WO1999021540A2 - Method of reducing craving in mammals - Google Patents
Method of reducing craving in mammals Download PDFInfo
- Publication number
- WO1999021540A2 WO1999021540A2 PCT/US1998/022255 US9822255W WO9921540A2 WO 1999021540 A2 WO1999021540 A2 WO 1999021540A2 US 9822255 W US9822255 W US 9822255W WO 9921540 A2 WO9921540 A2 WO 9921540A2
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- Prior art keywords
- antagonist
- cocaine
- food
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- agonists
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention is directed at reducing cravings in mammals. More specifically the present invention is directed at reducing the cravings of a mammal to any dopamine mediated cravings including food or addictive substances.
- Substances which are administered to reduce craving should not produce significant physiological effects, such as stimulation of mood or elevate blood pressure or heart rate. This could result in the substitution of one abused substance for another. Compounds which dampen the desire for the abused substance also should not exacerbate the physiological symptoms of the abused substance in the event the individual relapses and takes the abused substance. Substances administered to reduce craving also should not produce significant adverse affects, such as dysphoria, restlessness or stiffness.
- the present invention is directed at the use of D1/D 5 antagonists, D 1 /D5 partial agonists, or mixtures thereof alone or in combination with other CNS compounds for the preparation of a medicament for reducing cravings in a mammal, particularly cravings directed at food or an addictive substance, such as tobacco, alcohol or abused drugs.
- the D1 /D5 antagonist or D1 /D5 partial agonist is administered in a range of about 0.01 to about 500 mpk per day preferably about 1-150 mpk per day, to a mammal predisposed to cravings.
- Preferred D1/D5 antagonists are SCH 23390, SCH39166, BTS-73-947, NNC-22-0010, JHS-271 , JHS-198, JHS-136 and A69024, with SCH 39166 being particularly preferred.
- a preferred O./O 5 partial agonist is SKF 38393.
- D1/D5 antagonists or D,/D 5 partial agonists may be used in combination with compounds selected from the following CNS classes:
- Figure 1 plots the effects of a D1/D5 antagonist and a D2 antagonist in controlling movement as a function of dosage.
- Figure 2 plots the effects of a D1/D5 antagonist and a D2 antagonist in controlling movement as a function of dosage after the administration of cocaine.
- Figures 3 and 4 plot the systolic and diastolic blood pressure in humans before and after cocaine administration as a function of time with varying dosages of a preferred D1 /D5 antagonist and with a placebo.
- Figures 5 and 6 plot the heart rate and body temperature, respectively, before and after cocaine administration with varying dosages of a preferred D1/D5 antagonist and with a placebo.
- Figures 7 and 8 represent plots of the subjective euphoria and anxiety, respectively, before and after cocaine administration with varying dosages of a preferred D1 /D5 antagonist and with a placebo.
- Figure 9 represents a plot of the subjective desire to take cocaine as a function of time after being administered a preferred D1 /D5 antagonist or a placebo.
- Figures 10 and 11 represent plots of subjective assessments of good drug effects and bad drug effects respectively, as a function of time and dosage in subjects before and after cocaine administration.
- Figures 12 and 13 represents plots of positive and negative mood responses as a function of time after amphetamine administration and also administration of a preferred D j /D 5 antagonist or a placebo.
- Figures 14 and 15 show the chemical structures of selected compounds.
- Addictive substance is any substance which triggers a dopamine release in a susceptible mammal.
- Addictive substances include, but are not limited to, nicotine, alcohol, and psychomotor stimulants such as amphetamines, opiates, benzodiazepines, and barbiturates.
- Craving is an intense and prolonged desire or yearning for food or addictive substance frequently in response to environmental cues.
- a priming dose of an addictive substance can trigger relapse in mammals whose addictive-seeking behavior previously had been extinguished.
- Blockade of the dopamine Di site has been found to block the craving associated with abstinence and triggered by either a small dose of the addictive substance and/or associated cues.
- Pretreatment of a mammal with low doses of a D1 /D5 antagonist or a D1/D5 partial agonist suppresses or blocks the craving for food or the abused substance.
- D1 /D5 antagonist includes compounds which bind only to the Di receptor (pure Di antagonists), only to the D5 receptor (D5 antagonists) as well as compounds which bind to both receptors.
- D1/D5 partial agonists includes compounds which bind only to the Di receptor (pure Dl partial agonists) only to the D5 receptor (pure D5 partial agonists) as well as compounds which bind to both receptors and mimic dopamine under certain conditions.
- mixtures thereof is defined to include mixtures of two or more D,/D 5 antagonists, two or more D,/D 5 partial agonists, and one or more D ,/D 5 antagonist with one or more D,/D 5 partial agonist.
- preferred D ⁇ D j antagonists are:
- BTS-73-947 having the chemical name l-[l-(2- chlorophenyl)cyclopropyl]- 1 ,2,3, 4-tetrahy dro-7-hy droxy-6- methoxy-2-methyl-(S)-isoquinolinol
- NNC-22-0010 having the chemical name (+)-5-(5-bromo-2,3- dihy dro-7-benzofuranyl)-8-chloro-2, 3 ,4,5 -tetrahydro- 3 -methyl- 1H- 3-benzazepin-7-ol
- JHS-271 having the chemical name 8-chloro-3-[6- (dimethylamino)hexyl] -2,3,4,5-tetrahydro-5-phenyl- lH-3- benzazepin-7-ol JHS-198, having the chemical name 8-chloro-3-[6- (dimethylamino)hexyl]2,3 ,4,5-tetrahydro-5-phenyl- l H-3- benzazepin-7-ol with boranecarbonitrile ( 1 : 1 )
- JHS-136 having the chemical name 8-chloro-3-[4- (dimethylamino)butyl] -2,3,4,5-tetrahydro-5-phenyl- l H-3- benzazepin-7-ol and
- A-69024 having the chemical name l-[(2-bromo-4,5- dimethoxyphenyl)methyl] - 1 ,2,3 , 4-tetrahydro-6-methoxy-2-methyl- -7-isoquinolinol.
- 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 on Figures 14 and 15,
- the compounds preferably are administered at a dose of about 0.01 to about 500 mg/kg per day, preferably about 1 to about 150 mg/kg daily.
- the efficacy of representative compounds in suppressing cravings may be seen from the following tests.
- Example 1 illustrates that a D1 /D5 antagonist is effective in reducing the craving for an addictive substance, cocaine, while a D2/D3 antagonist was much less effective.
- Cocaine-produced increases in locomotor activity were blocked by D1/D5 antagonists, but not by D2/D3 antagonists unless relatively high doses were used.
- a selective D1/D5 antagonist, SCH 39166, and a selective D2/D3 antagonist, raclopride were studied on cocaine induced locomotor stimulation in male CF-1 mice. The mice were given an oral dose of SCH 39166, raclopride or vehicle, followed 20 minutes later by a dose of cocaine or vehicle administered subcutaneously (sc). Locomotor activity was measured 10 minutes later for an 8 minute period and is shown in Figure 1.
- This example shows that the preferred D1 /D5 antagonist was efficacious and did not exhibit significant adverse effects when administered to individuals after cocaine injections.
- Individuals selected for these tests were people who previously had exhibited a cocaine addiction and had volunteered for this program.
- the subjects were administered placebo, 10 mg of SCH39166, 25 mg of SCH 39166, or 100 mg of SCH 39166 two hours prior to an injection of 30 mg/kg of cocaine.
- Systolic and diastolic blood pressure in the individuals was measured from 2 hours prior to cocaine injection until approximately 4 hours after cocaine administration.
- the D1 /D5 antagonist SCH 39166 did not adversely affect the systolic and diastolic blood pressure elevations caused by cocaine.
- Figure 5 shows that the mean heart rate, in beats per minute, was not exacerbated after cocaine administration by SCH 39166, while Figure 6 shows that the elevation in body temperature attributed to cocaine administration was not worsened.
- the desire to take cocaine was measured as a function of time after administration of placebo or varying doses of SCH 39166.
- the desire to take cocaine was measured by the Visual Analog Scale test. This test procedure is described in the British Journal of Medical Psychology, Volume 47, pp 211-218 (1974). In this test the individuals are asked to subjectively rate their feelings to take cocaine on a scale of zero- 100, with zero representing no desire at all and 100 representing the strongest feelings. As may be seen in Figure 7, the euphoric "high" following cocaine administration was lower in patients who had been pre-treated with SCH 39166, particularly a dose of 100 mg.
- Figure 8 shows that the dysphoric effects, such as anxiety, after cocaine administration were lower in those patients who had been pre-treated with SCH 39166.
- the desire to take cocaine was significantly lower for the individuals who had been administered SCH 39166 compared with placebo. The greatest reduction in cocaine desire occurred in individuals administered 100 mg of SCH 39166.
- Figure 11 shows that the "bad drug effects" for all dosages of SCH 39166 at the same time point, as judged by the Visual Analog Scale test, were not significantly different from the placebo. Therefore, usage of this compound should not be adversely affected by negative opinions of the individuals to whom the drug is administered nor should it cause stimulation following administration.
- O l /O 5 antagonists and/or D,/D 5 partial agonists may prevent dietary relapse in the treatment of obesity by blocking the rewarding effects of dopamine at the O ⁇ /O 5 sites associated with cravings.
- Examples 3-5 provide other illustrations of the effect of a D1/D5 antagonist in reducing food cravings in a mammal.
- adult male rats (strain: CD) were trained to bar press for food on a fixed-ratio schedule of 30 (FR30). A rat had to press a bar 30 times in order to receive one 45 mg pellet of food. Each training session was 30 minutes long.
- the total response rate (total # of bar presses/ 30 minutes), i.e., the rate at which rats pressed the bar, was measured and then analyzed in animals that were initially given saline (control animals) and then doses of the D 1/D5 antagonists SCH23390 or SCH39166.
- Each group of six animals received one dose of drug given subcutaneously in a volume of 1 ml/kg 30 minutes before the start of the session.
- the doses of SCH 23390 were .003, .005, .01, and .03 milligrams per kilogram (mpk), while the doses of SCH 39166 were .001, .003, .01, .03, 0.1 and 0.3 (mpk)
- the 0.01 mpk dose of both SCH23390 and SCH 39166 significantly reduced the bar press rate relative to the rate of the saline-treated control animals. Both drugs produced a dose-related decrease in response rate until responses were eliminated at the highest dose.
- mice of a genetically obese strain i.e. ob/ob mice, aged 16 weeks were individually housed in Nalgene metabolism cages in a reverse light cycle room for the entire duration of the study. Mice were allowed food and water a_d libitum. The mice were divided into 5 groups of 4-5 mice each based on baseline food intake and body weight. Mice were dosed intraperitoneally (ip) with vehicle, 0.003, 0.03, 0.3, or 3.0 mg/kg SCH 39166 at the onset of the dark cycle and a known mass of standard rodent chow was provided. Food consumption was measured after five hours, and another ip injection of vehicle or drug was given. Food intake was measured again at 24 hours after the initial injection. These injections and measurements were continued for 72 hours. Seventy two hour cumulative food intake was decreased 17% at 3.0 mg/kg (p ⁇ 0.02).
- NPY neuropeptide "Y"
- SD Sprague-Dawley
- a dose of SCH39166 was injected intraperitoneally (ip). Thirty minutes later, a 3 mg i.c.v. injection of NPY was administered. The control animals received an ip injection of the vehicle methylcellulose. Thirty minutes later, animals received NPY (3 mg). A second group received 1 mpk of SCH39166 ip, and thirty minutes later received 3 mg of NPY. A third group of animals received 3 mpk of SCH39166 ip and thirty minutes later received 3 mg of NPY. Food intake was measured 2 hours, 4 hours, and 24 hours following NPY administration. Animals that received a pretreatment of 3 mpk SCH39166 demonstrated a significant decrease in food intake 2 hours after NPY administration.
- Table 1 shows the number of patients receiving placebo or the indicated dosage of SCH 39166 for a period of 28-25 days.
- the Body Mass Index (BMI) and the patient weight were measured at the beginning and end of the study.
- the BMI is determined by the weight (kg)/height 2 (meters).
- Patients having BMFs of 20.0-24.9 are considered to be of normal weight, while patients having BMI's over 25.0 are considered to be overweight.
- Table 1A lists the percentage of patients in each category with a weight loss of at least 5 pounds.
- Table IB indicates the percentage of patients with an initial BMI of 22 or less and the percentage of patients with a BMI of at least 26 who lost at least one unit of BMI. It may be seen from these tables that SCH 39166, particularly at 100 mg/day dosage, was especially effective in reducing weight in the obese population, i.e. a BMI of 26 of greater.
- the O l /O 5 antagonists or D,/D 5 partial agonists of the present invention may be used alone in treating food cravings or in combination with behavioral therapy; weight loss programs; with other CNS compounds described herein, particularly anti-obesity compounds including beta 3 agonists, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT 2c receptor agonists, glucagon-like peptide 1 , melanocortin peptides, cholecystokinin, corticotrophin releasing factor, leptin mimicking compounds and blockers, fat absorption blockers, and nicotine agonists.
- beta 3 agonists include beta 3 agonists, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT 2c receptor agonists, glucagon-like peptide 1 , melanocortin peptides, cholecystokinin, corticotrophin releasing factor, lept
- BMS 196,085 which has the chemical name [R-(R*,R*)]-[4-[2-[[2-(3- chlorophenyl)-2-hy droxy ethyl] amino] propyl]phenoxy] methanesulfonic acid;
- SR 58611 A which has the chemical name [R-(R*,S*)]-[[7-[[2-(3- chlorophenyl)-2-hydroxyethyl] amino] 5, 6,7,8 -tetrahy dro-2- naphthalenyl]oxy] acetic acid ethyl ester hydrochloride.
- the structures of these compounds are shown in Figure 15.
- the D,/D 5 antagonists or D,/D 5 partial agonists of the present invention may be used in combination with other agents which have been shown to modify use or desire to consume food including sibutramine, fluoxitine fenfluramine and analogs, amphetamine and analogs, phenteramine, diethylproprion and mazindol.
- Table 2 demonstrates the reduction in alcohol consumption for the patient population measured in days without consuming any alcohol.
- the D1/D5 antagonists and/or D1/D5 partial agonists of the present invention may be used alone in treating alcohol cravings or in combination with behavioral therapy, and/or with other CNS compounds described herein, particularly alcohol antagonistic drugs.
- Table 3 shows that low doses of SCH39166 also were efficacious in reducing cigarette smoking.
- the D1/D5 antagonist or D1/D5 partial agonist compounds of the present invention may be used alone in treating nicotine cravings or in combination with behavioral therapy, smoking cessation programs, nicotine replacement therapy, such as patches and gum, alone or in combination with other CNS compounds described herein, particularly buspirone and buproprion.
- the compounds of the present invention may be administered alone or in combination with other specified CNS compounds including: A. Anti-obesity compounds, including beta 3 agonists, sibutramine, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotrophin releasing factor, leptin mimicking compounds and blockers, fat absorption blockers and nicotine agonists.
- A. Anti-obesity compounds including beta 3 agonists, sibutramine, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotrophin releasing factor, leptin mimicking compounds and blockers, fat absorption blockers and nicotine agonists.
- Serotonin receptor agonists such as buspirone, gepirone and ipsapirone or serotonin receptor antagonists such as ritanserin, ketanserin, ondansetron, granisetron, sumitriptan, rizatriptan and eletriptan;
- Antipsychotic drugs such as haloperidol, flupenthixol, chlorpromazine and anxiolytics such as diazepam, lorazepam, triazolam, alprazolam and buspirone;
- Antidepressant drugs such as despiramine, imipramine, amitryptyline, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, buproprion and citalopram;
- E Dopaminergic agonists such as bromocriptine, amantadine;
- Anticonvulsants and mood stabilizers such as carbamazepine, phenytoin, lithium, valproic acid, vigabatrin, lamotrigine, tiagabine and zonisamide;
- Cocaine-like agonists such as mazindol, methylphenidate
- Alcohol and opiate antagonist drugs such as disulfiram, acamprosate and naltrexone.
- D1 /D5 antagonists or D1 /D5 partial agonists of the present invention in combination with the other CNS compounds noted above may permit lower doses of each compound to be used thereby providing increased efficacy while decreasing side effects.
- the preferred D1/D5 antagonist compounds are SCH 39166, SCH 23390 NNC-22-0010 and BTS-73-947.
- the preferred D1/D5 partial agonist compound is (+)SKF 38393.
- 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.
- the CNS compound When a CNS compound is administered in addition to the D,/ 5 antagonist or 0 ⁇ 5 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.
- the compounds may be administered to a mammal by any route of administration which will provide the requisite concentration of the D 1 /D5 antagonist or D1/D5 partial agonist.
- 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.
- a tablet of SCH 39166 may have the following composition, although other compositions 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.
- 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.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK581-2000A SK5812000A3 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
BR9814830-3A BR9814830A (en) | 1997-10-28 | 1998-10-26 | Desire reduction method in mammals |
EP98953826A EP1043980A2 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
IL13565998A IL135659A0 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
KR1020007004505A KR20010031470A (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
JP2000517699A JP2001520989A (en) | 1997-10-28 | 1998-10-26 | Methods for reducing cravings in mammals |
CA002308453A CA2308453A1 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
HU0100115A HUP0100115A2 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
AU11100/99A AU1110099A (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
NO20002149A NO20002149L (en) | 1997-10-28 | 2000-04-27 | Procedure for reducing mammalian addiction |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US95921397A | 1997-10-28 | 1997-10-28 | |
US08/959,213 | 1997-10-28 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO1999021540A2 true WO1999021540A2 (en) | 1999-05-06 |
WO1999021540A3 WO1999021540A3 (en) | 1999-09-02 |
WO1999021540B1 WO1999021540B1 (en) | 1999-10-28 |
Family
ID=25501785
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/022255 WO1999021540A2 (en) | 1997-10-28 | 1998-10-26 | Method of reducing craving in mammals |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1043980A2 (en) |
JP (1) | JP2001520989A (en) |
KR (1) | KR20010031470A (en) |
CN (1) | CN1283116A (en) |
AR (1) | AR015984A1 (en) |
AU (1) | AU1110099A (en) |
BR (1) | BR9814830A (en) |
CA (1) | CA2308453A1 (en) |
CO (1) | CO4970824A1 (en) |
HU (1) | HUP0100115A2 (en) |
IL (1) | IL135659A0 (en) |
NO (1) | NO20002149L (en) |
PE (1) | PE122299A1 (en) |
SK (1) | SK5812000A3 (en) |
WO (1) | WO1999021540A2 (en) |
ZA (1) | ZA989786B (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20010050225A (en) * | 1999-08-27 | 2001-06-15 | 실버스타인 아써 에이. | A pharmaceutical composition for the prevention and treatment of nicotine addiction in a mammal |
US6323239B1 (en) | 1998-08-05 | 2001-11-27 | Brookhaven Science Associates | Treatment of addiction to ethanol and addictive-related behavior |
US6395783B1 (en) | 2000-10-23 | 2002-05-28 | Brookhaven Science Associates, Llc | Treatment of PCP addiction and PCP addiction-related behavior |
US6410527B1 (en) * | 1998-03-02 | 2002-06-25 | Schering Corporation | Method of treating obsessive compulsive disorders, somatoform disorders, dissociative disorders, eating disorders, impulse control disorders, and autism |
US6462084B1 (en) | 2001-05-14 | 2002-10-08 | Brookhaven Science Associates, Llc | Treatment for obsessive-compulsive disorder (OCD) and OCD-related disorders using GVG |
US6890951B2 (en) | 1998-08-05 | 2005-05-10 | Brookhaven Science Associates Llc | Treatment of addiction and addiction-related behavior |
US8093300B2 (en) | 2001-11-05 | 2012-01-10 | Krele Pharmaceuticals, Inc. | Compositions and methods for increasing compliance with therapies using aldehyde dehydrogenase inhibitors and treating alcoholism |
EP3170499A1 (en) | 2010-09-01 | 2017-05-24 | Tonix Pharmaceuticals, Inc. | Treatment for cocaine addiction |
EP3057595A4 (en) * | 2013-10-18 | 2017-06-07 | Psyadon Pharmaceuticals, Inc. | Fused benzazepines for treatment of stuttering |
US11298361B2 (en) | 2012-07-12 | 2022-04-12 | Emalex Biosciences, Inc. | Fused benzazepines for treatment of Tourette's Syndrome |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110327350B (en) * | 2019-07-11 | 2021-02-23 | 温州医科大学 | Application of dopamine D1 receptor antagonist SCH39166 in preparation of drugs for treating pathological angiogenesis of eyes |
CN110833621A (en) * | 2019-12-06 | 2020-02-25 | 中国医科大学 | Application of dopamine receptor 1 antagonist in preparation of drug for treating mouse schizophrenia caused by ketamine |
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1998
- 1998-10-26 KR KR1020007004505A patent/KR20010031470A/en not_active Application Discontinuation
- 1998-10-26 EP EP98953826A patent/EP1043980A2/en not_active Withdrawn
- 1998-10-26 SK SK581-2000A patent/SK5812000A3/en unknown
- 1998-10-26 CA CA002308453A patent/CA2308453A1/en not_active Abandoned
- 1998-10-26 HU HU0100115A patent/HUP0100115A2/en unknown
- 1998-10-26 AU AU11100/99A patent/AU1110099A/en not_active Abandoned
- 1998-10-26 JP JP2000517699A patent/JP2001520989A/en not_active Withdrawn
- 1998-10-26 CO CO98062495A patent/CO4970824A1/en unknown
- 1998-10-26 WO PCT/US1998/022255 patent/WO1999021540A2/en not_active Application Discontinuation
- 1998-10-26 CN CN98812730A patent/CN1283116A/en active Pending
- 1998-10-26 BR BR9814830-3A patent/BR9814830A/en not_active Application Discontinuation
- 1998-10-26 IL IL13565998A patent/IL135659A0/en unknown
- 1998-10-27 ZA ZA989786A patent/ZA989786B/en unknown
- 1998-10-27 PE PE1998001010A patent/PE122299A1/en not_active Application Discontinuation
- 1998-10-27 AR ARP980105373A patent/AR015984A1/en unknown
-
2000
- 2000-04-27 NO NO20002149A patent/NO20002149L/en not_active Application Discontinuation
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WO1996013257A1 (en) * | 1994-10-27 | 1996-05-09 | Merck & Co., Inc. | Use of receptor potentiators |
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NO20002149L (en) | 2000-06-26 |
BR9814830A (en) | 2000-10-03 |
PE122299A1 (en) | 1999-12-04 |
JP2001520989A (en) | 2001-11-06 |
WO1999021540B1 (en) | 1999-10-28 |
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KR20010031470A (en) | 2001-04-16 |
IL135659A0 (en) | 2001-05-20 |
CA2308453A1 (en) | 1999-05-06 |
SK5812000A3 (en) | 2000-12-11 |
WO1999021540A3 (en) | 1999-09-02 |
AR015984A1 (en) | 2001-05-30 |
NO20002149D0 (en) | 2000-04-27 |
AU1110099A (en) | 1999-05-17 |
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HUP0100115A2 (en) | 2001-06-28 |
CN1283116A (en) | 2001-02-07 |
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