WO2008031928A1

WO2008031928A1 - Use of milnacipran for reducing the rewarding properties of alcohol during or after an alcohol withdrawal treatment

Info

Publication number: WO2008031928A1
Application number: PCT/FR2006/002104
Authority: WO
Inventors: Lucilla Mansuy; Martine Daoust; Mickael Naassila
Original assignee: Pierre Fabre Medicament
Priority date: 2006-09-14
Filing date: 2006-09-14
Publication date: 2008-03-20

Abstract

The present invention relates to the use of milnacipran for preparing a medicament for use in reducing the rewarding properties of alcohol during or after an alcohol withdrawal treatment, and also a product comprising milnacipran and an active ingredient which makes it possible to break a patient's alcohol dependency through action on the negative reinforcement effect of alcohol, as a combination product for simultaneous, separate or sequential use in alcohol withdrawal and/or maintaining abstinence from alcohol.

Description

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"Use of milnacipran to decrease the rewarding properties of alcohol during or after alcohol withdrawal treatment"

The present invention relates to the use of milnacipran for the preparation of a medicament for reducing the rewarding properties of alcohol during or after an alcohol withdrawal treatment and / or to maintain abstinence from alcohol. The subject of the invention is also a product comprising, on the one hand, milnacipran and, on the other hand, an active ingredient making it possible to disconnect a patient from alcohol by acting on the negative reinforcing effect of the alcohol, as a product of combination for simultaneous, separate or staggered use in alcohol withdrawal and / or maintenance of alcohol abstinence.

Drug addiction is defined as the set of behaviors that leads to a loss of control of substance use in order to feel the psychotropic effects. These substances capable of inducing this behavior belong to very different pharmacological classes such as opiates (morphine, heroin ...), psychostimulants (amphetamine, cocaine ...), cannabis, but also tobacco (nicotine), alcohol, hallucinogenic substances (LSD ..) and some tranquilizers (benzodiazepines). The common point of these substances of abuse is to increase the dopaminergic transmissions in the reward system and more especially in the nucleus accumbens.

Alcohol is classified as a hazardous substance because it induces very strong physical and mental dependencies and has strong general, neuronal and social toxicities. In the general adult population, alcohol is by far the most consumed psychoactive substance.

Indeed, alcohol remains a real public health problem in France, this substance is responsible for 45,000 deaths / year and about 2 million people suffer from dependence (14% of men and 4% of women). Alcohol dependence is characterized by a compulsive need to consume alcohol, an inability to limit its consumption, that is to say a loss of control, the appearance of a phenomenon of tolerance (increase the doses to achieve the same effect) and the development of a syndrome of abstinence to stop excessive consumption.

In alcohol-dependent patients, a major reason for continuing to drink is the appearance of abstinence manifestations, which are grouped under the term abstinence syndrome, such as anxiety, depression, irritability, emotional inconstancy, nervousness, fatigue, disturbance of sleep, and in some patients, delirium tremens or epileptiform seizures. These symptoms contribute significantly to patients' relapses.

Alcohol dependence is a highly recurrent condition and current treatments are moderately effective. The treatments recommended for the maintenance of abstinence are Pacamprosate (campral® or aotal®), naltrexone

(revia®) and disulfiram (antabuse®).

Alcohol dependence has its origins in the reinforcing effects of the product, ie in the fact that the product enhances the consumption of alcohol. These reinforcing effects of alcohol, like any other drug, may be positive or negative.

In the positive reinforcement mechanism, the drug is taken to derive a pleasant effect, while in the negative reinforcement mechanism, the drug is taken to avoid the unpleasant effects of lack. The positive reinforcement mechanism is part of a broader concept of psychological dependence where alcohol is taken for these rewarding properties, while that of negative reinforcement is rather a concept of physical dependence.

Thus, alcohol induces a positive reinforcement and anxiolytic effects that cause the development of an alcohol-seeking behavior, an irresistible desire to consume alcohol. By acting on this positive reinforcing effect of alcohol, that is to say by reducing the expectation of reward that alcohol consumption develops, the patient does not feel any advantage in consuming alcohol and therefore helps maintain abstinence from alcohol. "

Acute or chronic consumption of ethanol alters the functioning of many neurotransmission systems including glutamatergic, gabaergic, serotoninergic, dopaminergic, opioidic and noradrenergic systems. These systems are involved in the regulation of reward processes and the pharmacological modulation of these different systems is more or less effective in reducing the reinforcing effects of ethanol (self-administration, voluntary consumption, conditioned place preference: PPC). Only acamprosate and naltrexone targeting glutamatergic / gabaergic and opioid systems are currently used clinically to reduce palatability and the efficacy of these treatments remains modest despite promising preclinical results. This is why the discovery of new molecules that are effective in animal tests to assess the motivational effects of ethanol remains a major therapeutic issue. Milnacipran (Z (±) -2- (amino methyl) -N, N-diethyl-1-phenyl cyclopropane carboxamide) is a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NA). , used in the treatment of diseases of the central nervous system, including depression.

Milnacipran and its method of preparation are described in US Patent No. 4,478,836. Further information on Milnacipran can be found in the twelfth edition of the Merck Index under Entry No. 6,281. The dual reuptake inhibitors of serotonin and norepinephrine correspond to a well-known class of antidepressant agents that selectively inhibit reuptake of both serotonin and norepinephrine. For example, venlafaxine and duloxetine are also dual inhibitors of serotonin and norepinephrine. Studies have shown that the ratio of norepinephrine reuptake inhibition to serotonin inhibition by Milnacipran is approximately 2: 1 (Moret et al., 1985 Neuropharmacology 24 (12): 1211-1219 Palmier et al, 1989, Eur J Clin Pharmacol 37: 235-238).

Patent FR 2 759 906 describes the use of milnacipran in the treatment of psychiatric diseases including drug addiction detoxification. H is _Λ

reported that in alcoholics, milnacipran induces a significant decrease in the sensation of lack. This corresponds to an action on the negative reinforcement effect of alcohol and therefore on the physical dependence on alcohol.

From a model of PCP in a mammal (the rat), the inventors have now surprisingly discovered that milnacipran makes it possible to reduce the rewarding properties of ethanol in this mammal, which corresponds to a reduction in its dependence. alcohol, or a decrease in the positive reinforcement effect of alcohol. The experiment quantified the motivation of the future mammal to search for the drug after conditioning and to demonstrate that milnacipran decreased this motivation significantly. These observations make it possible to envisage a clinical translation in humans in terms of maintenance of weaning condition since it has induced a change in behavior that can be sustained.

The present invention relates to the use of milnacipran for the preparation of a medicament for reducing the rewarding properties of alcohol during or after an alcohol withdrawal treatment.

The present invention particularly relates to the use of milnacipran for the preparation of a medicament for reducing the craving for alcohol during or after an alcohol withdrawal treatment.

The present invention particularly relates to the use of milnacipran for the preparation of a medicament for limiting the risk of relapse in a patient weaned with alcohol.

In particular, the present invention relates to the use of milnacipran for the preparation of a medicament for maintaining abstinence from alcohol in an alcohol weaned patient. As part of an alcohol weaning or maintenance abstinence treatment, milnacipran can be advantageously combined with another active ingredient allowing the patient to be isolated from alcohol, in particular an active ingredient acting on the alcohol. negative reinforcing effect of alcohol, such as acamprosate.

The subject of the present invention is also a product comprising milnacipran and an active ingredient which makes it possible to relieve a patient of alcohol by action on the negative reinforcing effect of the alcohol, as a combination product for simultaneous, separate or spread over time, in alcohol withdrawal and / or maintenance of alcohol abstinence.

Said active ingredient for the purpose of releasing a patient from alcohol by action on the negative reinforcement of the alcohol is advantageously acamprosate.

Milnacipran means milnacipran in its racemic form or as enantiomers or even in the form of mixtures of enantiomers.

Figure 1 represents the experimental protocol.

Figure 2 shows the device used for the CPAP test.

Figure 3 shows the time spent in the chamber associated with ethanol

(lg / kg) measured in seconds on the day of pre-conditioning and the day of testing in 10-week-old Wistar rats. The time spent in the chamber associated with the psychoactive substance is represented as mean ± s.e.m. ANOVA at one lane and Tukey's post hoc test: ** p <0.01, * p <0.05 vs pre-conditioning. The number of animals per group = 10-20.

Experimentation "

In this study, the Placeholder Preference (PPC) model is used to measure the rewarding (positive or negative) effects of drugs. One can visualize the motivation of the animal to seek the drug after a period of conditioning. This device is interesting because if we pharmacologically block the rewarding effects, it is then possible to consider the use of these molecules in the treatment of dependence and / or relapses.

The CPAP model used in this study assesses the rewarding properties of substances of abuse, in which the animal is conditioned in a particular environment where he receives the drug and will then show a preference for it if he attributes to him a positive appetitive value.

I) The PPC test

In this behavioral test, the animal receives an addictive substance in a specific environment and a saline solution in another environment which enables it to associate the various environmental stimuli (tactile and visual) with the pharmacological effects of the psychoactive substance. The ability of the animal, in the absence of any injection, to determine and prefer the environment previously associated with the substance, to that previously associated with the saline solution, is then determined. This test thus makes it possible to evaluate the rewarding properties (appetitive value) positive or negative, defined as the animal's ability to search for a substance that is supposed to reproduce the sensation of pleasure observed in humans.

The typical PPC experiments are based on two distinct environments and rely on associative learning, that is, the association of two events with each other: an unconditional stimulus that provokes a response without resorting to learning (conditioning treatment with or without drugs) and the second stimulus (conditional stimulus) that does not naturally cause the same response because it can not be obtained without learning. The principle of CPD is based on this type of learning. Indeed, this behavioral test allows the motivational component to be assessed by the perception of the administration of a psychoactive substance associated with an environment. PPC is a model that has been widely used to study the rewarding effects of ethanol.

2) Materials and Methods

2.1) Substances

96.2 ° ethanol (Carlo Erba Reagents) and milnacipran were prepared in saline (0.9% NaCl) and injected i.p. at a rate of 1 ml / 200 g of weight of rats and mice. The injected ethanol solution is a solution containing 20% ethanol v / v.

2.2) Animals

Adult male animals (Wistar rats) are ordered at 8 to 9 weeks of age and acclimated to the facility 1 week before starting the conditioning protocol. The animals are kept under a 12h light / 12h night light with light between 7:00 to 19:00 and at 20 ° C. Water and food are available at all times except during the experiment.

2.3) Procedure used

The CPAP procedure takes place in three phases: pre-conditioning, conditioning and the preference test.

During pre-conditioning, the animal explores the two distinct environments, with the guillotine door open, for a period of 20 minutes, the optimal time for exploration in rodents for this type of test (Chaperon et al. 1998).

In a second step, a 4 days conditioning with two sessions per day was defined, which was also chosen according to a review of the literature, in order to optimize the procedure. Two substances are administered during the conditioning: saline solution (NaCl 0.9%) and the drug. Then, the animal is conditioned in such a way that it associates a given environment with the drug and the other with the saline solution.

Then the test day, the animal is placed in the device under the same conditions as the day of pre-conditioning without being under the influence of the drug. Various parameters are recorded such as: distance traveled, time spent, number of passes through the guillotine door and the time of inactivity in each environment.

If the rat attributes the drug a positive appetitive value, he will spend more time in the environment in which he received the drug (CPP). On the other hand, if the rat attributes a negative appetitive value to him, he will spend more time in the compartment in which he has received the saline solution (Conditioning Aversion, APC).

2.4) Experimental protocol

The CPAP test is conducted according to these different phases:

Pre-conditioning: On the first day, naïve and untreated rats are placed in the dish and freely explore both compartments for 20 minutes. The time spent in each environment is recorded thanks to an acquisition card connected to the motion sensors (photocells) connected to the computer and the Acti-track® software (Panlab S.I., Bioseb, France). Packaging: on days 2, 3, 4 and 5, the animals are randomly distributed receiving an intraperitoneal injection (ip) in the morning the saline solution (NaCl 0.9%) and in the afternoon the studied substance or vice versa and immediately placed and confined in a compartment for a 20-minute session, and then returned to their original cage. The administration of milnacipran is 10 minutes before the administration of ethanol

Day of the test: the day 6, like the session of the pre-conditioning, the animals are arranged in the center of the box and have the free choice between the two environments for a period of 20 minutes. The time spent in each environment is measured.

2.5) Apparatus

The room (45 x 45 x 34.5 cm ³ ) is divided into 2 compartments of the same size and separated by a removable central partition with a guillotine door. Room A consists of a grid floor with a very spaced mesh. The Plexiglas 1, 2 and 3 walls are covered with an opaque, beige-colored self-adhesive film. The wall 4 is covered with the same type of adhesive but black. Room B consists of a gray grid floor with a very tight mesh. The walls 1 ', 2', 3 'are covered with strips of black and white adhesive with a width of 5 cm each. The wall 4 'is black and opaque. A translucent band is kept on the plexiglass walls at a height of 3 cm from the ground, to allow the 16 photocells to record the cuts of the beams in the chambers. The movements of the animal are recorded by motion sensors (photocells) which are connected to an acquisition box which is itself driven by the ActiTrack® software (Panlab SI, Bioseb, France). The data recorded by ActiTrack is then transferred to the Exel (Microsoft) software.

The place preference is expressed as the time difference (in seconds) spent in the compartment associated with the drug during the pre-conditioning and the day of the test. These results are expressed as the mean ± s.e.m. ("Standard error mean" or standard error of the mean).

2.6) Statistical Analysis:

The statistical analysis of the results is carried out with Student's t-test for the comparison of two groups. To compare several groups with each other, a 2 or 3-way analysis of the variance with repeated measurements (ANOVA-MR) is used. The factors studied are the session (pre-conditioning / testing), the treatment (the drug) and the dose of the substance used. SigmaStat software (SPSS) is used to perform these different analyzes.

3) Results: Studies of the properties of milnacrpran and acamprosate on the sensitivity of the rewarding effects of ethanol in 10-week-old Wistar rats.

Our results show (Figure 3) that ethanol (1 g / kg) induces PCP in Wistar rats (1-way ANOVA-MR F ₍₁ , ₄₀ ) = 21.888, p0.001) whereas milnacipran for 40 mg / kg and acamprosate for 300 mg / kg inhibited the reward effects for ethanol at 1 g / kg (ANOVA-MR at 1 lane F _(1.20) = 0.059, p = 0.493 F ₍₁ , ₂₀₎ = 1.192, p = 0.303), whereas milnacipran at the dose of 10 mg / kg has no effect (ANOVA-MR at 1 lane F _{(1; 20)} = 6.396, p = 0.035). Interestingly, our results show that milnacipran alone at the highest dose (40mg / kg) has no effect (1-channel ANOVA-MR _(lj20) = 0.236, p = 0.639).

Interestingly, the administration of milnacipran at a dose of 40 mg / kg 10 min before ethanol injection throughout the conditioning phase (4 injections in total) prevents ethanol-induced CPAP, while the highest dose low of 10 mg / kg has no effect on ethanol-induced CPAP. Our results also show that for the highest dose of milnacipran at 40mg / kg administered alone, we have no rewarding effect (positive or aversive). The dose and timing of milnacipran were selected from a study that demonstrated that at this dose it induces an increase in extracellular serotonin and noradrenaline levels in the hippocampus of vigilant rats 40 min and 20 min after ip injection, respectively (Tachibana et al, 2004). Similarly, acamprosate at the tested dose of 300mg / kg given 10min before ethanol prevents ethanol-induced CPAP, which is consistent with another study that demonstrated that acamprosate at this same dose prevents the induction of CPAP with ethanol (2.0g / kg) in mice whereas acamprosate alone no effect on space preference (not inducing CPAP or APC) (Mcgeehan & Olive, 2003). It has also been shown in rats that acamprosate (200 mg / kg) does not induce CPAP (Kratzer & Schmidt, 2003). These results therefore show that milnacipran at the tested dose of 40 mg / kg is as effective as acamprosate (reference anti-craving molecule) in reducing the rewarding effects of ethanol.

Our results show that milnacipran, an inhibitor of 5HT and NA capture, inhibits the development of ethanol-induced CPAP.

Claims

1. Use of milnacipran for the preparation of a medicament for reducing the rewarding properties of alcohol during or after an alcohol withdrawal treatment.

2. Use according to claim 1 for reducing the desire for alcohol during or after an alcohol withdrawal treatment.

3. Use according to claim 1 or 2, to limit the risk of relapse in a patient weaned with alcohol.

Use according to any one of claims 1 to 3 for maintaining alcohol abstinence in an alcohol weaned patient.

5. Use according to any one of claims 1 to 4, characterized in that the milnacipran is combined with another active ingredient to help the patient to the alcohol, including an active ingredient acting on the effect of negative reinforcement of the alcohol.

6. Use according to claim 5, characterized in that the other active ingredient for the patient to disconnect the alcohol is acamprosate.

7. A product comprising milnacipran and an active ingredient for releasing a patient to alcohol by acting on the negative reinforcing effect of the alcohol, as a combination product for simultaneous, separate or spread use over time in withdrawal from alcohol and / or maintenance of alcohol abstinence. ^'

8. The product according to claim 7, characterized in that said active ingredient for releasing a patient to alcohol by action on the negative reinforcing effect of the alcohol is acamprosate.

9. Product according to claim 7 or 8, characterized in that the product is in the form of capsules, capsules or tablets containing 25 or 50 mg of milnacipran.