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(12) Patent Application Publication (10) Pub. No.: US 2006/0003992 A1 Wong Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0003992 A1 Wong Et Al US 2006OOO3992A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0003992 A1 Wong et al. (43) Pub. Date: Jan. 5, 2006 (54) NEW DRUG COMBINATIONS (60) Provisional application No. 60/259,286, filed on Jan. 2, 2001. (75) Inventors: Erik Ho Fong Wong, Ann Arbor, MI (US); Christopher C. Gallen, Publication Classification Wynnewood, PA (US); Torgny Svensson, Lidingo (SE) (51) Int. Cl. A6IK 3I/551 (2006.01) A6IK 3.1/5415 (2006.01) Correspondence Address: A6IK 3I/519 (2006.01) WARNER-LAMBERT COMPANY A6IK 31/496 (2006.01) 2800 PLYMOUTH RD A6IK 3III.37 (2006.01) ANN ARBOR, MI 48105 (US) (52) U.S. Cl. .................... 514/220; 514/259.41; 514/649; 514/225.8 (73) Assignee: Pharmacia & Upjohn Company, LLC (57) ABSTRACT (21) Appl. No.: 11/219,901 A composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or (22) Filed: Sep. 6, 2005 a pharmaceutically effective Salt thereof, and (b) a pharma ceutically effective amount of one or more neuroleptic Related U.S. Application Data agents or a pharmaceutically effective Salt thereof is pro Vided. The composition is useful in treating disorders or (62) Division of application No. 10/035,100, filed on Dec. diseases of the central nervous System, and particularly 28, 2001, now Pat. No. 6,964,962. useful in treating Schizophrenia. US 2006/0003992 A1 Jan. 5, 2006 NEW DRUG COMBINATIONS rotransmitter back into the presynaptic neuron. Abnormality in noradrenergic transmission results in various types of CROSS-REFERENCE TO RELATED depression, mental, behavioral, and neurological disorders APPLICATION attributed to a variety of Symptoms including a lack of energy, motivation, and interest in life. See generally, R. J. 0001. This application claims the benefit of the following Baldessarini, “Drugs and the Treatment of Psychiatric Dis provisional application: U.S. Ser. No. 60/259,286, filed Jan. orders: Depression and Mania” in Goodman and Gilman's 2, 2001, under 35 USC 119(e)(i), which is incorporated The Pharmacological Basis of Therapeutics, McGraw-Hill, herein by reference in its entirety. NY, N.Y., pp.432-439 (1996). BACKGROUND OF THE INVENTION 0010 Examples of norepinephrine reuptake inhibitors (both selective and not selective) include, but are not limited 0002) 1. Field of the Invention to the following: tandamine (CAS 42408-80–0; U.S. Pat. No. 0003. This invention describes new treatments that 3,904,617; U.S. Pat. No. 4,118,394), pirandamine (CAS should provide for relief from several nervous system dis 42408-79-7; U.S. Pat. No. 3,995,052), ciclazindol (CAS orders with reduced side effects, and it involves the admin 37751-39-6; U.S. Pat. No. 3,891,644; U.S. Pat. No. 3,957, istration of a norepinephrine reuptake inhibitor, preferably a 819; US 3976645), fluparoxan (U.S. Pat. No. 4,880,801), Selective norepinephrine reuptake inhibitor Such as the drug lortalamine (CAS 70384-91-7; U.S. Pat. No. 4,201,783), reboxetine, in combination with a neuroleptic agent (typical talsupram (CAS 21489-20-3), talopram (CAS 7182-51-6), or atypical antipsychotic agents). In particular, the combi prindamine, nomifensine (U.S. Pat. No. 3,577,424), vilox nation is to be used to treat Schizophrenia. azine (U.S. Pat. No. 3,712.890), tomoxetine (U.S. Pat. No. 4,314,081), duloxetine (U.S. Pat. No. 5,023,269), venlafax 0004 2. Technology Description ine (U.S. Pat. No. 4,535,186), milnacipran (U.S. Pat. No. 0005 The introduction of tricyclic antidepressants in the 4,478,836) and reboxetine (U.S. Pat. No. 4,229,449). The early 1960s has provided a major advance in the treatment term schizophrenia was first used in 1911 by Eugen Bleuler, of neuropsychiatric disorders. Reactive and endogenous a Swiss psychiatrist, to diagnose patients whose thought depressions, diagnoses formerly carrying grave prognostic processes and emotional responses Seemed to be discon implications, have become, with the introduction of the nected. The term Schizophrenia literally means split mind tricyclics, manageable disorders with a much Smaller toll on and many people still believe incorrectly that the condition the patient and the society as a whole. causes a Split personality (actually an uncommon problem involving dissociation). Schizophrenia is now used to 0006 The early tricyclic compounds were reuptake describe a cluster of Symptoms that typically includes delu inhibitors of all the catecholamines released in the Synaptic Sions, hallucinations, disordered thinking, and emotional cleft, thus resulting in prolongation and enhancement of the unresponsiveness. No clear-cut definition of Schizophrenia dopamine (DA), noradrenaline (NA) and Serotonin (5-hy exists even at this time and no single cause has been found droxytryptamine=5-HT) action. Lack of selectivity also to explain all aspects of this devastating Syndrome. Most causes undesired Side effects particularly on the acetylcho likely, the Symptoms are triggered by a number of disease line (especially the muscarinic component), and histamine processes coupled with genetic factors and environmental mediated neurotransmission. StreSSeS. 0007 Because of these unwanted pharmacodynamic 0011 Chemical treatment for those suffering from activities, cognitive impairment, Sedation, urinary and gas Schizophrenia include the use of neuroleptic agents (Some trointestinal tract disturbances, and increased intraocular times referred to as antipsychotic agents) of either the preSSure were limiting factors in the clinical use of these typical or atypical type. compounds and often required discontinuation of treatment. Of utmost concern were also the cardiac toxic effects and the 0012 Typical neuroleptic agents are those that block proconvulsant activity of this group of drugs. receptors of the neurotransmitter dopamine. These medica tions are also referred to as neuroleptic drugs, because they 0008 More recently, selective reuptake inhibitors for can cause a number of neurologic side effects. The first drug serotonin (SSRI) have been introduced with definite advan of this type used for treating Schizophrenia was chlorprom tages in regard to fewer Side effects without loSS of efficacy. azine (Thorazine; U.S. Pat. No. 2645640). Many other Fluoxetine is an example of Such an inhibitor that has had a antipsychotic drugs are now available, the most popular great amount of commercial Success. being haloperidol (Haldol; U.S. Pat. No. 3,438,991). Others 0009. Another class of compounds that has been pro include perphenazine (Trilafon; U.S. Pat. No. 2,766,235), posed for use in the treatment of depression is Selective thioridazine (Mellaril; dosage of 30-800 mg/day), norepinephrine reuptake inhibitors. Lower-than-normal lev mesoridazine (Serentil; U.S. Pat. No. 3,084.161), trifluop els of norepinephrine are associated with a variety of Symp erazine (Stelazine; U.S. Pat. No. 2,921,069), and fluphena toms including lack of energy, motivation, and interest in zine (Prolixin; U.S. Pat. No. 3,058,979). For the very severe life. Thus, a normal level of norepinephrine is essential to active phase of Schizophrenia, injections of an antipsychotic maintaining drive and capacity for reward. These neu drug are often given every four to eight hours until the rotransmitters travel from the terminal of a neuron acroSS a patient is calm. If possible, however, physicians prefer Small gap (i.e., the Synaptic cleft) and bind to receptor administering a drug orally. These drugs may be high- or molecules on the Surface of a Second neuron. This binding low-potency. Generally, higher doses are used to treat acute elicits intracellular changes that initiate or activate a episodes (e.g., 5 to 10 mg of haloperidol) and lower doses response or change in the postsynaptic neuron. Inactivation are given during periods of remission (e.g., 2 to 5 mg). occurs primarily by transport (i.e., reuptake) of the neu However, new Studies Suggest starting haloperidol treatment US 2006/0003992 A1 Jan. 5, 2006 with daily doses in the 4 to 5 mg range for two to three and risperidone (U.S. Pat. No. 4,804,663) are currently the weeks. The beneficial impact of these drugs is greatest on Standard atypical drugs, but new medication that may be psychotic Symptoms, particularly hallucinations and delu even more effective are becoming available. Clozapine Sions in the early and midterm Stages of the disorder. In (Clozaril) is the best known of these drugs. Clozapine was patients who are being treated for the first time, improve found to benefit up to half of patients with schizophrenia ment in psychotic Symptoms may be evident within one or who did not respond to other types of treatments, and there two days of treatment, although the full benefit of the drug is now Substantial evidence of its Superiority over typical usually evolves over about Six to eight weeks. Thought drugs. It is particularly useful in younger people, although disturbances are reduced more gradually. Some estimates of toxic side effects are common. Positive effects may not be poor responses to these drugs are as high as 40%. Antipsy evident for up to nine months. Clozapine has improved chotic drugs are also not very Successful in reducing nega negative Symptoms in short-term trials, longer ones are tive Symptoms, although people often show leSS withdrawal needed to See if the benefit is Sustained. It may also reduce and apathy because of the reduction in psychotic episodes. aggressive behavior and Suicidal impulses. Although the The most disturbing common side effects of high-dose or drug does not appear to cause tardive dyskinesia, it does high-potency therapy of typical antipsychotic drugs are have other Side effects including nasal congestion, drooling, those known as extrapyramidal Symptoms, which effect the low blood preSSure, headache, SleepleSSneSS, and Significant nerves and muscles controlling movement and coordination. weight gain. Serious Side effects include Seizures and, in up The most Serious long term extrapyramidal effect of antip to 1% of cases, agranulocytosis-a potentially life-threat Sychotic therapy is tardive dyskinesia, a condition associated ening decrease in the patients white blood cells.
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