CA2094157A1 - Use of endo-n-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2, 3-dihydro-3,3 dimethylindole-1-carboxamide in the treatment of dependence and withdrawal syndrome - Google Patents
Use of endo-n-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2, 3-dihydro-3,3 dimethylindole-1-carboxamide in the treatment of dependence and withdrawal syndromeInfo
- Publication number
- CA2094157A1 CA2094157A1 CA002094157A CA2094157A CA2094157A1 CA 2094157 A1 CA2094157 A1 CA 2094157A1 CA 002094157 A CA002094157 A CA 002094157A CA 2094157 A CA2094157 A CA 2094157A CA 2094157 A1 CA2094157 A1 CA 2094157A1
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- abuse
- drug
- substance
- cocaine
- dependence
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
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- Public Health (AREA)
- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
A method for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse in mammals including humans, which method comprises administering an effective non-toxic amount of an indoline derivative (e.g.
endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-_ 1-carboxamide) or a pharmaceutically acceptable salt or solvate thereof.
endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-_ 1-carboxamide) or a pharmaceutically acceptable salt or solvate thereof.
Description
W O 92/06689 2 0 ~ 415 7 PCT/GB91/01811 Use of endo-N-(8-methyl-8-azabicyclo[3.~.1]oct-3-yl)-2,3-dihydro-3, 3dimethylindole-1-carboxamide in the treatment of dependence and withdra~al s~ldro~e The present invention relates to a method for the relief or prevention of a withdrawal synclrome resulting from addiction 5 to a drug or substance of abuse and~or for the suppression of dependence on drugs or substances of abuse, and to the use of a compound in the preparation of a medicament for such method.
lo EP-0279114 relates to the use of compounds which act as antagonists of 5HT at 5-HT3 receptors for the relief or prevention of a withdrawal symptom resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse.
EP-0247266 discloses endo-N-(B-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide ~hereinafter called the Compound) and a process by which it can be prepared.
The Compound is described in EP-0247266 as having 5-HT M-receptor antagonist activity, anti-emetic activity and/or gastric motility enhancing activity.
25 It has now been shown that administration of the Compound can prevent, alleviate or reverse the withdrawal syndrome.
The Compound is therefore of use for the prevention or relief of a w:ithdrawal syndrome resulting from addiction to drugs or subsl:ances of abuse.
It has also been shown that the Compound suppresses - dependence on drugs or substances of abuse. The Compound is therefore also of use in reducing the cra~ing for a drug or substance of abuse after addition to that drug or substance, 35 and can therefore ~e used for maintainence therapy during remission from addition to drugs or substances of abuse.
W092/06~9 5~ -2- PCT/GB91/01811 The Compound may also be used for prophylactic treatment of subjects liable to become dependent on drugs or substances of abuses.
5 The effectiveness of the Compound for use according to the present invention in the treat:ment of a withdrawal syndrome resulting from addiction to a drug or substance of abuse, and for the suppression of dependence on a drug or substance of abuse, for example cocaine or benzodiazepines such as 0 diazepam, may be demonstrated in animals using standard tests, for example, the light dark exploration test in mice, the rat social interaction test, a marmoset behavioural test, the 'drinkometer' alcohol consumption test in rats, - and the cocaine discrimative stimulus paradigm in rats.
Accordingly, the present invention provides a method of treatment for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or 20 substances of abuse in mammals including humans, which ; method comprises administering an effective, non-toxic amount of the Compound or a pharmaceutically acceptable salt or solvate thereof to the mammal in need of such treatment.
2s The administration is preferably by way of a pharmaceutical composition.
, Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such 30 may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
3s ., ~
W092/0~9 2 ~ 9 4 1 5 7 PCT/GB91/01811 Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, 5 flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.
Suitable fillers for use include cellulose, mannitol, 0 lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and stareh derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.
5 Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or 20 other suitable vehicie before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, 25 emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edibla oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for 30 example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional fla~ouring or colouring agents.
.
Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or 3s elixirs or are presented as a dry product for reconstitution W092/06689 2 ~ 7 P~T/GB91/01~11 _4_ with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and 5 flavouring or colouring agents.
The oral compositions may be prepared by conventional methods of blendin~, filling or tabletting. Repeated blending operations may be used to distribute the acti~e o agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
For parenteral administration, fluid unit dose forms are 15 prepared containing the Compound of the present invention and a sterile vehicle. The Compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the Compound in a vehicle and filter sterilising 20 before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed 2s under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the Compound is suspended in the vehicle instead of being dissolved and sterilised by 30 exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the Compound of the invention.
35 An amount effective to treat the disorders hereinbefore described depends on the nature and severity of the disorder ' ~.
being treated and the weight of the mammal. However, a unit - dose for a 70kg adult will normally contain O.Ol to lOOOmg for example O.l to 500mg, of the Compound of the invention.
Unit doses may be administered once or more than once a day, 5 for example, 2, 3 or 4 times a day, more usually l to 3 times a day, that is in the range of approximately O.OOOl to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
No adverse toxicological effects are indicated at any of the lO aforementioned dosage ranges.
The invention also provides a pharmaceutical composition which comprises an effective amount of the Compound or a pharmaceutically acceptable salt or solvate thereof for the 15 relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the ` suppression of dependence on drugs or substances of abuse.
Such composition may be prepared in the manner as described 20 hereinbefore.
In a further aspect the invention provides the use of the Compound or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the relief 2s or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or Por the suppression of dependence on drugs or substances of abuse.
Such manufacture and treatment may be carried out in the 30 manner as described hereinbefore.
W092/06~9 9 ~ 1~ 7 -6- PCT/GB91/0181l Pharmacoloqlcal Data l. Cocaine Discriminative Stimulus Paradiqin 5 Action of test compound on the behavioural effects of cocaine in male hooded Lister rats as measured in the cocaine discriminative stimulus paradigm.
METHODS
RATS
- Nine male Hooded Lister rats initially weighing 200-250g were used throughout the experiment. They were housed in lS groups of four or five under a 12 hour light~dark cycle. The rats were fed according to a predetermined growth curve for this species so that their weights were maintained at 80-90 of their free feeding weights. Water was available ad lib.
Training and test sessions were conducted five days per 20 week.
~'..'..
APPARATUS
The apparatus consisted of a standard ventilated chamber 25 (Campden instruments) contained in a sound-attenuated box. `
The chamber was equipped with two retractable bars separated by a recess into which 45mg food pellets were dispensed.
Responses on the bars were automatically recorded by microcomputer.
TRAINING
The rats were initially trained to press the bars for food rewards on an FR-l (fixed ratio l) schedule of reinforcement 3s in 15 min. training sessions. Under this schedule, one press , ,.,. . , ~ ... .. . . . . . . . . . . . .
W092/06689 2 ~ 9 ~1~ 7 PCT/GB91/o~
on a bar resulted in one food pellet being dispensed to the - rat. On alternate days, the leEt or right bar was presented to the rat. As the rats became adept at performing this task, the fixed ratio was increased incrementally up to FR-5 10 (one reward for ten responses.
After the preliminary training had been established, drug ~ discrimination training commenced. Cocaine (5.0 mg/kg ip) or ; saline (1.0 mg/kg ip) were injected and both bars were 0 presented to each rat 15 minutes later. For each rat, one bar was paired with cocaine injection and the other bar was paired with vehicle (saline) injection. In order to balance for side preferences, cocaine was paired with the left bar for five rats and paired with the right bar for the 15 remaining four rats. Vehicle injections were paired with the other bar. Under these conditions of the FR-10 schedule, each rat was rewarded if it accumulated 10 responses on the correct bar (depending on whether it had received cocaine or vehicle). As discrimination training progressed, a VI
20 (variable interval) was introduced into the reinforcement schedule. At the onset of the training session, during a randomly determined interval the rats were not rewarded on either bar. After this interval the schedule switched into the FR-10 component until the rats produced ten correct 25 responses. The schedule then switched back to the VI
component. This tandem schedule continued through each 15 min. training session. As the rats acquired the the cocaine discrimination, the VI was progressively increased to 60 seconds ~VI-60; mean time = 60 sec; range = 14-108 sec.) In 30 addition, a punishment schedule was included in the FR
component which required the rat to respond on the correct bar on ten consecutive occasions in order to be rewarded.
This minimisecl the possibility of the rats alternating between bars i.n order to gain food rewards by chance. Thus 35 the final schedule of reinforcement was a tandem VI-60, FR-10 with punishment.
W092/0668s 7 -8- PCT/GB91/01811 Training injections were made in a restricted randomised order such that no rat received more than three consecutive treatments of cocaine or saline, and over the period of training there was an equal nur~ber of cocaine and saline s treatments TESTS
After approximately 60 training sessions, discrimination l0 control was achieved and tests were initiated. The rats were tested in 5 min. extinction sessions on Tuesdays and Fridays during which no food rewards were available. In order to maintain discrimination control, 15 min. training sessions were continued on intervening days such that the rats were trained after saline injection on Mondays and Thursdays and after cocaine injection on Wednesdays. This minimised the possiblity of residual cocaine effects being carried over on to test days. On the test days, the rats received ~pretreatment with test compound, (the Compound, 20 hydrochloride salt) (0.0025, 0.005 or 0.0l mg/kg sc) or vehicle (saline lml/kg sc) 45 min. prior to test, and cocaine hydrochloride (2.5 mg/kg ip) or vehicle (saline lml/kg ip) 30 min. prior to test. These eight treatment combinations were administered in random order, and each rat 2s received every ~reatment. After completion of this random scheme four extra treatments were conducted in which rats were pretreated with test compound (0.00125 or 0.02 mg/kg sc) 45 min. prior ~o test and cocaine hydrochloride ~2.5 mgtkg ip) or vehicle ~saline lml/kg ip) 30 min. prior to 30 test.
DRUGS
Cocaine hydrochloride (Sigma) was dissolved in isotonic 35 saline and injected in a volume of l ml/kg ip. Test compound ,`
was dissolved in isotonic saline and was injected in the ;
: ' :.
_9_ flank in a volume of 1 ml/kg sc. Vehicle solutions were isotonic saline and were injected in a volume of l ml/kg ip (cocaine vehicle) and l ml/kg sc (test compound vehicle).
Drug doses are expressed as the base equivalent.
s DATA PRESENTATION AND STATISTICAL ANALYSIS
The number of responses on the cocaine training bar was expressed as a percentage of the total number of responses 0 accumulated on both bars in the 5 min. extinction tests. The total number of responses accumulated on both bars in the 5 min. extinction tests was also noted. Data was analysed by two factor analysis or variance with rat and treatment as the independent variables, and by Dunnett's t-test to allow for multiple comparisons with a control group.
.
RESULTS
Analysis of the results for the percent cocaine bar 20 responses provided strong evidence that treatments affected ` responding (F(8,56)=32.2, P<0.00l). Responding after saline control was 11.8+3.3%, and this was increased to 87.0+6.4%
for the cocaine controt (t(7)=9.96, P<0.0l). Compared to the cocaine control, the 0.0l mg/kg dose of test compound 25 significantly attenuated cocaine-appropriate responding (t(7)=4.73, P<0.0l). The 0.0025 and 0.005 doses of test compound showed a similar trend although the results were not significant. The attenuation of cocaine-appropriate responding was never sufficient to reach the low levels seen 30 with the saline control such that the percent responding with cocaine after the pretreatments with the different doses of test compound were still significantly higher than the responding after saline (lowest t(7)=9.46t P<0.0l).
35 Analysis of the total responses indicated that treatment did not affect response rate (F(7,56)=0~99, p>0.4).
WO~/06689 2 ~ 7 PCT/GB91/0181l --10-- ~' DISCUSSION
The data reported here provide e~idence that the test compound (0.01 mg/kg), significantly attenuated the 5 interoceptive effects caused by cocaine in rats without producing full blockade. These effects were produced by doses of test compound which did not reduce response rates and therefore there was no evidence that the attenuation of the cue was due to confounding non-specific effects (eg 10 anaesthesia, catalepsy, seizure activity). The anxiolytic profile of the test compound together with the inhibitory effects on the cocaine cue demonstrated in this study suggest that this compound has potential therapeutic efficacy to block cocaine self-administration and dependence.
lo EP-0279114 relates to the use of compounds which act as antagonists of 5HT at 5-HT3 receptors for the relief or prevention of a withdrawal symptom resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse.
EP-0247266 discloses endo-N-(B-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide ~hereinafter called the Compound) and a process by which it can be prepared.
The Compound is described in EP-0247266 as having 5-HT M-receptor antagonist activity, anti-emetic activity and/or gastric motility enhancing activity.
25 It has now been shown that administration of the Compound can prevent, alleviate or reverse the withdrawal syndrome.
The Compound is therefore of use for the prevention or relief of a w:ithdrawal syndrome resulting from addiction to drugs or subsl:ances of abuse.
It has also been shown that the Compound suppresses - dependence on drugs or substances of abuse. The Compound is therefore also of use in reducing the cra~ing for a drug or substance of abuse after addition to that drug or substance, 35 and can therefore ~e used for maintainence therapy during remission from addition to drugs or substances of abuse.
W092/06~9 5~ -2- PCT/GB91/01811 The Compound may also be used for prophylactic treatment of subjects liable to become dependent on drugs or substances of abuses.
5 The effectiveness of the Compound for use according to the present invention in the treat:ment of a withdrawal syndrome resulting from addiction to a drug or substance of abuse, and for the suppression of dependence on a drug or substance of abuse, for example cocaine or benzodiazepines such as 0 diazepam, may be demonstrated in animals using standard tests, for example, the light dark exploration test in mice, the rat social interaction test, a marmoset behavioural test, the 'drinkometer' alcohol consumption test in rats, - and the cocaine discrimative stimulus paradigm in rats.
Accordingly, the present invention provides a method of treatment for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or 20 substances of abuse in mammals including humans, which ; method comprises administering an effective, non-toxic amount of the Compound or a pharmaceutically acceptable salt or solvate thereof to the mammal in need of such treatment.
2s The administration is preferably by way of a pharmaceutical composition.
, Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such 30 may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
3s ., ~
W092/0~9 2 ~ 9 4 1 5 7 PCT/GB91/01811 Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, 5 flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.
Suitable fillers for use include cellulose, mannitol, 0 lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and stareh derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.
5 Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or 20 other suitable vehicie before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, 25 emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edibla oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for 30 example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional fla~ouring or colouring agents.
.
Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or 3s elixirs or are presented as a dry product for reconstitution W092/06689 2 ~ 7 P~T/GB91/01~11 _4_ with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and 5 flavouring or colouring agents.
The oral compositions may be prepared by conventional methods of blendin~, filling or tabletting. Repeated blending operations may be used to distribute the acti~e o agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
For parenteral administration, fluid unit dose forms are 15 prepared containing the Compound of the present invention and a sterile vehicle. The Compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the Compound in a vehicle and filter sterilising 20 before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed 2s under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the Compound is suspended in the vehicle instead of being dissolved and sterilised by 30 exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the Compound of the invention.
35 An amount effective to treat the disorders hereinbefore described depends on the nature and severity of the disorder ' ~.
being treated and the weight of the mammal. However, a unit - dose for a 70kg adult will normally contain O.Ol to lOOOmg for example O.l to 500mg, of the Compound of the invention.
Unit doses may be administered once or more than once a day, 5 for example, 2, 3 or 4 times a day, more usually l to 3 times a day, that is in the range of approximately O.OOOl to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
No adverse toxicological effects are indicated at any of the lO aforementioned dosage ranges.
The invention also provides a pharmaceutical composition which comprises an effective amount of the Compound or a pharmaceutically acceptable salt or solvate thereof for the 15 relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the ` suppression of dependence on drugs or substances of abuse.
Such composition may be prepared in the manner as described 20 hereinbefore.
In a further aspect the invention provides the use of the Compound or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the relief 2s or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or Por the suppression of dependence on drugs or substances of abuse.
Such manufacture and treatment may be carried out in the 30 manner as described hereinbefore.
W092/06~9 9 ~ 1~ 7 -6- PCT/GB91/0181l Pharmacoloqlcal Data l. Cocaine Discriminative Stimulus Paradiqin 5 Action of test compound on the behavioural effects of cocaine in male hooded Lister rats as measured in the cocaine discriminative stimulus paradigm.
METHODS
RATS
- Nine male Hooded Lister rats initially weighing 200-250g were used throughout the experiment. They were housed in lS groups of four or five under a 12 hour light~dark cycle. The rats were fed according to a predetermined growth curve for this species so that their weights were maintained at 80-90 of their free feeding weights. Water was available ad lib.
Training and test sessions were conducted five days per 20 week.
~'..'..
APPARATUS
The apparatus consisted of a standard ventilated chamber 25 (Campden instruments) contained in a sound-attenuated box. `
The chamber was equipped with two retractable bars separated by a recess into which 45mg food pellets were dispensed.
Responses on the bars were automatically recorded by microcomputer.
TRAINING
The rats were initially trained to press the bars for food rewards on an FR-l (fixed ratio l) schedule of reinforcement 3s in 15 min. training sessions. Under this schedule, one press , ,.,. . , ~ ... .. . . . . . . . . . . . .
W092/06689 2 ~ 9 ~1~ 7 PCT/GB91/o~
on a bar resulted in one food pellet being dispensed to the - rat. On alternate days, the leEt or right bar was presented to the rat. As the rats became adept at performing this task, the fixed ratio was increased incrementally up to FR-5 10 (one reward for ten responses.
After the preliminary training had been established, drug ~ discrimination training commenced. Cocaine (5.0 mg/kg ip) or ; saline (1.0 mg/kg ip) were injected and both bars were 0 presented to each rat 15 minutes later. For each rat, one bar was paired with cocaine injection and the other bar was paired with vehicle (saline) injection. In order to balance for side preferences, cocaine was paired with the left bar for five rats and paired with the right bar for the 15 remaining four rats. Vehicle injections were paired with the other bar. Under these conditions of the FR-10 schedule, each rat was rewarded if it accumulated 10 responses on the correct bar (depending on whether it had received cocaine or vehicle). As discrimination training progressed, a VI
20 (variable interval) was introduced into the reinforcement schedule. At the onset of the training session, during a randomly determined interval the rats were not rewarded on either bar. After this interval the schedule switched into the FR-10 component until the rats produced ten correct 25 responses. The schedule then switched back to the VI
component. This tandem schedule continued through each 15 min. training session. As the rats acquired the the cocaine discrimination, the VI was progressively increased to 60 seconds ~VI-60; mean time = 60 sec; range = 14-108 sec.) In 30 addition, a punishment schedule was included in the FR
component which required the rat to respond on the correct bar on ten consecutive occasions in order to be rewarded.
This minimisecl the possibility of the rats alternating between bars i.n order to gain food rewards by chance. Thus 35 the final schedule of reinforcement was a tandem VI-60, FR-10 with punishment.
W092/0668s 7 -8- PCT/GB91/01811 Training injections were made in a restricted randomised order such that no rat received more than three consecutive treatments of cocaine or saline, and over the period of training there was an equal nur~ber of cocaine and saline s treatments TESTS
After approximately 60 training sessions, discrimination l0 control was achieved and tests were initiated. The rats were tested in 5 min. extinction sessions on Tuesdays and Fridays during which no food rewards were available. In order to maintain discrimination control, 15 min. training sessions were continued on intervening days such that the rats were trained after saline injection on Mondays and Thursdays and after cocaine injection on Wednesdays. This minimised the possiblity of residual cocaine effects being carried over on to test days. On the test days, the rats received ~pretreatment with test compound, (the Compound, 20 hydrochloride salt) (0.0025, 0.005 or 0.0l mg/kg sc) or vehicle (saline lml/kg sc) 45 min. prior to test, and cocaine hydrochloride (2.5 mg/kg ip) or vehicle (saline lml/kg ip) 30 min. prior to test. These eight treatment combinations were administered in random order, and each rat 2s received every ~reatment. After completion of this random scheme four extra treatments were conducted in which rats were pretreated with test compound (0.00125 or 0.02 mg/kg sc) 45 min. prior ~o test and cocaine hydrochloride ~2.5 mgtkg ip) or vehicle ~saline lml/kg ip) 30 min. prior to 30 test.
DRUGS
Cocaine hydrochloride (Sigma) was dissolved in isotonic 35 saline and injected in a volume of l ml/kg ip. Test compound ,`
was dissolved in isotonic saline and was injected in the ;
: ' :.
_9_ flank in a volume of 1 ml/kg sc. Vehicle solutions were isotonic saline and were injected in a volume of l ml/kg ip (cocaine vehicle) and l ml/kg sc (test compound vehicle).
Drug doses are expressed as the base equivalent.
s DATA PRESENTATION AND STATISTICAL ANALYSIS
The number of responses on the cocaine training bar was expressed as a percentage of the total number of responses 0 accumulated on both bars in the 5 min. extinction tests. The total number of responses accumulated on both bars in the 5 min. extinction tests was also noted. Data was analysed by two factor analysis or variance with rat and treatment as the independent variables, and by Dunnett's t-test to allow for multiple comparisons with a control group.
.
RESULTS
Analysis of the results for the percent cocaine bar 20 responses provided strong evidence that treatments affected ` responding (F(8,56)=32.2, P<0.00l). Responding after saline control was 11.8+3.3%, and this was increased to 87.0+6.4%
for the cocaine controt (t(7)=9.96, P<0.0l). Compared to the cocaine control, the 0.0l mg/kg dose of test compound 25 significantly attenuated cocaine-appropriate responding (t(7)=4.73, P<0.0l). The 0.0025 and 0.005 doses of test compound showed a similar trend although the results were not significant. The attenuation of cocaine-appropriate responding was never sufficient to reach the low levels seen 30 with the saline control such that the percent responding with cocaine after the pretreatments with the different doses of test compound were still significantly higher than the responding after saline (lowest t(7)=9.46t P<0.0l).
35 Analysis of the total responses indicated that treatment did not affect response rate (F(7,56)=0~99, p>0.4).
WO~/06689 2 ~ 7 PCT/GB91/0181l --10-- ~' DISCUSSION
The data reported here provide e~idence that the test compound (0.01 mg/kg), significantly attenuated the 5 interoceptive effects caused by cocaine in rats without producing full blockade. These effects were produced by doses of test compound which did not reduce response rates and therefore there was no evidence that the attenuation of the cue was due to confounding non-specific effects (eg 10 anaesthesia, catalepsy, seizure activity). The anxiolytic profile of the test compound together with the inhibitory effects on the cocaine cue demonstrated in this study suggest that this compound has potential therapeutic efficacy to block cocaine self-administration and dependence.
2. Rat Social Interaction Test INTRODUCTION
One ma~or therapeutic drawback to the use of benzodiazepine anxiolytics is the development of tolerance to the drugs and the induction of a withdrawal syndrome on cessation of treatment, where symptoms of anxiety (e.g. irritability, 2s tension, restlessness, foreboding, tremor, headache, sweating and insomnia) pose a particular difficulty in the majority of patients ~Marks 1985). In the present study the effects of test compound on withdrawal from diazepam were studied using the rat social interaction test of anxiety 30 (File, 1985). In this test low light familiar conditions were used to facilitate the observation of anxiogenic responses.
METHODS
Male CD rats ~Charles River) were housed in groups of 6 under a 12h light (lights on 7.00 a.m.) cycle with free W092/066~9 2 ~ 9 415 7 PCT/GB91/~1811 access to food (standard rat chow) and water in a room adjacent ~o the testing room. They were orally dosed for 14 days with vehicle or diazepam (40 mg/kg) twice daily. On day 11 rats were individually housed in the same room and on s days 13 and 14 were placed in the social interaction chamber (made of black perspex 54 cm x 37 cm x 26 cm with a transparent perspex front side and no lid, floor divided into 24 squares by white lines) under red light for 10 mins.
On day 15, one day after the la~st dose of diazepam or 10 vehicle, they were administered vehicle or test compound (0.01 or 0.1 mg/kg p.o.) 12h and 30 min pretest and placed with an unfamiliar weight matched (+30g) pair mate into the social interaction chamber in an adjacent room. Active social interaction (sniffing, grooming, following, mounting, boxing, biting, crawling over/under) and locomotion (no. of squares entered) was scored by remote video monitoring by a 'blind' observer over the next 15 mins. The rats were then removed and the box carefully wiped wlth a damp cloth before testing of a subsequent pair of rats. Daily body weight 20 change was monitored for each rat over the whole 15 day experimental period.
Dru~s: Diazepam and test compound were ground in a pestle and mortar and suspended (dissolved test compound) in 25 1% methyl cellulose. All drug doses refer to free base and were given in a volume of 1 ml/kg p.o.
STATISTICS
30 The ability of test compound to reverse the effects of withdrawal from chronic diazepam was assessed by 2 way ANOVA
and Newman ~eul's test.
W092/0 ~ ~ 7 PCTtGB~l/01811 Effect of withdrawal from chronic diazepam (40 mq/kq) and Compound substitution.
One day withdrawal from chronic diazepam (40 mg/kg p.o., 5 b.i.d. x 14 days, vehicle day 15 12h and 30 min pretest p.o.) significantly suppressed social behaviours (Table) in the social interaction test under low light familiar conditions, but had no effect on locomotion (Table).
Administration of test compound (the Compound, hydrochloride 10 salt) (0.01 or 0.1 mg/kg p.o.) to chronic diazepam (40 mg/kg) withdrawn rats 12h and 30 min pretest significantly reversed the deficit in social interaction scores (Table).
None of the above treatments affected locomotion (Ta~le).
Withdrawal from chronic diazepam treatment lowered social interaction of rats but not locomotion during the test.
This is consistent with the induction of anxiety (File 20 1985). This anxiogenic-like response is similar to that reported by Costall et al (1989) using the same anxiety model. Costall et al ~1989) also reported an anxiogenic response to diazepam withdrawal in the mouse light/dark box test of anxiety. These results in animal tests may model 25 the clinical anxiogenic response to cessation of prolonged benzodiazepine treatment (Marks 1985). The ability of the Compound to reverse the anxiogenic effects of chronic diazepam withdrawal suggests that the Compound has potential therapeutic ef~icacy in the treatment of anxious pa~ients 30 particularly those withdrawn from long term (or short) treatment with benzodiazepines.
WO 92/06689 2 0 9 ~15 7 PCI~/GB91/01811 REFERENCE S
Costall, B., Jones, B.J., Kelly, M.E., Naylor, R.J., Onaivi, E.S. and Tyers, M.B., (1989) Ondansetron inhibits a behavioural consequence of withdrawal from drugs of abuse. Pharmacol. Biochem. Behav., 36, 339-344.
File, S.E. (1985) Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour.
Neuropsychobiology 13, 55-62.
Marks, J., (1985) Description of the benzodiazepine withdrawal reaction. In : Marks. J., ed. The benzodiazepines, use, overuse, misuse, abuse.
Lancaster: MTP Press Ltd; pp 33-38.
.,,, ~ ........ .. ,; ~",,~, " , ,~,~ "" ",,,,".,,.,,,,,", ,~,"" ,,,;,,,, ,,, ,. ," ~;", "~
W092/06689 PCT/GB91/0l8l1 2~ 41~7 -14-Table:
Effect of the Compound, hydrochloride salt (0.01 or 0.1 mg/kg) or vehicle (p.o. on day 15, 12h and 30 min pretest) 5 on the behavioural response to withdrawal from chronic diazepam (40mg/kg p.o., b.i.d., x 1~ days) in the rat social - interaction test.
_ o Treatment Treatment Mean ~ SEM
Days 1-14 Dav 15 _ Total Locomotion Interaction (Squares . .
Scores (S) crossed) ,:
_ _ _ ~
Vehicle Vehicle 161.7i9.9 438.0 + 36.7 -.. _ l _ . _~ :' 20Diazepam Vehicle 92.1+7.9 447.2 + 16.7 ; 4Omg/kg _. . _ .
Diazepam Compound, HCl 149.3ill.3++ 407.5 + 23.3 4Omg/kg O.Olmg/kg 25 - _ _ _ .
Diazepam Compound, HCl 133.8ill.5+ 427.4 + 16.5 40mg/kg O.lmg/kg ~ . . _ ~
30 Significantly different from vehicle ~ vehicle treated group ** p<O . 01 Significantly different from diazepam + vehicle treated group + p<O.05 ++ p<O.Ol -by Dunnett' s test following significant 1 way ANOVA-
One ma~or therapeutic drawback to the use of benzodiazepine anxiolytics is the development of tolerance to the drugs and the induction of a withdrawal syndrome on cessation of treatment, where symptoms of anxiety (e.g. irritability, 2s tension, restlessness, foreboding, tremor, headache, sweating and insomnia) pose a particular difficulty in the majority of patients ~Marks 1985). In the present study the effects of test compound on withdrawal from diazepam were studied using the rat social interaction test of anxiety 30 (File, 1985). In this test low light familiar conditions were used to facilitate the observation of anxiogenic responses.
METHODS
Male CD rats ~Charles River) were housed in groups of 6 under a 12h light (lights on 7.00 a.m.) cycle with free W092/066~9 2 ~ 9 415 7 PCT/GB91/~1811 access to food (standard rat chow) and water in a room adjacent ~o the testing room. They were orally dosed for 14 days with vehicle or diazepam (40 mg/kg) twice daily. On day 11 rats were individually housed in the same room and on s days 13 and 14 were placed in the social interaction chamber (made of black perspex 54 cm x 37 cm x 26 cm with a transparent perspex front side and no lid, floor divided into 24 squares by white lines) under red light for 10 mins.
On day 15, one day after the la~st dose of diazepam or 10 vehicle, they were administered vehicle or test compound (0.01 or 0.1 mg/kg p.o.) 12h and 30 min pretest and placed with an unfamiliar weight matched (+30g) pair mate into the social interaction chamber in an adjacent room. Active social interaction (sniffing, grooming, following, mounting, boxing, biting, crawling over/under) and locomotion (no. of squares entered) was scored by remote video monitoring by a 'blind' observer over the next 15 mins. The rats were then removed and the box carefully wiped wlth a damp cloth before testing of a subsequent pair of rats. Daily body weight 20 change was monitored for each rat over the whole 15 day experimental period.
Dru~s: Diazepam and test compound were ground in a pestle and mortar and suspended (dissolved test compound) in 25 1% methyl cellulose. All drug doses refer to free base and were given in a volume of 1 ml/kg p.o.
STATISTICS
30 The ability of test compound to reverse the effects of withdrawal from chronic diazepam was assessed by 2 way ANOVA
and Newman ~eul's test.
W092/0 ~ ~ 7 PCTtGB~l/01811 Effect of withdrawal from chronic diazepam (40 mq/kq) and Compound substitution.
One day withdrawal from chronic diazepam (40 mg/kg p.o., 5 b.i.d. x 14 days, vehicle day 15 12h and 30 min pretest p.o.) significantly suppressed social behaviours (Table) in the social interaction test under low light familiar conditions, but had no effect on locomotion (Table).
Administration of test compound (the Compound, hydrochloride 10 salt) (0.01 or 0.1 mg/kg p.o.) to chronic diazepam (40 mg/kg) withdrawn rats 12h and 30 min pretest significantly reversed the deficit in social interaction scores (Table).
None of the above treatments affected locomotion (Ta~le).
Withdrawal from chronic diazepam treatment lowered social interaction of rats but not locomotion during the test.
This is consistent with the induction of anxiety (File 20 1985). This anxiogenic-like response is similar to that reported by Costall et al (1989) using the same anxiety model. Costall et al ~1989) also reported an anxiogenic response to diazepam withdrawal in the mouse light/dark box test of anxiety. These results in animal tests may model 25 the clinical anxiogenic response to cessation of prolonged benzodiazepine treatment (Marks 1985). The ability of the Compound to reverse the anxiogenic effects of chronic diazepam withdrawal suggests that the Compound has potential therapeutic ef~icacy in the treatment of anxious pa~ients 30 particularly those withdrawn from long term (or short) treatment with benzodiazepines.
WO 92/06689 2 0 9 ~15 7 PCI~/GB91/01811 REFERENCE S
Costall, B., Jones, B.J., Kelly, M.E., Naylor, R.J., Onaivi, E.S. and Tyers, M.B., (1989) Ondansetron inhibits a behavioural consequence of withdrawal from drugs of abuse. Pharmacol. Biochem. Behav., 36, 339-344.
File, S.E. (1985) Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour.
Neuropsychobiology 13, 55-62.
Marks, J., (1985) Description of the benzodiazepine withdrawal reaction. In : Marks. J., ed. The benzodiazepines, use, overuse, misuse, abuse.
Lancaster: MTP Press Ltd; pp 33-38.
.,,, ~ ........ .. ,; ~",,~, " , ,~,~ "" ",,,,".,,.,,,,,", ,~,"" ,,,;,,,, ,,, ,. ," ~;", "~
W092/06689 PCT/GB91/0l8l1 2~ 41~7 -14-Table:
Effect of the Compound, hydrochloride salt (0.01 or 0.1 mg/kg) or vehicle (p.o. on day 15, 12h and 30 min pretest) 5 on the behavioural response to withdrawal from chronic diazepam (40mg/kg p.o., b.i.d., x 1~ days) in the rat social - interaction test.
_ o Treatment Treatment Mean ~ SEM
Days 1-14 Dav 15 _ Total Locomotion Interaction (Squares . .
Scores (S) crossed) ,:
_ _ _ ~
Vehicle Vehicle 161.7i9.9 438.0 + 36.7 -.. _ l _ . _~ :' 20Diazepam Vehicle 92.1+7.9 447.2 + 16.7 ; 4Omg/kg _. . _ .
Diazepam Compound, HCl 149.3ill.3++ 407.5 + 23.3 4Omg/kg O.Olmg/kg 25 - _ _ _ .
Diazepam Compound, HCl 133.8ill.5+ 427.4 + 16.5 40mg/kg O.lmg/kg ~ . . _ ~
30 Significantly different from vehicle ~ vehicle treated group ** p<O . 01 Significantly different from diazepam + vehicle treated group + p<O.05 ++ p<O.Ol -by Dunnett' s test following significant 1 way ANOVA-
Claims (9)
1. A method for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse in mammals including humans, which method comprises administering an effective, non-toxic amount of endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide or a pharmaceutically acceptable salt or solvate thereof to the mammal in need of such treatment.
2. A method according to claim 1 wherein the drug or substance of abuse is cocaine.
3. A method according to claim 1 wherein the drug or substance of abuse is a benzodiazepine.
4. Use of endo-N-(8-methyl-8-azabicyclo (3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse in mammals including humans.
5. Use according to claim 4 wherein the drug or substance of abuse is cocaine.
6. Use according to claim 4 wherein the drug or substance of abuse is a benzodiazepine.
7. A pharmaceutical composition for the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse in mammals including humans, which comprises an effective amount of endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-1-carboxamide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutical carrier.
8. A composition according to claim 7 wherein the drug or substance of abuse is cocaine.
9. A composition according to claim 7 wherein the drug or substance of abuse is a benzodiazepine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9022537.6 | 1990-10-17 | ||
| GB909022537A GB9022537D0 (en) | 1990-10-17 | 1990-10-17 | Novel treatment |
| GB9112236.6 | 1991-06-07 | ||
| GB919112236A GB9112236D0 (en) | 1991-06-07 | 1991-06-07 | Novel treatment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2094157A1 true CA2094157A1 (en) | 1992-04-18 |
Family
ID=26297808
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002094157A Abandoned CA2094157A1 (en) | 1990-10-17 | 1991-10-17 | Use of endo-n-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2, 3-dihydro-3,3 dimethylindole-1-carboxamide in the treatment of dependence and withdrawal syndrome |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0553160A1 (en) |
| JP (1) | JPH06501946A (en) |
| KR (1) | KR930702979A (en) |
| AU (1) | AU8728591A (en) |
| CA (1) | CA2094157A1 (en) |
| IE (1) | IE913621A1 (en) |
| WO (1) | WO1992006689A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399562A (en) * | 1994-02-04 | 1995-03-21 | G. D. Searle & Co. | Indolones useful as serotonergic agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0247266B1 (en) * | 1986-01-07 | 1993-03-10 | Beecham Group Plc | Indole derivatives having an azabicyclic side chain, process for their preparation, intermediates, and pharmaceutical compositions |
| US4948803A (en) * | 1986-11-21 | 1990-08-14 | Glaxo Group Limited | Medicaments for treatment on prevention of withdrawal syndrome |
| GB8701022D0 (en) * | 1987-01-19 | 1987-02-18 | Beecham Group Plc | Treatment |
-
1991
- 1991-10-16 IE IE362191A patent/IE913621A1/en not_active Application Discontinuation
- 1991-10-17 AU AU87285/91A patent/AU8728591A/en not_active Abandoned
- 1991-10-17 JP JP3516506A patent/JPH06501946A/en active Pending
- 1991-10-17 CA CA002094157A patent/CA2094157A1/en not_active Abandoned
- 1991-10-17 EP EP91917909A patent/EP0553160A1/en not_active Withdrawn
- 1991-10-17 WO PCT/GB1991/001811 patent/WO1992006689A1/en not_active Application Discontinuation
- 1991-10-17 KR KR1019930701141A patent/KR930702979A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992006689A1 (en) | 1992-04-30 |
| IE913621A1 (en) | 1992-04-22 |
| JPH06501946A (en) | 1994-03-03 |
| AU8728591A (en) | 1992-05-20 |
| KR930702979A (en) | 1993-11-29 |
| EP0553160A1 (en) | 1993-08-04 |
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