WO2012033874A1

WO2012033874A1 - Method of treating compulsive self-injurious behaviors

Info

Publication number: WO2012033874A1
Application number: PCT/US2011/050758
Authority: WO
Inventors: Richard E. Chipkin
Original assignee: Chipkin Richard E
Priority date: 2010-09-10
Filing date: 2011-09-08
Publication date: 2012-03-15

Abstract

A method of treating compulsive behaviors in veterinary animals is disclosed. The method comprises administering to the mammal an effective amount of a D₁/D₅ antagonist or a D₁/D₅ partial agonist alone or in combination with other specified CNS compounds.

Description

METHOD OF TREATING COMPULSIVE SELF-INJURIOUS BEHAVIORS

FIELD OF THE INVENTION

[0001] The present invention is directed to a method for treating compulsive behaviors in animals which can also be self injurious, by administering to the animal an effective amount of a D1/D5 antagonist.

BACKGROUND OF THE INVENTION

[0002] Compulsive behavior in animals, also referred to as stereotypy has been described as acts that are often repetitive, exaggerated or sustained. These acts appear abnormal because although they arise out of normal behavior, they occur in an inappropriate, excessive or out of context manner. This behavior has been described in veterinary animals, including companion animals, farm and commercial animals as well as zoo animals. These behaviors are costly, time-consuming behaviors that cause distress and functional impairment and at times can be self injurious.

[0003] Compulsive behaviors in dogs and cats include such acts as licking, chewing, fence-running, pacing, spinning, tail-chasing (Overall and Dunham, JAVMA, Vol 221, No. 10, 2002). In horses, the behaviors are called "cribbing," and in addition include such acts as stall- walking, weaving, stall-kicking, tongue playing and pawing (Leuscher et al., Equine vet. J., Suppl. 27, 1998, 14-18). Cribbing is defined as an act which involves the horse grabbing a solid object, such as the stall door or fence rail, with his incisors, arching his neck, pulling against the object, and sucking in air, and is particularly notable for the inhaling air. This is relevant because it can lead to colitis (J. B. Mulder, Veterinary Heritage, v.16, No. 2: 61-65, 1993) and potentially death,

[0004] The pathophysiology of compulsive behaviors is thought to involve such diverse neurotransmitters as dopamine, glutamate, endorphins, and serotonin. Large doses of dopaminergic drags, such as amphetamine or apomorphine, are effective in inducing sterotyped behavior in animals, whereas the dopamine antagonist haloperidol results in suppression of spontaneously occurring stereotyped behavior (Kennes D, et al, J Pharmacol 153:19-24, 1988). It has been shown that a knockdown mutation of the dopamine transporter gene (DAT) leads to hyper dopaminergic mutant mice that have stronger and more rigid synctatic grooming chain patterns than wild type control mice (Berridge et al., BMC Biology 2005, 3:4).

BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG. 1. Effect of ecopipam (SCH 39166) or vehicle (VEH) on apomorphine (APO; 3mg/kg sc) - induced climbing (O) or sniffing (□) in mice. Each point for SCH39166 is the mean of 10 to 20 animals.

[0006] FIG. 2. Effect of ecopipam (SCH39166) or vehicle apomoiphine (APO;

3mg/kg sc) stereotypy in rats. Each point is the mean of six rats. * Significantly different from vehicle, P<.05, Mann- Whitney U Test.

[0007] FIG. 3. Response to an effective dose of ecopipam (0.25 mg kg) (n) and saline ( a) injected intraperitoneally. A 76% reduction in scratching was demonstrated at 30 minutes. PO.05 at 15, 20, 25, and 30 mmutes.

[0008] FIG. 4. Dose response curve of a range of concentrations of ecopipam (ca) injected intraperitoneally. ED₅₀ was -0.05 mg/kg for intraperitoneal injections.

[0009] FIG. 5. Response to 0.25 mg/kg ecopipam (■) and saline (oa) administered subcutaneously. A 77% reduction in scratching was demonstrated at 30 minutes. P<0.05 at all time points.

[0010] FIG. 6. Ecopipam' s effectiveness over time when ecopipam was administered intraperitoneally at a dose of 0.25 mg/kg. Controls (0), 5 minutes (□), 15 minutes (Δ), 30 minutes (x).

[0011] FIG. 7. Ecopipam's effectiveness over time when oral gavage was used to administer ecopipam at a dose of 2.5 mg/kg. Controls (0), 60 minutes (□), 30 minutes (Δ), 120 minutes (x). [0012] FIG. 8. Cataleptic effect after subcutaneous injection of a 0.25 mg/kg dose of ecopipam (i) and saline (□). Catalepsy was measured at 3 time points. P<0.05 at all 3 time points.

[0013] FIG. 9. Cataleptic effect after oral gavage was used to administer a 2.5 mg/kg dose of ecopipam(H) and saline (□). Catalepsy was measured at 3 time points. There was no significant difference between the two conditions.

[0014] FIG. 10. Ecopipam and raclopride induced catalepsy at different doses. Drags were administered subcutaneously and counts were made at 10 minute intervals. Saline (0), 0.25 mg/kg ecopipam (■), 0.05 mg/kg ecopipam (Δ), 0.25 mg/kg raclopride (x) and 0.1 mg/kg raclopride (*).

[0015] FIG. 11. Lack of a cataleptic effect after a 0.25 mg/kg dose of raclopride administered subcutaneously. Catalepsy was measured at 3 time points none of which reached a significant difference. Saline (□) and 0.25 mg/kg raclopride (■).

[0016] FIG. 12. Lack of significant change in scratching activity after a subcutaneous administration of 50 mg/kg of sulpiride. Saline(ca) and 50 mg/kg sulpiride (a).

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention is directed to a method for treating compulsive behaviors in animals.

[0018] One embodiment of the invention is a method for treating compulsive behaviors in horses, such as crib biting, wind sucking, stall walking, stall kicking, weaving, head bobbing, pawing, tongue playing, flank sucking by administering to the horse an effective amount of a Ό1/Ό5 antagonist.

[0019] Another embodiment of the invention is a method for treating compulsive behaviors in dogs, such as circling, tail chasing, pacing, jumping in place, flank sucking, fence running, fly biting, self mutilation, hair or air biting, chasing light reflections, staring, freezing, and excessive barking, by administering to the dog an effective amount of a D₁/D5 antagonist.

[0020] Another embodiment of the invention is a method for treating compulsive behaviors in cats, such as chewing legs or feet, excessive grooming, tail chasing and wool or fabric sucking or chewing, pica, excessive marking, freezing, sudden agitation and skin rippling, ducking and circling and persistent meowing by administering to the cat an effective amount of a D₁/D5 antagonist.

[0021] Another embodiment of the invention is a method for treating compulsive behaviors in birds such as feather and skin picking by administering to the bird an effective amount of a D₁/D5 antagonist.

[0022] Another embodiment of the invention is a method for treating compulsive behaviors iri bovines or porcines by administering to the animal an effective amount of a D₁/D5 antagonist.

[0023] Compulsive behaviors have been typically categorized as grooming, locomotory, vocalization, aggressive, hallucinatory behaviors and oral or ingestive behaviors. Grooming behaviors, for example, can include, lick granuloma (acral lick), compulsively licking objects, self-scratching, chewing feet, hair and nails, etc., flank sucking and air licking.

[0024] "Locomotory behaviors" can include, for example, running and jumping, pacing, head shaking, paw shaking, tail swishing, freezing, whirling, tail chasing, walking in a pattern, as along a fence, digging and floor scratching.

[0025] "Vocalization behaviors" include, for example, rhythmic barking, growling or snarling at self, barking at food, crying and howling.

[0026] "Aggressive behaviors" include, for instance, staring, air batting, jaw snapping, pouncing, prey chasing or searching, ducking, and fly chasing.

[0027] "Hallucinatory behaviors" include chasing imaginary prey. [0028] "Oral or ingestive behaviors" include, for example, excessive drinking, polyphagia, excessive drooling, gravel and dirt eating, stone chewing, wool sucking, and eating fabrics.

[0029] Compulsive mounting has been categorized as a "sexual behavior."

[0030] Self injurious behavior is also referred to as self-harm, self-inflicted violence, or self-mutilation. One skilled in the art will recognize that stereotypies and compulsive behaviors as described herein can lead to self injurious behaviors or self mutilation.

[0031] Stereotypies or compulsive behaviors in horses can include, for example, cribbing, wind sucking, wood chewing, stall walking, stall kicking, weaving, head bobbing, pawing, tongue playing, flank sucking. A description of some of the common behaviors is as follows: Cribbing occurs when horses grasp surfaces with their incisor teeth - such as the feed bin, their stall door or a fence board— and then arch their necks, pull a big gulp of air into their upper throat and abruptly release the air with a grunt. Wind-sucking occurs when the horse doesn't use a stationary object to steady herself when she takes the air back into her throat. Wood chewing occurs when horses nibble on any available wood surface. Weaving occurs when horses weave rock back and forth against or in front of their stall doors or stall walls. Head bobbing occurs when horses stand relatively still and bob their heads up and down repeatedly. Head weaving occurs when horses stand still and repeatedly swing their heads from side to side. Other behaviors similar to head bobbing and head weaving are head-shaking and head-nodding. Stall walking or circling occurs when horses pace back and forth close to the front of their stalls, although some circle continuously around the entire stall. Flank-biting occurs when horses repeatedly bite at their flanks, legs or tail, or at the sides of their body and their lower shoulder blade area. Aside from being self injurious to the horses, some of these behaviors cause damage to the stalls the horses are housed in.

[0032] In dogs, the stereotypies can range from acral lick dermatitis (ALD), light/shadow chasing, fly-snapping, flank sucking, and tail chasing. In cats, some examples of compulsive behaviors include chewing legs or feet, chewing or licking objects, wool sucking or eating and pica, freezing, sudden agitation and skin rippling, ducking, and circling, persistent meowing, avoiding imaginary objects, staring at shadows, or startling without obvious cause. In birds, feather-picking is a common problem. This behavior can be self injurious when in severe instances the birds become denuded risking infection, hypothermia, or fatal hemorrhage. (Grindlinger, HM.; Arch Gen Psychiatry. 1991; 48(9):857).

[0033] Compulsive behaviors are confinement induced conflict behaviors that arise out of frustration or stress. However, the behavior soon becomes fixed and is shown even in the absence of obvious stressors. Compulsive behaviors in animals have compelling parallels with human obsessive-compulsive disorder (OCD).

[0034] Animal models have been used to understand the mechanisms underlying pathological grooming and explore treatment options. A mouse model in which compulsive scratching is induced by a subcutaneous injection in the back of the neck of serotonin or a serotonin releasing agent, compound 48-80, has proved useful in investigating the potential of various drugs in treating compulsive behaviors. The same drug treatments that have proved effective against scratching and licking in dogs and crib-biting in horses were effective against induced scratching in mice (Wald, et al, Exp. Clin. Psychopharmacol. 2009 Jun; 17(3): 191-7).

[0035] In a preferred embodiment, the Di /D₅ antagonist or D] /D₅ partial agonist is administered in a range of about 0.01 to about 500 mg/kg (milligrams per kilogram) per day preferably about 1-150 mg/kg per day, to an animal demonstrating symptoms. Preferred Dj /D₅ antagonists are SCH 23390, SCH39166, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS- 136 and A69024, NNC687, with SCH 39166 being particularly preferred. Preferred DI agonists are adrogolide (ABT 431;DAS431), A86929; A381393; A77636; dihydrexidine (DAR0100); fenoldapam; SKF75670A; SKF 81297; SKF82958; dinapsoline. A preferred Di /D₅ partial agonist is SKF 38393.

[0036] Ό1ΙΌ5 antagonists such as SCH 39166 and SCH 23390 block stereotypies '"duced by nnnmnrn irifi Fimire 1 shows that SCH 391 6 blocked climbine and sniffins in mice. The minimal effective dose was 1 mg/kg PO. Figure 2 shows that SCH39166 blocks apomorphine induced stereotypy in rats. The minimal effective dose was 10 mg/kg PO.

[0037] Ecopipam (SCH 39166), a specific dopamine Di antagonist, when administered in different doses and by various routes, inhibited compulsive scratching in mice. (Fig. 1). The reduction in scratching was accompanied by distinctive catalepsy and sedation. The ED50 for intraperitoneal injection was 0.05 mg/kg (Fig. 2); the ED50 for oral gavage was 2.5 mg/kg, and for subcutaneous injection was 0.1 mg/kg. The duration of action of an intraperitoneal injection of 0.25 mg/kg ecopipam was 45 minutes (Fig. 4). Catalepsy (as measured by the length of time that a mouse stood holding on to a horizontal bar with its forepaws) lasted for 208 seconds at 30 minutes after a dose of 0.25 mg/kg ecopipam administered subcutaneously (Fig. 8). There was negligible catalepsy after doses of 0.05 mg/kg subcutaneous and 2.5 mg/kg PO.

[0038] In comparison, 0.25 mg/kg subcutaneous injection of raclopride, a potent dopamine D₂ antagonist, produced a 63 % inhibition of scratching and 130 seconds of catalepsy after 30 minutes (Fig. 8). In addition, a 50 mg/kg dose of sulpiride, another D₂ antagonist, was completely ineffective.

[0039] The preferred Di /D₅ antagonist compounds are SCH 39166, SCH 23390 NC- 22-0010 and BTS-73-947. A preferred D1 D5 partial agonist is SKF 38393, which has the chemical name 2,3,4,5-tetrahydro-l-phenyl-l-H-3-benzazepine-7,8-diol. The structures of these compounds are shown below.

NN C - 22- 0010 JHS 271 JHS 198

[0040] Since animals that display compulsive behaviors often suffer from anxiety, another embodiment of the present invention is co-administering the D1/D5 antagonist with anti-anxiety medications. The

/D₅ antagonists or Di D₅ partial agonists may be used in combination with compounds selected from the following CNS classes: Antipsychotic drags, such as haloperidol, flupenthixol, chlorpromazine, chlorpromazine, fluphenazine,

perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, and aripiprazole; Anxiolytics such as diazepam, lorazepam, triazolam, alprazolam, buspirone, alprazolam, chlordiazepoxide, clonazepam and tandospirone hydroxyzine; Antidepressant drugs such as despiramine, imipramine, amitryptyline, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, buproprion, venlafaxine and citalopram. Mood stabilizing drugs such as carbamazepine, topiramate and lithium. [0041] Other drags include: mazindol, methylphenidate, disulfiram, acamprosate, naltrexone, memantine, D-serine, dextromethoφhan, GY I-52466, texampanel, perampanel, and talampanel.

[0042] The compounds are administered at a dose from about 0.0001 mg to 2g/day, preferably from 0.01 to about 500 mg/kg per day, more preferably about 1 to about 150 mg/kg daily.

[0043] While the examples set forth below are directed at Ό_\ !D₅ antagomsts, it is anticipated that pure Di antagonists, pure D₅ antagonists, pure Di partial agonists and pure D₅ partial agonists and Di /D5 partial agonists also will prove efficacious in treating compulsive behaviors.

Abbreviations and Definitions:

[0044] "Di D₅ partial agonists" as defined herein include compounds which bind selectively to the Di receptor (pure Di partial agonists) selectively to the D5 receptor (pure D5 partial agonists) as well as compounds which bind to both receptors and mimic dopamine under certain conditions. The term "mixtures thereof is defined to include mixtures of two or more D5 antagonists, two or more Dt /D5 partial agonists and one or more Di /D₅ antagonist with one or more Dj /D₅ partial agonist. Among the preferred D] /D₅ antagonists are:

[0045] SCH 39166, having the chemical name (-)-trans-6,7,7a,8,9, 13b-hexahydro-3- chloro-2-hydroxy-N-methyl-5H-benzo [d]-naphtho-[2, 1 -b]azepine

[0046] SCH 23390, having the chemical name (d)-7-chloro-8-hydroxy-3 -methyl- 1 - phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine maleate

[0047] BTS-73-947, having the chemical name l-[l-(2-chlorophenyl)cyclopropyl]- 1 ,2,3 ,4-tetrahydro-7-hydroxy-6-methoxy-2 -methyl-(S)-isoquinolinol

[0048] NNC-22-0010, having the chemical name (+)-5-(5-bromo-2,3-dihydro-7- benzof½anyl)-8-cWoro-2,3,4,5-tetiahydro-3 m ethyl-lH-3-benzazepin-7-ol [0049] JHS-271 , having the chemical name 8-chloro-3-[6-(dimethylamino)hexyl]- 2,3,4,5-tetrahydro-5-phenyl-lH-3-benza zepin-7-ol

[0050] JHS- 198, having the chemical name 8-chloro-3-[6- (dimethylamino)hexyl] 2 , 3 ,4,5 -tetrahydro-5 -phenyl- 1 H-3 -benzaz epin-7-ol with

boranecarbonitrile (1 :1)

[0051] JHS-136, having the chemical name 8-chloro-3-[4-(dimethylamino)butyl]- 2,3,4,5-tetrahydro-5-phenyl-lH-3-benza zepin-7-ol and

[0052] A-69024, having the chemical name l-[(2-bromo-4,5- dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6-methoxy-2-met hyl-7-isoquinolinol.

[0053] Veterinary animals herein include domestic pets or companion animals, farm animals, zoo and commercial animals.

[0054] Animals to be treated for repetitive behaviors include, but are not limited to, birds and mammals, for example, captive "wild" birds and mammals, such as those living in zoos or animal preserves, especially species that are predatory or can be predatory, such as feline, canine and ursine species, domestic animals, such as those raised for meat or furs (e.g., chickens, pigs, cattle, minks), and those animals kept as pets or for recreational purposes, such ¹ as rats, mice, cats, dogs, horses, and various types of birds, such as parrots, cockatoos, parakeets, pigeons and the like.

[0055] "Horses" as used herein includes those domesticated animals that are usually called "horses," but also those animals that are sometimes classified by size as being ponies or miniature horses. "Of an equine species" refers herein not only to horses, donkeys, and the like but also to equine hybrids, such as mules and hinnies.

[0056] Similarly, "dogs" refers herein not only to domestic dogs, but also to wild dogs and canine hybrids.

[0057] "Bovine" refers herein to cows or bulls. Similarly, "porcine" refers herein to pigs, hogs or swine. [0058] "PO" and "po" refers to per os or by mouth or oral gavage. "SC", "sc" and "Sub-Q" refers to subcutaneous. "IP" refers to intraperitoneal.

[0059] Agents to be used in methods of treating an animal for compulsive behavior can be employed in combination with a non-sterile or sterile carrier. Such carriers may include, but are not limited to, saline, buffered saline, dextrose, water, ethanol, surfactants, such as glycerol, excipients such as lactose and combinations thereof. The formulation can be chosen by one of ordinary skill in the art to suit the mode of administration. The chosen route of administration will be influenced by such factors as the solubility, stability and half-life of the agent, for instance. The compositions may be administered in any effective, convenient manner, including administration by topical, oral, anal, vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, transdermal or intradermal routes, among others.

[0060] In addition, the amount of the compound will vary depending on the size, age, body weight, general health, sex, and diet of the host, and the time of administration, the biological half-life of the compound, and the particular characteristics and symptoms of the disorder to be treated. Adjustment and manipulation of established dose ranges are well within the ability of those of skill in the art, and preferably minimize side effects and toxicity.

[0061] Since the present invention in certain embodiments may comprise the administration of a combination of two components, the components can be co-administered simultaneously or sequentially, or in a single pharmaceutical composition. Where the components are administered separately, the number of doses of each component given per day may not necessarily be the same, e.g. where one component may have a greater duration of activity, and will, therefore, be administered less frequently. The formulations can be prepared using conventional pharmaceutical excipients and additives using conventional techniques. The components may be administered in any conventional oral or parenteral dosage form, such as capsule, tablet, powder, cachet, suspension or solution. Where a CNS compound is administered in addition to the Di D5 antagonist or Di /D5 partial agonist, the CNS compound generally will be administered within the known dosing ranges for that compound. The exact dose administered will be determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. [0062] The compounds may be administered to a mammal by any route of

administration which will provide the requisite concentration of the Ό /D5 antagonist or Dj /D₅ partial agonist. When the drug is administered orally by capsule or tablet, the daily dose will range from about 0.1 to about 500 mg kg daily, more preferably from about 0.1 to about 150 mg/kg daily, most preferably from about 0.1 to about 10 mg/kg daily. The compounds preferably are administered 1-3 times per day.

[0063] A pharmaceutical preparation containing SCH 39166 may have the composition described in Example 4, although other compositions such as tablets may be suitable. The tablet may be coated by standard techniques using any approved dye. It is contemplated that a sustained release formulation also could be utilized for administering this compound over an extended time.

[0064] Since, the present invention may comprise the separate administration of two compounds, the present invention also relates to combining separate pharmaceutical compositions in kit form. The kit preferably will include directions for the administration of the separate components.

[0065] While the present invention has been described in conjunction with specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary sldll in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

EXAMPLE 1

Preparation of Drugs

[0066] Drugs (SCH39166 free base (micronized) and SCH23390 maleate, haloperidol and apomorphine) were either solubilized or suspended in 0.4% aqueous methylcellulose. The volume of injection was 10 ml/kg for all studies in rodents. Oral injections were accomplished by placing a blunt-nose, feeding tube down the animals' throat and into the esophagus. The drug suspension/solution was then administered directly into the stomach. EXAMPLE 2

Effect of SCH 39166 on apomorphine induced climbing and sniffing in mice

[0067] Male, CF1 mice (18-22 g) were used. The studies were done according to the method described by Gerhardt et al. Life Sci. 37:2355-2363, 1985. Briefly, vehicle or drugs were administered PO 60 min before apomorphine (3 mg/kg SC), a dose determined previously to cause maximal climbing and sniffing scores. The injected mice were then singly placed in circular wire-mesh cages (15 cm high and 12 cm in diameter). Twenty minutes later, the amount of time the mouse spent on the cage wall s with all four feet off the table-top was recorded, for a maximum of 60 sec. Thereafter, each mouse was observed (15 sec) and rated for stereotyped sniffing according to following rating scale: 0, no sniffing; 1, moderate sniffing; 2, constant sniffing. The raters were not blind to the treatment It is notewortliy that vehicle-treated mice fail to climb and show a sniffing score of 1 using this test. Data were analyzed using a nonparametric analysis of variance.

EXAMPLE 3

Effect of SCH 39166 on apomorphine induced stereotypy in rats

[0068] Male, Sprague-Dawley rats (200-250 g), fasted overnight, were used. This test was done as described previously (Chipkin and Latranyi, Eur. J. Pharmacol. 136: 371-375, 1987). Briefly, either vehicle or drug was injected PO 60 min before injection of a omoφhine (3 mg/kg SC), a dose determined previously to cause maximum stereotypy. Stereotypy was then scored every 5 min (during 15-sec periods) for 30 min. The scores for each 5 min block for each rat were then summed and used to calculate the group mean, which was plotted against the dose on a log scale. Stereotypy scoring was done according to Costall and Naylor (1975) as follows: 0, no stereotypy; 1, discontinuous sniffing; 2, continuous sniffing; 3;

continuous sniffing with discontinuous biting, gnawing and licking; 4, continuous biting, gnawing and licking. EXAMPLE 4

Preparation of pharmaceutical compositions containing SCH 39166 as the active ingredient

No. Ingredient mg/capsule mg/capsule

1. SCH 39166 5.0 25.0

2. Lactose USP 114.0 94.0

3. Sodium Starch Glycolate NF 6.0 6.0

4. Povidone USP ( 29/32) 4.0 4.0

5. Magesium Stearate NF 1.0 1.0

TOTAL 30.0 mg 130.0 mg

[0069] Mix items 1 -4 in a suitable blender for 10-15 minutes. Add item 5 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules with a suitable encapsulating machine.

EXAMPLE 5

Administration

[0070] Administer the capsules of Example 4 (containing mg of SCH 39166), once a day until the abnormal behavior has either stopped or stabilized.

EXAMPLE 6

Mouse model of compulsive scratching

[0071] Random-bred male Swiss- Webster mice purchased from Taconic, Inc. and between 2 and 6 months old were kept on hardwood bedding, fed Purina chow, and handled in accordance with the rules of the Tufts Institutional Animal Care and Use committee.

[0072] To induce scratching, 0.1 ml of serotonin creatinine sulfate (Sigma), 0.4 mg/ml in 0.9% sodium chloride containing 1 mg/ml L-ascorbic acid, was injected subcutaneously in the interscapular region (Kuraishi et al, Eur J Pharmacol. 1995; 275: 229-33). To test the effect of drugs, a drag solution or plain saline was injected five minutes prior to induction of scratching. For the following 30 minutes, the cumulative number of scratches with a hind paw was recorded at 5 minute intervals. Each experimental mouse was paired with a simultaneously injected control. The mean numbers of scratches for a group of 5 experimental mice was compared with that of a group of controls by a Student's t test, and differences were considered significant for a p value of 0.05 or less.

[0073] The bar assay for catalepsy was carried out by holding a mouse by the base of the tail and lowering it so that its forepaws come into contact with and grasp a 20 cm long glass rod suspended 5 cm above a 2 cm deep layer of hardwood chip bedding. If the mouse did not remain standing and holding on to the rod after the first attempt an additional two attempts were made (after the 3rd failed attempt a score of 0 seconds was awarded). Catalepsy was measured as the time in seconds during which the mouse kept its forepaws on the bar. The maximal cutoff point was 300 seconds.

[0074] A quantitative normalization technique as described by Vandesompele

(Vandesompele et al, Genome Biol. 2002; 18; 3(7) RESEARCH0034) was used to standardize the data points in the comparison charts.

EXAMPLE 7

Preparation of drugs

[0075] Drugs were dissolved in 0.9% sodium chloride containing 1 mg/ml L-ascorbic acid. The volume of drug solution administered was 0.1 ml/10 g body weight for

intraperitoneal injection or oral gavage, and 0.05 ml/10 g body weight for subcutaneous injections. Control animals were administered saline plus ascorbic acid.

EXAMPLE 8

Sunnre inn of comnuhive scratching in mice after intraneritoneal. injection nf ecnninnm

[0076] In the experimental model described in Example 6, a cumulative count of scratching was counted at 5-minute intervals after subcutaneous injection of 40 μg 5- hydroxytryptamine (5-HT). Ecopipam was administered 5 minutes prior to 5-HT injection at a dose of 0.25 mg/kg intraperitoneally. Figure 3 illustrates atypical response to an effective dose of ecopipam. There was a 76% decrease in scratching after the injection of 0.25 mg kg ecopipam.

[0077] The response to a range of different doses is shown in Fig 4. The ED50, or dose that produced a 50% decrease in scratching, was ~0.05 mg/kg ecopipam.

EXAMPLE 9

Effect of altering the route of administration of ecopipam

[0078] In the experimental model described in Example 6, a subcutaneous injection was nearly as effective in decreasing scratching in mice as intraperitoneal injection of the same dose of 0.25 mg/kg ecopipam (Fig 5). Administration by oral gavage confirmed decreased bioavailability, known from previous reports (Chipkin et al, J Pharmacol Exp. Ther. 1988; 247: 1093-1102).

EXAMPLE 10

Duration of action of ecopipam

[0079] In the experimental model described in Example 6, estimation of the duration of response was obtained by varying the interval between the injection of ecopipam and the injection of serotonin. As indicated in Fig 6, the effect of an intraperitoneal dose of 0.25 mg/kg ecopipam wore off after 45 minutes.

[0080] In similar experiments, ecopipam was given by oral gavage. The duration of action of a dose of 2.5 mg/kg was between 60 and 120 minutes. (Fig. 7). Fig. 7 demonstrates that the reduction in scratching after 30 minutes and 60 minutes was similar, however after 2 hours the effect was gone completely.

EXAMPLE 11

Catalepsy in mice after ecopipam

[0081] In the experimental model described in Example 6, appreciable catalepsy was seen after a 0.25 mg/kg ecopipam administered subcutaneously (Fig 8), but very little after 2.5 mg/kg PO (Fig 9). EXAMPLE 12

Comparison with other dopaminergic agents

[0082] In the experimental model described in Example 6, raclopride, a potent D₂ antagonist administered subcutaneously was less active in reducing scratching when compared to ecopipam administered subcutaneously (Fig 10). It also produced less catalepsy (Fig 11).

[0083] Sulpiride, a less potent D₂ antagonist, administered subcutaneously was ineffective against serotonin-induced scratching, even at a high dose of 50 mg/kg (Fig. 12).

EXAMPLE 13

Combination with NMDA antagonists

[0084] A low dose of ecopipam administered in combination with a low dose of memantine, an NMDA antagonist. Other drags administered in combination with ecopipam include naltrexone and dextromethorphan.

Summary and Conclusion:

[0085] All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.

Claims

CLAIMS:

1. A method for treating compulsive behaviors in a veterinary animal comprising administering an effective amount of a D1/D5 antagonist, a D1/D5 partial agonist or mixtures thereof.

2. The method of claim 1 wherein the D1/D5 antagonist is administered in a daily dosage range of about 0.01 to about 500 mg/kg.

3. The method of claim 1 wherein the D1 D5 antagonist is administered in a daily dosage range of about 1 to about 150 mg/kg.

4. The method of claim 1 wherein the D1/D5 partial agonist is administered in a daily dosage range of about 0.01 to about 500 mg/kg..

5. The method of claim 1 wherein the D1/D5 partial agonist is administered in a daily dosage range of about 1 to about 150 mg/kg.

6. The method of claim 1 wherein the D1/D5 partial agonist is administered in a daily dosage range of about 0.01 to about 5 mg/kg.

7. The method of claim 1 wherein the D1/D5 partial agonist is administered in a daily dose of 0.25 mg/kg.

8. A method of claim 1 wherein the compulsive behavior comprises one or more of grooming, locomotory, oral, ingestive, vocalization, aggressive, hallucinatory behaviors.

9. The method of claim 1 wherein the route of administration is oral.

10. The method of claim 1 wherein the route of administration is by injection.

11. The method of claim 1 wherein the route of administration is by feeding tube into the stomach.

12. The method of claim 1 wherein the effective amount is administered 1-3 times a day.

13. The method of claim 1 wherein the veterinary animal is a horse, dog, cat, bird, cow or pig.

14. The method of claim 1 wherein the veterinary animal is a horse.

15. The method of claim 12 wherein the compulsive behavior comprises one or more of: crib-biting, wind sucking, stall walking, stall kicking, weaving, head bobbing, pawing, tongue playing, flank sucking.

16. The method of claim 1 wherein the veterinary animal is a dog.

17. The method of claim 14 wherein the compulsive behavior is selected from the group consisting of: circling, tail chasing, pacing, jumping in place, flank sucking, fence running, fly biting, self mutilation, hair or air biting, chasing light reflections, staring, freezing, and excessive barking.

18. The method of claim 1 wherein the veterinary animal is a cat.

19. The method of claim 16 wherein the compulsive behavior comprises one or more of chewing legs or feet, excessive grooming, tail chasing, wool or fabric sucking, chewing, pica, excessive marking, freezing, sudden agitation, skin rippling, ducking, circling and persistent meowing.

20. The method of claim 1 wherein the veterinary animal is a bird.

21. The method of claim 18 wherein the compulsive behavior comprises one or more of feather picking and skin picking.

22. The method of claim 1 wherein the veterinary animal is a bovine.

23. The method of claim 1 wherein the veterinary animal is porcine.

24. The method of claim 1 wherein the D1/D5 antagonist comprises one or more of SCH39166, SCH23390, SCH 12679, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136, and A69024.

25. The method of claim 1 wherein the D1/D5 partial agonist is SKF 38393.

26. The method of claim 1 wherein the D1/D5 antagonist is SCH39166.

27. The method of claim 24 wherein the effective amount of SCH39166 is administered in combination with one or more of memantine, naltrexone and dextromethorphan.

28. The method of claim 1 wherein the effective amount of a D1/D5 antagonist, a Ό1/Ό5 partial agonist or mixtures thereof is administered in combination with anti-anxiety medications.

29. The method of claim 1 wherein the effective amount of a D1/D5 antagonist, a D1/D5 partial agonist or mixtures thereof is administered in combination with one or more of despiramine, imipramine, amitryptyline, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, bupropion, citalopram, mazindol, methylphenidate, disulfiram, acamprosate, naltrexone, memantine, D-serine, dextromethorphan, GYKI- 52466, texampanel, perampanel, talampanel, carbamazepine, topiramate and lithium.

30. A composition comprising an effective amount of at least one compound of claim 1 in combination with a least one pharmaceutically acceptable carrier.

31. A kit for treating compulsive behaviors in a veterinary animal comprising at least one compound of claim 1.