Title:  Inhibition of psychostimulant-induced and nicotine-induced craving

United States Patent:  6,517,812

Issued:  February 11, 2003

Inventors:  Breiter; Hans C. (Lincoln, MA); Rosen; Bruce R. (Lexington, MA); Marota; John J. A. (Boston, MA); Mandeville; Joseph B. (Somerville, MA); Kosofsky; Barry E. (Swampscott, MA)

Assignee:  The General Hospital Corporation (Boston, MA)

Appl. No.:  159659

Filed:  September 24, 1998

The invention provides methods for inhibiting psychostimulant-induced or nicotine-induced craving of additional psychostimulants (e.g., cocaine or amphetamine) or nicotine. In these methods, D1-like antagonists or D1-like agonists are administered to a patient dependent on psychostimulant drugs or nicotine and therefore susceptible to, or suffering from, such a craving. Also disclosed is an animal model system useful for measuring the ability of test compounds to inhibit pyschostimulant-induced or nicotine-induced cravings in humans.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods for inhibiting in a human a psychostimulant-induced or nicotine-induced craving for additional psychostimulants or nicotine. By inhibiting such a drug-induced craving, the binge-like behavior typically associated with the use of addictive drugs (e.g., cocaine, amphetamine, or nicotine) can be inhibited. Preferred candidates for treatment in accordance with the invention are patients who are psychostimulant-dependent or nicotine-dependent. Generally, the typical patient is susceptible to, or suffering from, a psychostimulant-induced or nicotine-induced craving; such patients can be identified simply on the basis of their having consumed a psychostimulant or nicotine in the 30 seconds to 120 minutes prior to administration of a D1-like agonist or antagonist to the patient. Typically, the patient is a compulsive user of a psychostimulant or of nicotine. In an alternative method, the pattern of brain activation in the patient (as determined, for example, by fMRI as described herein) indicates that the patient is suffering from a craving induced by a psychostimulant or nicotine (e.g., sustained signal maxima in the nucleus accumbens and negative signal changes in the amygdala).

Once a patient is identified as being psychostimulant-dependent or nicotine-dependent (and therefore susceptible to, or suffering from, a psychostimulant-induced or nicotine-induced craving), a D1-like antagonist or D1-like agonist is administered to the patient in an amount effective to inhibit the craving. Examples of suitable D1-like antagonists include, without limitation, SCH 39166; SCH 23390; SCH 23388; A-69024; bulbocapnine; butaclamol HCl, (+)-; fluphenzanine HCl; fluphenthixol 2 HCl, cis-(Z)-, fluspirilene; haloperidol; SCH-12679; SKF-83566; thioridazine HCl; thiothixine HCl; trifluoperazine 2HCl; and trifluorperidol HCl. Examples of suitable D1-like agonists include A-86929; 6-chloro-PB HBr, (.+-.)-(SKF 81297); SKF 38393; A-69024, N-allylnorapomorphine HBr, R(-)-; apomorphine HCl, R(-)-; 6-bromo-APB HBr, r(+)-; 6-Chloro-APB HBr,(.+-.)-(SKF-82958); Pergolide methanesulfonate, and SKF 77434. Other D1-like antagonists and D1-like agonists are known in the art and can be used in practicing the invention. Such agonists and antagonists, as well as additional suitable agonists and antagonists, are available from commercial suppliers such as Research Biochemicals International. Conventional methods can be used to identify additional D1-like antagonists and D1-like agonists, which also can be used in practicing the invention. If desired, the D1-like antagonists and agonists can be used in combination (e.g., at a ratio from 1:1 up to 10:1).

D1-like antagonists and D1-like agonists can be formulated for administration to the patient by any of a variety of known routes. For example, solid formulations of the D1-like antagonists or D1-like agonists for oral administration may contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid. Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid. Tablet binders that may be used include acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose. Lubricants that may be used include magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.

Liquid formulations of the D1-like antagonists or D1-like agonists for oral administration prepared in water or other aqueous vehicles may contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. The liquid formulations may also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), wetting agents, sweeteners, and coloring and flavoring agents. Various liquid and powder formulations can be prepared by conventional methods for inhalation by the patient.

Injectable formulations of the D1-like agonists and D1-like antagonists may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injections, water soluble versions of the compounds may be administered by the drip method, whereby a pharmaceutical formulation containing the D1-like agonist or D1-like antagonist and a physiologically acceptable excipient is infused into the patient. Physiologically acceptable excipients include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients. For intramuscular preparations, a sterile formulation of a suitable soluble salt form of the agonist or antagonist can be dissolved and administered in a pharmaceutical excipient, such as Water-for-Injection, 0.9% saline, or 5% glucose solution.

The optimal concentration of the D1-like antagonist or D1-like agonist in each pharmaceutical formulation varies according to the formulation itself. Typically, the pharmaceutical formulation contains the agonist or antagonist at a concentration of about 0.1 to 90% by weight (such as about 1-20% or 1-10%). Appropriate dosages of the D1-like antagonist or D1-like agonist can readily be determined by those of ordinary skill in the art of medicine by assessing inhibition of drug-induced craving in the patient, and increasing the dosage and/or frequency of treatment as desired. The optimal amount of the D1-like antagonist or agonist for inhibiting craving of a psychostimulant or nicotine may depend upon the mode of administration, the age and the body weight of the patient, and the condition of the patient. Typically, a D1-like antagonist is administered at a dosage of 0.001 to 100 mg/kg of body weight of the patient; e.g., the antagonist is administered at a dosage of 0.1 to 1.0 mg/kg. A D1-like agonist typically is administered at a dosage of 0.001 to 100 mg/kg of body weight of the patient, e.g., at a dosage of 0.1 to 1.0 mg/kg.

In a typical method of treatment, the patient is a compulsive user of a psychostimulant or nicotine. Treatment of an addiction to a psychostimulant or nicotine thus generally involves a regimen in which a D1-like antagonist or D1-like agonist is repeatedly administered to the patient. Typically, the D1-like antagonist or D1-like agonist is administered to the patient once every two days, once daily, or even more frequently to alleviate the drug dependency, and typically over a time span of about 1 to 12 months or even life-long if needed.

Claim 1 of 20 Claims

What is claimed is:

1. A method for inhibiting a cocaine-induced craving in a mammal, the method comprising:

identifying the mammal as being cocaine-dependent and

administering to the mammal SCH 23390 in an amount effective to inhibit craving of cocaine.
 

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