Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • 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
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/24—Antidepressants

Definitions

• the present invention relates to the use of an alkanoyl L- carnitine for the preparation of a medicament for the treatment of anhedonia.
• Anhedonia is an aspect of personality usually present in patients with schizophrenia and other pathologies (Can. Psychiatr. Assoc. J. 1978 Nov; 23 (7):487-92) characterized by the reduced sensitivity to stimuli that patients once enjoyed. J. Clin. Pharm. Ther. 2000 Oct; 25(5):363-71 discloses the use of the sertraline for the treatment of such pathology.
• an object of the present invention is the use of an alkanoyl L-carnitine wherein the alkanoyl group, linear or branched has 2-5 carbon atoms, or a pharmaceutically acceptable salt thereof, for the prep ⁇ aration of a medicament for the treatment of anhedonia.
• the alkanoyl L-carnitine is selected from the group comprising acetyl; propionyl; valeryl; isovaleryl; butyryl; and isobutyryl L- carnitine, preferred is acetyl L-carnitine.
• pharmaceutically acceptable salt of alkanoyl L-carnitine it is meant any of its salt with an acid that does not give rise to undesirable toxic or side effects. These acids are well known to pharmacologists and to experts in pharmacy.
• Non-limiting examples of these salts are for example: chloride, bromide, orotate, acid aspartate, acid citrate, citrate magnesium, acid phosphate, fumarate .and acid fumarate, fumarate magnesium, lactate, maleate .and acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulphate, phosphate glucose, tartrate, acid tartrate, tartrate magnesium, 2-amine ethanesulphonate, magnesium 2-amine ethanesulphonate, tartrate coline and trichloroacetate .
• the anhedonia model is based on the observation that the fact of being exposed to a repeated unavoidable stress prevents the development of an appetitive behaviour induced and maintained by a highly palatable food (vanilla sugar) in rats fed ad libitum (Behav.
• the animals treated with acetyl L-carnitine showed to be completely protected against the negative effects of stress on the vanilla sugar induced/ maintained acquisition of an appetitive behaviour (VAB) by preventing the dopaminergic transmission from decreasing in the nucleus accumbens (Nacs) as a result of stress.
• VAB appetitive behaviour
• acetyl L-carnitine is the only effective medicament to antagonize the decreasing effect of repeated stress exposure on dopaminergic transmission in the Nacs.
• the acetyl L-carnitine enables the animals to perceive palatable food as a sufficient reinforcement to sustain motivated appetitive behaviour.
• the first experiment aimed at investigating whether the treatment with acetyl L-carnitine may prevent the negative effect of chronic stress on the acquisition of appetitive behaviour sustained by vanilla sugar (VAB) in rats.
• VAB vanilla sugar
• the rats were treated with physiological solution (PS) or acetyl L-carnitine (ALCAR).
• PS physiological solution
• ALCAR acetyl L-carnitine
• VAB [control group (CTR)]: 10 rats were treated with physiological solution (1 ml/kg IP) twice a day (BID) for 14 days. Then, a three- week training trial in a Y-maze was started (Y maze) (Brain. Res. Protocols 7(1): 1 1-20; 2001).
• acetyl L-carnitine 10 rats were treated with acetyl L-carnitine (10 mg/kg IP, BID, in a volume of 1 ml/kg) for 14 days.
• acetyl L-carnitine + Stress 10 rats were treated with acetyl L- carnitine (10 mg/kg, IP, BID) for 14 days. Then, animals were exposed to the sequence of: - pre-test; - test; - Y-maze training and simultaneously exposed to the chronic stress procedure on alternate days (maze one day, and stress the next day) for three weeks, while continuing treatment with acetyl L-carnitine.
• the Y-maze was made up of three wings.
• the vanilla sugar for the acquisition of the appetitive behaviour was in one of the two diverging wings (VAB training, 3 weeks) .
• VAB the physiological solution was administered to the animals (1 ml/kg IP, BID) for 8 days, and then the rats were trained in the Y-maze for VAB acquisition while continuing the treatment with physiological solution for 3 weeks
• Stress + VAB the animals were exposed to the pre-test. Twenty- four hours later they were subjected to the escape test, and then exposed to the chronic stress procedure for 7 days. On day 9, they started their training in the Y-maze while exposed to stress on alternate days;
• acetyl L-carnitine + Stress + VAB the animals were exposed to the pre-test. Twenty-four hours later they underwent the escape test.
• the rats were administered a single dose of cocaine 5 mg/kg IP in 0.1 ml volume of water, and dialysed within the next 60 minutes.
• the values represent the mean ⁇ standard error.
• 5 *** p ⁇ o.001 compared with VAB group and ALCAR + Stress + VAB group.
• the values represent the mean ⁇ standard error.
• *** p ⁇ 0.001 compared with the Naive group, ALCAR + Stress + VAB group, and IMI + Stress + VAB group at the end of the training period.
• the rats treated with acetyl L-carnitine recovered their capacity to acquire motivated appetitive behaviour and avoid negative stimuli. Furthermore, the levels of extraneuronal dopamine in the Nacs of the rats trained for VAB during chronic stress exposure and treated with acetyl L-carnitine were superimposable to the levels recorded in the control rats, either in basal conditions or after one single administration of cocaine.
• the VAB model is a model of motivated appetitive behaviour sustained by the palatable taste of vanilla sugar. Though fed ad libitum with a standard diet, the rats ate the vanilla sugar pellets eagerly, the consumption of which induces a significant increase of dopamine output in the Nacs (Behav. Pharmacol. 8: 619-628, 1997).
• the rats When exposed to chronic stress, the rats either may or may not be attracted by vanilla sugar pellets and consume them or not. Nevertheless, no variation occurs on the levels of extraneuronal dopamine in the limbic system of the rats eating the sweet pellets .
• the dopamine increase in some discrete zones of the brain such as the pre-frontal cortex and the Nacs after the exposure to an environmental stimulus has been associated to the contingent importance acquired by such stimulus when it is perceived.
• the increase in monoammine output reveals what is the level of importance of a certain stimulus to the body perceiving it.
• vanilla sugar pellets in the control rats is an important stimulus, which increases the release of dopamine in the Nacs and can sustain a motivated appetitive behaviour aimed at being repeated.
• the aim of this experiment was to determine whether a 7-day exposure to stress would modify the output of dopamine and serotonine in the pre-frontal cortex (CPF) and in the shell of the nucleus accumbens (Nacs), as well as to assess the effects of acetyl L-carnitine, IMI or FLX on such modifications.
• CPF pre-frontal cortex
• Nacs nucleus accumbens
• mice Sixty rats were divided in 6 groups of 10 animals each, as follows: a) Control (Crt): the animals were administered physiological solution 1 ml/ kg IP, BID for 8 days; b) acetyl L-carnitine: the animals were administered acetyl L- carnitine 10 mg/kg IP, BID for 8 days; c) Stress: the animals were exposed to the pre-test, they were tested for escape 24 hours later, and then they were exposed to the chronic stress protocol for 7 days, while receiving physiological solution (for 8 days); d) acetyl L-carnitine + Stress: the animals were exposed to the pretest, they were tested for escape 24 hours later, and then they were exposed to the chronic stress protocol for 7 days, while receiving acetyl L-carnitine 10 mg/kg IP, BID, for 8 days; e) IMI + Stress: the animals were exposed to the pre-test, they were tested for escape 24 hours later, and then they were exposed to the chronic stress protocol for 7 days, while receiving IMI
• the basal levels of dopamine were determined over 60 minutes.
• the rats were offered 5 vanilla sugar pellets (Meal 1); 4 samples of dialysis fluid were taken over the next 60 minutes.
• the rats were offered vanilla sugar one more time (Meal 2), and samples of dialysis fluid were taken over 60 minutes.
• the acetyl L-carnitine might be defined as the first compound capable to antagonize the anhedonia induced by chronic stress.
• Figures 5 and 6 show that after a 7-day exposure to stress, the basal levels of dopamine in the Nacs were significantly higher in the rats treated with acetyl L-carnitine than in the control rats; furthermore, the basal levels of dopamine in the Stress group rats were significantly lower than in the controls in the same limbic zone. Besides, the increase of dopamine in the Nacs after the acute administration of cocaine resulted to be significantly higher in the rats treated with acetyl L-carnitine and remarkably lower in the animals belonging to the Stress group than in the control rats.
• the animals belonging to the Stress group ate the two meals of vanilla sugar without showing significant modifications in the output of extraneuronal dopamine in the Nacs.
• the protective effect of the acetyl L-carnitine on the VAB acquisition during exposure to chronic stress is justified by the capacity to prevent the reduction of the stress-induced dopaminergic transmission in the Nacs.
• the acetyl L-carnitine is the only known compound capable to antagonize the decrease of the dopaminergic transmission in the Nacs resulting from a repeated exposure to stress.
• the mechanism of such effect seems to be linked to its capacity of increasing the output of dopamine in the same area in the control rats.
• acetyl L-carnitine is the only known compound capable to antagonize the negative effects of the exposure to chronic stress on the acquisition of motivated appetitive behaviour.

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Epidemiology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Emergency Medicine (AREA)
• Gynecology & Obstetrics (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pain & Pain Management (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (12)

Applications Claiming Priority (4)

Related Child Applications (1)

Publications (1)

Family

ID=26332845

Family Applications (1)

Country Status (16)

Cited By (2)

Citations (1)

Family Cites Families (1)

• 2002
  • 2002-05-24 KR KR10-2003-7015576A patent/KR20040003031A/ko not_active Ceased
  • 2002-05-24 PL PL02367628A patent/PL367628A1/xx unknown
  • 2002-05-24 EP EP02741156A patent/EP1399143B1/en not_active Expired - Lifetime
  • 2002-05-24 CZ CZ20033222A patent/CZ20033222A3/cs unknown
  • 2002-05-24 US US10/478,998 patent/US20040171685A1/en not_active Abandoned
  • 2002-05-24 MX MXPA03010920A patent/MXPA03010920A/es active IP Right Grant
  • 2002-05-24 CA CA002448246A patent/CA2448246A1/en not_active Abandoned
  • 2002-05-24 DK DK02741156T patent/DK1399143T3/da active
  • 2002-05-24 WO PCT/IT2002/000339 patent/WO2002096411A1/en not_active Ceased
  • 2002-05-24 HU HU0400007A patent/HUP0400007A2/hu unknown
  • 2002-05-24 JP JP2002592921A patent/JP2004532867A/ja active Pending
  • 2002-05-24 AT AT02741156T patent/ATE345124T1/de not_active IP Right Cessation
  • 2002-05-24 PT PT02741156T patent/PT1399143E/pt unknown
  • 2002-05-24 SK SK1586-2003A patent/SK15862003A3/sk unknown
  • 2002-05-24 DE DE60216090T patent/DE60216090T2/de not_active Expired - Fee Related
  • 2002-05-24 ES ES02741156T patent/ES2275881T3/es not_active Expired - Lifetime
• 2005
  • 2005-12-20 US US11/311,406 patent/US20060148896A1/en not_active Abandoned

Patent Citations (1)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events