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(12) United States Patent (10) Patent No.: US 6,750,235 B1 Rosenbaum (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 6,750,235 B1 Rosenbaum (45) Date of Patent: Jun USOO675O235B1 (12) United States Patent (10) Patent No.: US 6,750,235 B1 ROSenbaum (45) Date of Patent: Jun. 15, 2004 (54) PRAMIPEXOLE ASATREATMENT FOR OTHER PUBLICATIONS COCAINE CRAVING Cain et al., “D3 receptor test in vitro predicts decreased (75) Inventor: Jerrold Rosenbaum, Newton, MA cocaine self-administration in rats' NeuroReport (US) 8:2373-2377, 1997.* Abstract of EP 417,637 A2, Kutter et al., Mar. 20, 1991.* (73) Assignee: The General Hospital Corporation, Bayuk et al., “The effects of pramipexole on cue induced Boston, MA (US) craving” 38" Annual Meeting of American College of Neu ropsychopharmacology, Abstract 51 (Dec. 1999). (*) Notice: Subject to any disclaimer, the term of this Buydens-Branchey et al. “Buspirone attenuates withdrawal patent is extended or adjusted under 35 symptoms in cocaine addicts” 38" Annual Meeting of U.S.C. 154(b) by 0 days. American College of NeuropSychopharmacology, Abstract (21) Appl. No.: 10/088,628 52 (Dec. 1999). Caine et al., “Dreceptor test in vitro predicts decreased (22) PCT Filed: Sep. 28, 2000 cocaine self-administration in rats' NeuroReport (86) PCT No.: PCT/US00/26634 8:2373-2377 (1997). Eiler et al., “Double-blind comparison of bromocriptine and S371 (c)(1), placebo in cocaine withdrawal' Am. J. Drug Alcohol Abuse (2), (4) Date: Jun. 12, 2002 21:65–79 (1995). (87) PCT Pub. No.: WO01/22820 Filip et al., “The role of dopamine receptor subtypes in the discriminative Stimulus effects of amphetamine and cocaine PCT Pub. Date:Apr 5, 2001 in rats' Pol. J. Pharamcol. 49:21-30 (1997). Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/156,860, filed on Sep. 30, 1999. Primary Examiner Dwayne C. Jones (51) Int. Cl." ....................... A61K 3.1425. A61K 31/53 (74) Attorney, Agent, or Firm—Clark & Elbing LLP (52) U.S. Cl. ........................ 514/367; 514/242; 514/241 (57) ABSTRACT (58) Field of Search ................................. 514/367,241, 514/242 Disclosed herein are methods foe reducing Stimulant depen dency or craving, involving administration of a (56) References Cited therapeutically-effective amount of a dopamine agonist, Such as pramipexole. U.S. PATENT DOCUMENTS 5,650,420 A 7/1997 Hall et al. .................. 514/367 9 Claims, 1 Drawing Sheet U.S. Patent Jun. 15, 2004 US 6,750,235 B1 FGURE US 6,750,235 B1 1 2 PRAMPEXOLE AS A TREATMENT FOR By “Stimulant' is meant any Substance that temporarily COCAINE CRAVING increases functional activity, and preferably cardiac, respiratory, cerebral, nervous, vascular, motor, or vasomotor This application claims the benefit of Provisional Appli functional activity. Preferred stimulants include, without cation No. 60/156,860 filed Sep. 30, 1999. 5 limitation, cocaine, amphetamines, methamphetamine, and methylphenidate. BACKGROUND OF THE INVENTION By “therapeutically-effective amount” is meant an This invention relates to methods for the treatment of amount of a pramipexole compound Sufficient to produce a cocaine craving. healing, curative, or ameliorative effect either in the treat Cocaine is a highly addictive pyschoStimulant that causes ment of a Stimulant dependency or in the Symptoms of a Sensations of euphoria and craving, resulting in physiologi Stimulant dependency, for example, cocaine craving. cal as well as psychological damage. Although cocaine use By “dependency” is meant any form of behavior that leads to a multitude of physiological complications, its indicates an altered or reduced ability to make decisions primary target of action is the central nervous System. resulting, at least in part, from the use of Stimulants. Rep Cocaine withdrawal following abstinence causes, among 15 resentative forms of dependency behavior may take the form other Symptoms, an intense craving for the abused drug, of antisocial, inappropriate, or illegal behavior and include which in turn frequently results in the relapse into renewed those behaviors directed at the desire, planning, acquiring, drug use. Epidemiological Studies point to a high incidence and use of Stimulants. This term also includes the psychic of multiple Substance abuse among cocaine users, a finding craving for a drug that may or may not be accompanied by that has significant Societal and medical repercussions. a physiological dependency, as well as a State in which there To date, approved pharmacotherapies for cocaine abuse is a compulsion to take a drug, either continuously or and dependence have proven Scarce despite the acute need periodically, in order to experience its psychic effects or to for Such therapies. avoid the discomfort of its absence. Forms of “dependency” include habituation, that is, an emotional or psychological SUMMARY OF THE INVENTION 25 dependence on a compound to obtain relief from tension and In general, the invention features methods for treating emotional discomfort, as well as physical or physiological Stimulant dependencies, Such as cocaine craving, by admin dependence, that is, use of a compound to prevent with istering a therapeutically-effective amount of a dopamine drawal Symptoms. agonist, for example, pramipexole. By "craving” is meant a behavior that reflects a consum In one aspect, the invention provides a method of treating ing desire, longing, or yearning for a Stimulant. This term a patient (for example, a human) with a stimulant depen may refer to aspects of behaviors that are components of a dency by administering a therapeutically-effective amount dependency. of pramipexole to the patient. In preferred embodiments of The present invention provides a number of advantages. this aspect, the Stimulant dependency is a Stimulant craving 35 Importantly, it provides one of the first therapeutics for the and the Stimulant is cocaine. treatment of Stimulant cravings (such as cocaine craving). In In a related aspect, the invention provides a method of addition, the pramipexole utilized herein is non-toxic, is treating a human diagnosed with cocaine craving by admin pharmocokinetically understood, and is known to be well istering a therapeutically-effective amount of pramipexole to tolerated by humans, as is evidenced by its approval for the the human. 40 treatment of Parkinson's Disease. In preferred embodiments of both of the above aspects of the invention, the method further includes administering a BRIEF DESCRIPTION OF THE DRAWINGS therapeutically-effective amount of an antidepressant or an FIG. 1 is a schematic illustration of the molecular struc anticonvulsant, for example, lamotrigine. ture of pramipexole, marketed as MirapeX in the United By “treating is meant the medical management of a 45 States. patient with the intent that a cure, amelioration, or preven tion of a dependency or a relapse or associated disease, DETAILED DESCRIPTION OF THE pathological condition, or disorder will result. This term INVENTION includes active treatment, that is, treatment directed Specifi cally toward improvement of the dependency or associated 50 The invention described herein features methods involv cure of a disease, pathological condition, or disorder, and ing the administration of pramipexole (or other dopamine also includes causal treatment, that is, treatment directed D3/D2 agonists) for the treatment of Stimulant dependency, toward removal of the cause of the dependency or associated and preferably for the treatment of cocaine craving and its disease, pathological condition, or disorder. In addition, this Symptoms, as well as cocaine dependency and associated term includes palliative treatment, that is, treatment 55 Self-destructive behaviors. designed for the relief of Symptoms rather than the curing of Described below is an example of the Successful use of the dependency, disease, pathological condition, or disorder; pramipexole for the treatment of cocaine craving and related preventive treatment, that is, treatment directed to preven Symptoms. This example is provided for the purpose of tion of the dependency or associated disease, pathological illustrating the invention, and should not be construed as condition, or disorder; and Supportive treatment, that is, 60 limiting. treatment employed to Supplement another Specific therapy Treatment of Cocaine Craving Using Pramipexole directed toward the improvement of the dependency or Mr. A, a 34 year-old single, Successful busineSS man, was asSociated disease, pathological condition, or disorder. The referred for evaluation of possible bipolar disorder. Cur term “treating” also includes Symptomatic treatment, that is, rently depressed, he had in the previous year brought finan treatment directed toward constitutional Symptoms of the 65 cial ruin on himself by a pattern of cocaine freebasing and dependency or an associated disease, pathological condition, Sexual and other extravagance that absorbed nearly one or disorder. million dollars. US 6,750,235 B1 3 4 Along with current major depression, persisting cocaine excipients, Sterile water, Saline, polyalkylene glycols Such as craving but rare use, and a question of past primary or polyethylene glycol, oils of vegetable origin, or hydroge Secondary (to Substance abuse) mania, he manifested an nated napthalenes. extraordinary movement disorder with constant restleSSneSS If desired, slow release or extended release delivery and thrashing of his legs, leaving the inner aspects of his Systems may be utilized. Biocompatible, biodegradable lac knees and thighs bruised and discolored with hematomas in tide polymer, lactide / gly collide copolymer, or various Stages of evolution and resolution. polyoxyethylene-polyoxypropylene
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