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(12) Patent Application Publication (10) Pub. No.: US 2004/0229941A1 Hassman Et Al

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US 2004O229941A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0229941A1 HaSSman et al. (43) Pub. Date: Nov. 18, 2004 (54) ANALEPTIC AND ANTIDEPRESSANT Related U.S. Application Data COMBINATIONS (60) Provisional application No. 60/469,989, filed on May (75) Inventors: Howard A. Hassman, Moorestown, NJ 13, 2003. (US); Rodney J. Hughes, Kennett Square, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ...................... A61K 31/343; A61K 31/137 CEPHALON, INC. (52) U.S. Cl. ........................... 514/469; 514/617; 514/649 145 BRANDY WINE PARKWAY WEST CHESTER, PA 19380-4245 (US) (57) ABSTRACT (73) Assignee: Cephalon, Inc., West Chester, PA (21) Appl. No.: 10/844,134 Compositions and methods for the treatment of depressive disorders through the administration of modafinil with anti (22) Filed: May 12, 2004 depressants. US 2004/0229941 A1 Nov. 18, 2004 ANALEPTIC AND ANTIDEPRESSANT nocturnal Sleep. Pathological Somnolence, whether due to COMBINATIONS narcolepsy or other causes, is disabling and potentially dangerous. Causes of pathological Somnolence, other than BACKGROUND OF THE INVENTION narcolepsy, include chronic Sleep loSS; Sleep apnea; and other sleep disorders. Whether due to narcolepsy or other 0001) 1. Modafinil causes, pathological Somnolence produces episodes of unin 0002 Modafinil, CHNOS, also known as 2-(benzhy tended sleep, reduced attention, and performance errors. drylsulfinyl) acetamide, or 2-(diphenylmethyl) sulfinyl Consequently, it is linked to a variety of transportation and acetamide, is a Synthetic acetamide derivative with wake industrial accidents. A therapeutic agent that reduces or promoting activity, the Structure of which has been described eliminateS pathological Somnolence would have important in French Patent No. 78 05 510 and in U.S. Pat. No. implications not only for individual patients, but also for 4,177.290 (290), and which has been approved by the public health and Safety. United States Food and Drug Administration for use in the 0007. Other uses of modafinil have been presented. U.S. treatment of excessive daytime Sleepiness associated with Pat. No. 5,180,745 discloses the use of modafinil for pro narcolepsy. A method of preparation of a racemic mixture is Viding a neuroprotective effect in humans, and in particular described in the 290 patent and a method of preparation of for the therapy of Parkinson's disease. The levorotatory a levorotatory isomer is described in U.S. Pat. No. 4,927,855 form of modafinil, i.e., (-) benzhydrylsulfinyl-acetamide, (both incorporated herein by reference). The levorotatory may have potential benefit for therapy of depression, hyper isomer is reported to be useful for treatment of hyperSomnia, somnia and Alzheimer's disease (U.S. Pat. No. 4,927,855). depression, Alzheimer's disease and to have activity towards European Published Application 547952 discloses the use of the Symptoms of dementia and loSS of memory, especially in modafinil as an anti-ischemic agent. European Published the elderly. Application 594507 discloses the use of modafinil to treat 0003. The primary pharmacological activity of modafinil urinary incontinence. is to promote wakefulness. Modafinil promotes wakefulneSS 0008 U.S. Pat. No. RE37,516 discloses pharmaceutical in rats (Touret et al., 1995; Edgar and Seidel, 1997), cats compositions having a defined particle size, and in particular (Lin et al., 1992), canines (Shelton et al., 1995) and non compositions wherein 95% of the cumulative total of the human primates (Hernant et al., 1991) as well as in models effective amount of modafinil particles in the composition mimicking clinical situations, Such as sleep apnea (English have a diameter less than about 200 microns. bulldog sleep disordered breathing model) (Panckeri et al., 1996) and narcolepsy (narcoleptic canine) (Shelton et al., 0009 2. Antidepressants 1995). 0010 Antidepressants, including selective serotonin 0004 Modafinil has also been described as an agent with reuptake inhibitors (SSRIs) have become first choice thera activity in the central nervous System, and as a useful agent peutics in the therapy of depression, certain forms of anxiety in the treatment of Parkinson's disease (U.S. Pat. No. and Social phobias. In Some instances, SSRIs can be more 5,180,745); in the protection of cerebral tissue from favored because they are effective, well tolerated and have ischemia (U.S. Pat. No. 5,391,576); in the treatment of a favorable Safety profile compared to the classic tricyclic urinary and fecal incontinence (U.S. Pat. No. 5,401.776); antidepressants. and in the treatment of Sleep apneas and disorders of central 0011. However, there can be problems associated with origin (U.S. Pat. No. 5,612,379). U.S. Pat. No. 5,618,845 any anti-depressant. Current antidepressant therapy can describes modafinil preparations of a defined particle size exhibit a delayed onset and modest proportion in achieving less than about 200 microns. In addition, modafinil may be response or remission. For example, the response at 6 weeks used in the treatment of eating disorders, or to promote to the selective serotonin reuptake inhibitor (SSRI) fluox weight gain or stimulate appetite in humans or animals (U.S. etine is about 50%. Remission rates with SSRIs at 8 weeks Pat. No. 6,455,588, incorporated herein by reference), or in are about 35%. Delayed, incomplete and lack of response of the treatment of attention deficit hyperactivity disorder a major depressive disorder to antidepressant therapy can be (ADHD) (U.S. Pat. No. 6,346,548, incorporated herein by problematic for numerous reasons, including premature reference), or fatigue, especially fatigue associated with treatment discontinuation. Sometimes Symptoms even multiple sclerosis (U.S. Pat. No. 6,488,164, incorporated worsen during the first weeks of therapy. In other cases, herein by reference). non-compliance can be related to Side effects, including 0005) Modafinil has been shown to be effective in treat Sexual dysfunction. ing narcolepsy, sleepiness, excessive sleepiness (e.g., sleepi 0012 Fatigue and excessive sleepiness are among the ness associated with disorders of Sleep and wakefulness), Symptoms of a major depressive disorder, and can be excessive daytime SleepineSS associated with narcolepsy, adverse experiences associated with antidepressant therapy Parkinson's disease, urinary incontinence, multiple Sclerosis and are often residual Symptoms inadequately treated with fatigue, ADHD, Alzheimer's disorder, Sleep apnea, obstruc SSRI antidepressant therapy. tive sleep apnea, depression, and ischemia. 0013 In addition, patients sometimes suffer side effects 0006 Narcolepsy is a chronic disorder characterized by asSociated with antidepressant therapy and withdrawal of intermittent Sleep attacks, persistent, excessive daytime antidepressant therapy. sleepiness and abnormal rapid eye movement (“REM”) Sleep manifestations, Such as sleep-onset REM periods, 0014. Because residual symptoms to antidepressant cataplexy, Sleep paralysis and hypnagogic hallucinations, or therapy predisposes patients with depression to a greater risk both. Most patients with narcolepsy also have disrupted of relapse and greater probability of recurrence, rapid US 2004/0229941 A1 Nov. 18, 2004 achievement of remission is an important consideration in tyline hydrochloride, iprindole, isocarboxazid; ketipramine choosing the most appropriate treatment Strategy. fumarate; lofepramine hydrochloride, lortalamine; mapro tiline; maprotiline hydrochloride; melitracen hydrochloride; 0.015 New therapies that address one or more of these millacemide hydrochloride; minaprine hydrochloride; mir problems are needed. tazapine; moclobemide; modaline Sulfate, napacitadine hydrochloride; napameZole hydrochloride; nefazodone SUMMARY OF THE INVENTION hydrochloride; nisoxetine, nitrafudam hydrochloride; 0016. In one embodiment, the present invention includes nomifensine maleate, nortriptyline hydrochloride; octrip a method of enhancing the activity of an antidepressant in an tyline phosphate, opipramol hydrochloride; Oxaprotiline animal Subject, preferably a human. The method includes hydrochloride; oxypertine, paroxetine; phenelZine Sulfate; the Step of pre-treating the Subject with an effective amount pirandamine hydrochloride, pizotyline; pridefine hydrochlo of one or more analeptics, including but not limited to ride, prolintane hydrochloride; protriptyline hydrochloride; modafinil and/or co-administering an effective amount of quipazine maleate, rolicyprine; Seproxetine hydrochloride; one or more analeptics, including but not limited to modafi Sertraline hydrochloride; Sibutramine hydrochloride; nil, with an antidepressant. Sulpiride, SuritoZole; tametraline hydrochloride; tampramine fumarate; tandamine hydrochloride; thiaZeSim hydrochlo DETAILED DESCRIPTION OF THE ride; thozalinone; tomoxetine hydrochloride; traZOdone INVENTION hydrochloride; trebenzomine hydrochloride; trimipramine; trimipramine maleate; Venlafaxine hydrochloride, Vilox 0.017. 1. Analeptic Agents azine hydrochloride, Zimeldine hydrochloride, Zometapine. 0.018 Analeptics are drugs that principally act as or are 0022. In certain embodiments, the antidepressant used as a central nervous System Stimulant. Preferred for use includes citalipram, fluoxetine, fluoxetine hydrochloride, in the practice of the invention are analeptics that operate on paroxetine, paroxetine hydrochloride, and/or clomipramine the sleep-wake centers of the brain and that lack the phar
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  • (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness Et Al

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    USOO6264,917B1 (12) United States Patent (10) Patent No.: US 6,264,917 B1 Klaveness et al. (45) Date of Patent: Jul. 24, 2001 (54) TARGETED ULTRASOUND CONTRAST 5,733,572 3/1998 Unger et al.. AGENTS 5,780,010 7/1998 Lanza et al. 5,846,517 12/1998 Unger .................................. 424/9.52 (75) Inventors: Jo Klaveness; Pál Rongved; Dagfinn 5,849,727 12/1998 Porter et al. ......................... 514/156 Lovhaug, all of Oslo (NO) 5,910,300 6/1999 Tournier et al. .................... 424/9.34 FOREIGN PATENT DOCUMENTS (73) Assignee: Nycomed Imaging AS, Oslo (NO) 2 145 SOS 4/1994 (CA). (*) Notice: Subject to any disclaimer, the term of this 19 626 530 1/1998 (DE). patent is extended or adjusted under 35 O 727 225 8/1996 (EP). U.S.C. 154(b) by 0 days. WO91/15244 10/1991 (WO). WO 93/20802 10/1993 (WO). WO 94/07539 4/1994 (WO). (21) Appl. No.: 08/958,993 WO 94/28873 12/1994 (WO). WO 94/28874 12/1994 (WO). (22) Filed: Oct. 28, 1997 WO95/03356 2/1995 (WO). WO95/03357 2/1995 (WO). Related U.S. Application Data WO95/07072 3/1995 (WO). (60) Provisional application No. 60/049.264, filed on Jun. 7, WO95/15118 6/1995 (WO). 1997, provisional application No. 60/049,265, filed on Jun. WO 96/39149 12/1996 (WO). 7, 1997, and provisional application No. 60/049.268, filed WO 96/40277 12/1996 (WO). on Jun. 7, 1997. WO 96/40285 12/1996 (WO). (30) Foreign Application Priority Data WO 96/41647 12/1996 (WO).