,620, filed Aug. 8, 2007.109Office Action dated Sep. 18, 2008, in U.S. Appl. No. 11/835,590, filed Aug. 8, 2007.110Office Action dated Sep. 27, 2007, in U.S. Appl. No. 11/752,213, filed May 22, 2007.111Office Action dated Sep. 28, 2007, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.112Office Action dated Sep. 29, 2004, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.113Okuda et al., "One case of Sub lumbar Melagra that Responds to Serotonin-Noradrenaline Reuptake Inhibitors and Milnacipran Hydrochloride," Pain Clinic, 23:1111-1112 (2002).114O'Malley, et al., Treatment of Fibromyalgia with Antidepressants, J. Gen. Intern. Med., vol. 15, pp. 659-666, 2000.115O'Malley, Patrick G., et al. Treatment of Fibromyalgia with Antidepressants. 2000. J. Gen. Intern. Med, 15:659-666.116Palmer et al., 1989, Eur J Clin Pharmacol 37:235-238.117Pande et al., "Three randomised, placebo-controlled, double-blind trials of pregabalin treatment of generalized anxiety disorder (GAD)," 10(Suppl. 3): 344 Abstract (2000).118Patel, et al., The Placebo Effect in Irritable Bowel Syndrome Trials: A Meta-Analysis, Neurogastroenterol. Motil., vol. 17, . pp. 332-340, 2005.119PCT/US02/40976 (WO 03/053426), International Preliminary Report on Patentability/Written Opinion dated Nov. 15, 2003.120PCT/US02/40976 (WO 03/053426), International Search Report dated May 2, 2003.121PCT/US03/031622 (WO 2004/030633), International Preliminary Report on Patentability/Written Opinion dated Jun. 3, 2004.122PCT/US03/031622 (WO 2004/030633), International Search Report dated Jun. 3, 2004.123PCT/US03/23088 (WO 2004/009069), International Preliminary Report on Patentability/Written Opinion dated May 3, 2005.124PCT/US03/23088 (WO 2004/009069), International Search Report dated Dec. 11, 2003.125PCT/US2006/037714 (WO 2007/038620), International Preliminary Report on Patentability/Written Opinion dated Apr. 1, 2008.126PCT/US2006/037714 (WO 2007/038620), International Search Report dated Aug. 23, 2007.127PCT/US2007/075549 (WO 2008/021932), International Preliminary Report on Patentability/Written Opinion dated Feb. 10, 2009.128PCT/US2007/075549 (WO 2008/021932), International Search Report dated Sep. 19, 2008.129PCT/US2007/075555 (WO 2008/019388), International Preliminary Report on Patentability/Written Opinion dated Feb. 10, 2009.130PCT/US2007/075555 (WO 2008/019388), International Search Report dated Sep. 12, 2008.131PCT/US2008/064471 (WO 2008/147843), International Preliminary Report on Patentability/Written Opinion dated Nov. 24, 2009.132PCT/US2008/064471 (WO 2008/147843), International Search Report dated Aug. 21, 2008.133Peghini et al., "Imipramine decreases oesophageal pain perception in human male volunteers," Gut, 42: 807-813 (1998).134Puech et al., "Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability," Int. J. Psychopharm., 12: 99-108 (1997).135Quijada-Carrera et al., "Comparison of tenoxicam and bromazepan in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial," Pain, 65: 221-225 (1996).136Quintero et al., 2000, Pharmacology, Biochemistry and Behavior 67:449-458.137Rao et al., "The neuropharmacology of centrally-acting analgesic medications in fibromyalgia," Rheum. Dis. Clin. N. Amer. 28: 235-259 (2002).138Rao et al., "Pharmacological therapies in fibromyalgia," Best Pract. Res. Clin. Rheumatol., 17: 611-627 (2003).139Reid et al., 2000, British Medical Journal 320:292-296.140Reimann et al., Interaction of the Central Analgesic, Tramadol, with the Uplake and Release of 5-hydroxytryptamine in the rat brain in vitro, Br J Pharmacol. Jan. 1992; 105(1):147-51.141Reimann, et al., Effects of the Central Analgesic Tramadol on the Uptake and Release of Noradrenaline and dopamine in vitro, Br J Pharmacol. Mar. 1993; 108(3):806-11.142Reneric et al., "Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test," Psychopharmacology, 136: 190-197 (1998).143Response dated Jan. 23, 2009, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.144Response to Final Office Action Under 37 C.F.R. 1.116 dated Apr. 15, 2008, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.145Response to Final Office Action Under 37 C.F.R. 1.116(b) dated Jan. 17, 2007, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.146Response to Final Office dated Nov. 5, 2008, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.147Response to Office Action and Applicant Statement of Interview Summary dated Jun. 17, 2009, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.148Response to Office Action dated Dec. 12, 2008, in U.S. Appl. No. 11/752,213, filed May 22, 2007.149Response to Office Action dated Dec. 14, 2007, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.150Response to Office Action dated Dec. 27, 2007, in U.S. Appl. No. 11/752,213, filed May 22, 2007.151Response to Office Action dated Dec. 29, 2004, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.152Response to Office Action dated Jul. 14, 2006, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.153Response to Office Action dated Jun. 10, 2005, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.154Response to Office Action dated Nov. 16, 2005, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.155Response to Office Action Under 37 C.F.R. 1.111 dated Jun. 7, 2007, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.156Response to Office Action Under 37 C.F.R. 1.111 dated Nov. 24, 2008, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.157Response to Office Action Under 37 C.F.R. 1.111 dated Nov. 27, 2007, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.158Response to Restriction Requirement dated Jun. 4, 2008, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.159Response to Restriction Requirement dated Mar. 4, 2008, in U.S. Appl. No. 11/752,213, filed May 22, 2007.160Response to Restriction Requirement dated Nov. 16, 2006, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.161Response with amended claims dated Jun. 17, 2008, in European Application No. 02793880.2.162Response with amended claims dated Nov. 24, 2005, in European Application No. 02793880.2.163Restriction Requirement dated Feb. 4, 2008, in U.S. Appl. No. 11/752,213, filed May 22, 2007.164Restriction Requirement dated May 16, 2008, in U.S. Appl. No. 10/623,431, filed Jul. 18, 2003.165Restriction Requirement dated Oct. 20, 2006, in U.S. Appl. No. 10/678,767, filed Oct. 3, 2003.166Ruoff, "Depression in the patient with chronic pain," J. Fam. Pract., 43 (Suppl.): S25-S33 (1996).167Sanchez et al., 1999, Cellular and Molecular Neurobiology 19(4):467-489.168Saper et al., "Nefazodone for chronic daily headache prophylaxis: an open-label study," Headache, 41: 465-474 (2001).169Seltzer et al., 1990, Pain 43:205-218.170Shuto et al., "Synthesis of (+)-and (-)-milnaciprans and their conformationally restricted analogs," Tetrahedron Lett. 37(5): 641-644 (1996).171Shuto et al., (+)-(Z)-2-(Aminomethyl)-1-phenycyclopropanecarboximide Derivatives as a New Prototype of NMDA Receptor Antagonists, J Med. Chem., 1995, 2964-2968, 38.172Shuto et al., (1s,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC), a New Class of NMDA-Receptor Antagonist: Molecular Design by a Novel Conformational Restriction Strategy, Jpn. J. Pharmacol., 2001, 207-213, 85.173Shuto et al., "Synthesis of (+)-and (−)-milnaciprans and their conformationally restricted analogs," Tetrahedron Lett. 37(5): 641-644 (1996).174Shuto et al., Synthesis and Biological Activity of Conformationally Restricted Analogs of Milnacipran: (1s,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, an Efficient Noncompetitive N-Methyl-D-aspartic Acid Receptor Antagonist, J. Med. Chem., 1996, 4844-4852,39.175Shuto et al., Synthesis and Biological Activity of Conformationally Restricted Analogs of Milnacipran: (1s,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, Is a Novel Class of NMDA Receptor Channel Blocker, J. Med. Chem., 1998, 3507-3514, 41.176Sindrup et al., "Efficacy of pharmacological treatment of neuropathic pain: an update and effect related to mechanism of drug action," Pain, 83: 389-400 (1999).177Spencer and Wild, 1998, supra.178Swaynok et al., "Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat," Pain, 82: 149-158 (1999).179Tatsumi et al., 1997, European Journal of Pharmacology 340:249-258.180Thema, "The drug induced alleviation of carcinoma pain," Much. Med. Wochenschr, 124:855-856 (1982), Abstract.181Turcotte et al., 2001, Neuropsychopharmacolgy 24(5):511-521.182U.S. Appl. No. 10/623,431, filed Jul. 18, 2003, by Jay D. Kranzler et al.; Final Office Action dated Oct. 28, 2009.183U.S. Appl. No. 10/678,767, filed Oct. 3, 2003, by Srinivas G. Rao et al.; Amendment accompanying request for continued examination dated Sep. 3, 2009.184U.S. Appl. No. 10/678,767, filed Oct. 3, 2003, by Srinivas G. Rao et al.; Non-Final Office Action dated Jan. 8, 2010.185U.S. Appl. No. 11/535,237, filed Sep. 26, 2006, by Srinivas G. Rao et al.; Non-Final Office Action dated Mar. 3, 2010.186U.S. Appl. No. 11/535,237, filed Sep. 26, 2006, by Srinivas G. Rao et al.; Restriction Requirement dated Oct. 23, 2009.187U.S. Appl. No. 11/752,213, filed May 22, 2007, by Jay D. Kranzler et al.; Non-Final Office Action dated Jun. 25, 2009.188U.S. Appl. No. 11/835,620, filed Aug. 8, 2007, by Srinivas G. Rao et al.; Final Office Action dated Jul. 2, 2009.189U.S. Appl. No. 12/125,302, filed May 22, 2008, by Srinivas G. Rao et al.; Non-Final Office Action dated Nov. 23, 2009.190Vaishnavi et al., "Milnacipran: A comparative analysis of human monoamine uptake and transporter binding affinity," Biol Psychiatry, 55: 320-322 (2004).191Viazzo et al., 1996, Tetrahedron Left. 37(26):4519-4522.192Vitton et al., "A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia," Hum Psychopharmacol Clin Exp, 19: S27-S35 (2004).193Wakamatsu, "Preclinical Review of Milnacipran-Part II: Clinical Review-," Jpn Pharmacology & Therapeutics, 30:141-155 (2002).194Ware et al., How to Score Version 2 of the SF-36 Health Survey (Standard & Acute Forms). 3rd ed. 2000, Lincoln, R1: Quality Metric.195Watson et al., "amitriptyline versus maprotline in postherpetic neuralgia: a randomized, double-blind, crossover trial," Pain, 48: 29-36 (1992).196Wesselman, "Interstitial cystitis: A chronic visceral pain syndrome," Urology, 57(Suppl. 64): 32-39 (2001).197Wessely et al., "Functional somatic syndromes: one or many?," Lancet, 354: 936-939 (1999).198Witter et al. 2003. Chronic pain and fibromyalgia: the regulatory perspective. Best Practice Res Clin Rheumatology 17(4):541-46.199Wolfe et al., "Health Status and Disease Severity in Fibromyalgia: Results of a Six-Center Longitudinal Study", Arthritis Rheum., vol. 40, No. 9, (1997), pp. 1571-1579.200Wolfe et al., "Preference of Nonsteroidal Antiinflammatory Drugs Over Acetaminophen by Rheumatic Disease Patients", Arthritis Rheumatism, vol. 43, No. 2, (2000), pp. 378-385.201Wolfe et al., "The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia", Arthritis Rheumatism, vol. 33, No. 2 (1990) pp. 160-172.202Wolfe et al., "The Prevalence of Characteristics of Fibromyalgia in General Population", Arthritis Rheumatism, vol. 38, No. 1 (1995) pp. 19-28.203Wolfe et al., "A double-blind placebo controlled trial of fluoxetine in fibromyalgia," Scand. J. Rheum., 23: 255-259 (1994).204Woolf et al., "Neuropathic pain: aetiology, symptoms, mechanisms, and management," Lancet, 353: 1959-1964 (1999).205Yoshimura et al., "The involvement of the tetrodotoxin-resistant sodium channel Nav1.8 (PN3/SNS) in a rat model of visceral pain", J. Neurosci., vol. 21, No. 21, (2001), pp. 8690-8696.206Yunus et al., "Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation," J. Rheumatol., 19: 846-850 (1992).207Zelter et al., 2000, Pain 89:19-24.Faire pivoterImage d'origineAccueil Google - Plan du site - T�l�chargements par lot sur l'USPTO - R�gles de confidentialit� - Conditions d'utilisation - � propos de Google�Brevets - Envoyer des commentairesDonn�es fournies par IFI CLAIMS Patent Services©2012 Google