__________________________________________________________________________compound formula patent reference__________________________________________________________________________flupenthixol ## str13 ## u . s . pat . no . 3 , 192 , 204thiothixene (&# 34 ; navane &# 34 ;) ## str14 ## u . s . pat . no . 3 , 310 , 553desipramine ## str15 ## belgian patent 614616 and british patent 908788imipramine ## str16 ## u . s . pat . no . 2 , 554 , 736fluphenazine ## str17 ## u . k . patent 829 , 246 u . k . patent 833 , 473 u . s . pat . no . 3 , 194 , 733 u . s . pat . no . 3 , 058 , 979perazine ## str18 ## u . k . patent 780 , 193pimozide ## str19 ## french m3695 u . s . pat . no . 3 , 196 , 157fluspirilene ## str20 ## u . s . pat . no . 3 , 238 , 216haloperidol ## str21 ## u . s . pat . no . 3 , 438 , 991loxapine ## str22 ## u . s . pat . no . 3 , 546 , 226 u . s . pat . no . 3 , 412 , 193amoxapine ## str23 ## u . s . pat . no . 3 , 663 , 696pifluthixol (= 6 - fluoro - flupenthixol ) __________________________________________________________________________ also useful in the method of the present invention are the pharmaceutically active compounds disclosed and / or claimed , as well as pharmaceutically acceptable salts thereof and if applicable , pharmaceutically acceptable esters thereof , in the patent references listed hereinabove , the entire contents of such patent references are hereby incorporated by reference herein . the pharmaceutically active compounds of the present invention can exist as optical isomers and both racemic and diastereomeric mixtures of these isomers which may exist for certain compounds , as well as the individual optical isomers are all within the scope of the present invention . while the racemic mixtures can be separated into their individual isomers through well - known techniques such as , for example , the separation of diastereomeric salts formed with optically active adjuncts , e . g ., acids or bases followed by conversion back to the optically active substrates ; in most instances , for the compounds of the present invention , the preferred optical isomer can be synthesized by means of stereospecific reactions , beginning with the appropriate stereoisomer of the desired starting material . as indicated above , the present invention also pertains to pharmaceutically acceptable non - toxic salts of these compounds , containing , for example , na + , li + , k + , ca ++ and mg ++ . such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions . metal salts can be prepared by reacting the metal hydroxide with a compound of this invention . examples of metal salts which can be prepared in this way are salts containing li + , na + , k + . a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound . in addition , salts may be formed from acid addition of certain organic and inorganic acids , e . g ., hc1 , hbr , h 2 so 4 or organic sulfonic acids . finally , it is to be understood that the pharmaceutically active compounds for use in the present invention in their un - ionized , as well as zwitterionic form , and / or in the form of solvates are also considered part of the present invention . pharmaceutically acceptable esters of compounds for use in the invention containing oh groups can also be utilized in this invention . such esters can be prepared by esterification of the oh groups with , for example , carboxylic acids , sulphonic acids or phosphonic acid . carboxylic acid esters derived from c 1 - c 10 - alkylcarboxylic acids , unsubstituted or substituted benzoic acids or c 1 - c 6 - alkyl sulphonic are non - limiting examples of acids which can be employed to produce esters for use in this invention . the present invention can be employed to treat humans suffering from habit disorders , including substance addiction or abuse . non - limiting examples of habit disorders which can be treated by the present invention include the following : ( 1 ) cocaine addiction , abuse or dependency , including addiction to crack ( cocaine in ready - to - smoke form ), injectable cocaine and cocaine taken by nasal inhalation , ( 5 ) addiction to , abuse of or dependency on halucinogens , e . g ., mescaline , lsd and psylocibin , ( 6 ) addiction to , abuse of or dependency on amphetamines and other stimulants , e . g ., methamphetamine and methylphenidate , ( 7 ) addiction to , abuse of or dependency on opiates , e . g ., heroin , morphine , &# 34 ; demerol &# 34 ; ( meperidine ), methadone , codeine , opium , dilaudid and fenatanyl , ( 9 ) addiction to , abuse or dependency on pcp ( phencyclidine , &# 34 ; angel dust &# 34 ;), ( 10 ) addiction to , abuse of or dependency on stimulant - halucinogens , e . g ., mda , mdma , tma and others , certain components of the pharmacology of the pharmaceutically active compounds described for use in this invention , e . g ., flupenthixol , particularly their interaction with monoaminergic pathways in discrete brain areas , provide a rationale for the role of the active compound , e . g ., flupenthixol , in antagonizing substance addiction in general . continued over - indulgence or inappropriate consumption of foods , as well as habitual use of other addictive substances , relies in part on &# 34 ; craving &# 34 ;. in subjects suffering from substance addictions , &# 34 ; craving &# 34 ; is more of a subjective demand , for the addictive substance . the interactions of the active compound , e . g ., flupenthixol with monoaminergic transmission in brain regions associated with pleasure , reward and appetite appears to result in reducing craving . it is preferred that the pharmaceutically active compound for use in the present invention be formulated into pharmaceutical preparations . such preparations are composed of one or more of the compounds for use in the present invention in association with a pharmaceutically acceptable carrier . the reference remington &# 39 ; s pharmaceutical sciences . 17th edition , a . r . gennaro , editor ( mack publishing company , 1985 ), discloses typical carriers and methods of preparation . the pharmaceutically active compound described for use in the present invention can be administered topically or systemically to humans . by systemic administration is intended , oral , rectal , buccal , nasal and parenteral ( i . e ., intramuscular , intravenous and subcutaneous ) routes . generally it will be found that when the pharmaceutically active compound is administered orally , a larger quantity of the pharmaceutically active compound is required to produce the same effect as the smaller quantity given parenterally . in accordance with good clinical practice , it is preferred to administer the pharmaceutically active compound at a concentration level that will produce effective antihabitual effects without causing any harmful or untoward side effects and without resulting in a neuroleptic effect in the patient . therapeutically , the pharmaceutically active compound is preferably administered as a pharmaceutical composition comprised of an effective anti - habitual amount of the pharmaceutically active compound or a pharmaceutically acceptable salt thereof or an ester thereof and a pharmaceutically acceptable carrier , as stated herein . pharmaceutical compositions for effecting such treatment will contain a major or minor amount , e . g ., from 95 to 0 . 5 % of the pharmaceutically active compound in combination with a pharmaceutical carrier , the carrier comprising one or more solid , semi - solid , or liquid diluents , fillers and formulation adjuvants which are non - toxic inert and pharmaceutically acceptable . such pharmaceutical compositions are preferable in dosage unit form , i . e ., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response . other therapeutic agents can also be present . pharmaceutical compositions providing from about 1 to 50 mg of the pharmaceutically active compound per unit dose are preferred and are conventionally prepared as tablets , lozenges , capsules , powders , aqueous or oily suspensions , syrups , elixirs , and aqueous solutions . preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents , ( e . g ., syrup , acacia , gelatin , sorbitol , tragacanth or polyvinylpyrrolidone ), fillers ( e . g ., lactose , sugar , corn starch , calcium phosphate , sorbitol or glycine ), lubricants ( e . g ., magnesium stearate , talc , polyethylene glycol or silica ), disintegrants ( e . g ., starch ) and wetting agents ( e . g ., sodium lauryl sulfate ). solutions or suspensions of the pharmaceutically active compound with conventional pharmaceutical vehicles are employed for parenteral compositions , such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection . such compositions having the desired clarity , stability and adaptability for parenteral use are obtained by dissolving from 0 . 1 % to 10 % by weight of the pharmaceutically active compound in water or a vehicle comprising a polyhydric aliphatic alcohol , such as glycerine , propylene glycol and polyethylene glycol or mixtures thereof . the polyethylene glycols comprise a mixture of non - volatile , usually liquid , polyethylene glycols which are soluble in both water and organic liquids and have molecular weights from about 200 to 1500 . on the basis of testing , an intramuscular effective dose of the pharmaceutically active compound , e . g ., flupenthixol , could be expected to be from about 2 to about 80 mg weight with about 2 to 60 mg a preferred dosage range and preferably 2 to 20 mg . for pifluthixol an intramuscular effective dose could be expected to be 1 to 20 mg , preferably 1 to 10 mg . such dose to be administered every 10 to 20 days . for clinical applications , however , the dosage and dosage regimen in each case should be carefully adjusted , utilizing sound professional judgment and consideration of the age , weight and condition of the recipient , the route of administration and the nature and gravity of the habit or craving . the dosage may vary based on the medical status of the recipient , e . g ., dosages may have to be decreased in cases of impaired metabolism or increased in cases of enhanced metabolism . in some instances , a sufficient therapeutic effect can be obtained at lower doses , while in others , larger doses will be required . the specific habit or craving sought to be controlled by this invention may influence the mode and frequency of administration . for example , for crack addiction , intramuscular administration is preferred , however , for tobacco addiction , a slow release administration , e . g ., transdermal patches or slow dissolving tablets or capsules , may be preferred . the invention will now be described with reference to the following non - limiting examples . ten outpatients at a drug abuse treatment program were selected as subjects . all subjects smoked cocaine and met the study criteria of over 50 grams of cocaine use during the preceding 12 weeks . all subjects also met inclusion criteria of having failed to attain abstinence during treatment exposure of at least three weeks within the preceding 12 months . all subjects also met dsm - iiir ( diagnostic and statistical manual of the american psychiatric association , third edition , revised ) criteria for cocaine dependence . subjects who met dsm - iiir criteria for current or past abuse or dependence on another substance of abuse , or for major psychiatric disorder , were excluded . subjects were also excluded if major axis i psychiatric disorder other than substance abuse occurred in a first degree relative , based on proband interview . major medical illness was ruled out for all subjects by medical history interviews and physical examinations . the subjects were evaluated in at least weekly clinical contacts . patients were given semi - structured interviews based on an abbreviated version of the weekly cocaine use inventory and craving scale . subjects also submitted at least weekly urine specimens for analysis of cocaine metabolites and other drug use . reports were also solicited from drug - free significant others on a biweekly basis to substantiate subject reports . subjects were assessed for current or past major psychiatric disorder using dsm - iiir criteria in a 45 minute intake interview . the subjects had all used cocaine within one week of beginning the trial . they were provided with an initial dose of intramuscular benztropine ( 4 mg ) for prophylaxis against possible extrapyramidal reactions ( no subject demonstrated such a reaction or required a second benztropine dose ). subjects were then given 20 mg ( n = 8 ) or 10 mg ( n = 2 ) intramuscular ( im ) flupenthixol decanoate . all subjects were admitted to an outpatient drug treatment program , and all were provided psychotherapeutic treatment - as - usual , including daily group meetings and weekly individual psychotherapy contacts . urine specimens from the subjects were analyzed for benzoylecgonine using enzyme immuno - assay techniques . nine of the ten subjects reported substantial amelioration of cocaine craving within three days of flupenthixol administration . flupenthixol decanoate was well - tolerated in these subjects . neither extrapyramidal effects or exacerbation of anhedonia were described . craving for cocaine decreased by 72 % ( means +/- sem ; 13 . 4 +/- 0 . 8 v 3 . 7 +/- 0 . 8 , t = 9 . 80 ( paired ), p = 0 . 001 ) at the end of the first week of treatment ( fig1 ) and remained decreased . individual subject characteristics and response characteristics are described in table 1 . table 1 . __________________________________________________________________________subject characteristicsand response characteristics cocaine other drugs priorage sex use / week used treatment response to flupenthixol__________________________________________________________________________30 female 6 gms mj three attempts decreased depression at etoh up to one month decreased craving at duration three days cocaine use in continuous use . first week , then abstin - ence through 62 weeks . 37 male 13 gms mj five months in decreased depression at treatment with day two decreased craving continuous use . at day two abstient through 5 months of flupenthixol treatment . 34 female 8 gms mj four early term - abstinent 10 weeks , inations without sporadic use for 6 weeks , engagement in abstinent for 9 months ; treatment . flupenthixol discontinued at 22 weeks . 35 male 18 gms etoh seven months in sixteen weeks of treatment with abstinence on cis - continuous use . flupenthixol followed by 6 weeks of sporadic use ; abstinent for 8 following months . 33 male 33 gms etoh four months in use in first week ; treatment with abstinent through 13 intermittent weeks of flupenthixol use . treatment . 25 male 8 gms mj six weeks in use in first week , treatment with abstinent through 12 weekly use then weeks of flupenthixol full relapse . treatment . 22 male 23 gms mj three weeks in abstinent through 12 treatment with weeks of flupenthixol intermittent treatment ; craving use . decrease at day 2 . 30 male 2 gms mj three weeks in use in first week etoh treatment with abstinent through 12 intermittent weeks of flupenthixol use . treatment . 25 female 14 gms mj three weeks in craving decrease at day 2 etoh treatment with abstinent through 10 continuous use . weeks of flupenthixol treatment . 25 male 4 gms mj three weeks in dropped out immediately treatment with after flupenthixol . continuous use . returned to treatment 2 months later . __________________________________________________________________________ mj = marijuana etoh = ethanol eighty - eight per cent of the subjects ceased all cocaine use during the first treatment week , and the remainder in the second week , of flupenthixol decanoate treatment . responding subjects uniformly described an amelioration of dysphoric symptoms , including anhedonia . seventy - seven per cent of the subjects described a clear increase in energy by the third day after injection . seventy - seven per cent of the subjects also reported substantial decreases in the magnitude of craving induced by environmental cues . contrasted to prior maximum stays in treatment , the duration of retention in treatment was increased 260 % ( means +/- sem ; 8 . 7 +/- 2 . 7 v 23 . 0 +/- 6 . 9 , t = 2 . 61 ( paired ), p = 0 . 028 ). compared to prior medication regimens employed with these subjects ( using heterocyclic antidepressants ) both compliance to psychotherapeutic treatment and retention were markedly improved . the one non - responding subject dropped out almost immediately after 10 mg flupenthixol administration . he was subsequently readmitted after a full relapse lasting over 2 months . both he , and other subjects treated informally before this study at higher doses , described more neuroleptic - like effects than the responding subjects , including anhedonia , increased rather than decreased craving for cocaine , and often diminished intensity or duration of cocaine &# 39 ; s euphoric effects , but not complete blockade , when cocaine smoking was resumed . these flupenthixol effects directly produced substantial subjective distress , refusal of further flupenthixol administration ( rather than subject use of the blocking effects to aid treatment ) and discontinuation of treatment . flupenthixol decanoate effectively reduced craving for cocaine and facilitated abstinence in this sample . this is believed to be the first report of practical clinical efficacy for a depot preparation in stimulant abusers , and the first report of pharmacological efficacy for a treatment specific for &# 34 ; crack &# 34 ; abuse . flupenthixol decanoate was well tolerated , markedly and rapidly decreased cocaine craving and use , and produced a 260 per cent increase over prior treatments in average time retained in treatment . it will be appreciated that the instant specification is set forth by way of illustration and not limitation , and that various modifications and changes may be made without departing from the spirit and scope of the present invention .
a method for treating habit disorders in a human patient comprising administering to the patient an anti - habitual amount of a pharmaceutically active compound , which results in activation of a brain reward system , e . g ., flupenthixol , or esters thereof or pharmaceutically acceptable salts thereof , either alone or in admixture with a physiologically acceptable diluent .