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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the use of acetyl L-carnitine for the preparation of a medicament having analgesic activity.
• analgesia it is meant a condition where the stimulus of pain present in the body is not perceived as pain.
• An analgesic is a medicament capable of producing analgesia, i.e. disappearance of pain, by interfering with the perception of the nociceptive stimulus without inducing anesthesia or loss of conscience.
• pre-emptive analgesia it is meant a therapeutical strategy involving the precocious administration of a substance before the painful event, capable of blocking the stimulus of pain before it reaches the central nervous system, thus preventing the facilitatory response raised by the nociceptive input to the spinal cord.
• the pre-emptive analgesic property of the acetyl L-carnitine is not known, while its antalgic activity in peripheral neuropathy of different aetiology has been studied. This supposed antalgic activity was attributed to the neurotrophic action of the substance, i.e. its capacity to protect the peripheral nerve and/ or stimulate its regeneration. Such use of acetyl L-carnitine is described in Clin. Drug Invest.
• This study also differs from the present invention, since it concerns the neuropathic pain and the interventionist therapeutic approach, rather than pre-emptive (block of painful input) or preventive (before pain onset) as described in the present invention.
• this work discloses the capacity of the acetyl L-carnitine to maintain an efficient stress response in the old rats through a mechanism linked to the slowing down of the age-dependent loss of the glucocorticoid receptors located in the hippocampus, thus favoring the positive ageing of the cellular structures in terms of maintenance and function.
• the indomethacin is active both in the prevention or reduction of post- surgical pain in patients undergoing surgical interventions.
• the side effects of this compound are: single or multiple ulcerations of the upper gastro-intestinal tract and frontal headache (Goodman and Gilman's: The pharmacological basis of therapeutics. Hardman JG, Limbird LE; Molinoff PB, Ruddon RW, editors: McGraw-Hill, 1997).
• Clonidine and ketamine which are compounds used as preemptive analgesics, give rise to undesirable effects, such as sedation, anesthesia and immobility (Goodman and Gilman's: The pharmacological basis of therapeutics. Hardman JG, Limbird LE; Molinoff PB, Ruddon RW, editors: McGraw-Hill, 1997).
• the acetyl L-carnitine possesses analgesic activity and can be used as an agent useful for the preventive therapy for pain.
• the compound according to the present invention can be used as a pre-emptive analgesic medication, as for example for the preventive therapy of post-surgical pain.
• an object of the present invention is the use of the acetyl L-carnitine, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament having analgesic activity.
• Another object of the present invention is the use of acetyl L- carnitine, or a pharmaceutically acceptable salt thereof, for the preparation of medicament for the preventive therapy for pain.
• a further object of the present invention is the use of acetyl L- carnitine or a pharmaceutically acceptable salt thereof, for the preparation of a medication with high pre-emptive analgesic activity.
• a still further object of the present invention is the use of the acetyl L-carnitine, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the preventive therapy of post- surgical pain.
• salt of the acetyl L-carnitine it is meant any salt thereof with an acid that does not give rise to undesirable toxic effects. These acids are well known to pharmacologists and experts in pharmacy.
• Non-limiting examples of these salts are: 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 ethane sulphonate, magnesium 2-amine ethanesulphonate, tartrate coline and trichloroacetate .
• the following examples illustrate the invention.
• the anti-no ciceptive profile of acetyl L-carnitine was assessed in mice by carrying out both traditional tests on analgesia, such as hot-plate test (thermal stimulus) and abdominal constriction test (chemical stimulus), and some experimental models of hyperalgesia induced by: intraperitoneal administration (IP) of 0.3% and 0.6% acetic acid solution; morphine withdrawal syndrome; administration of kainic acid (20 mg/kg, IP); administration of N-methyl-D-aspartate (1.64 ⁇ g/mouse intrathecal)
• the first experiment was the hot-plate test. Male Swiss Webster mice weighing between 22 and 30 g were used.
• test was carried out according to O'Callaghan and Holtzman in J. Pharmacol. Exp. Ther. 197: 533-537, 1976.
• a stainless steel container is to be placed in a bain-marie at a temperature of 52.5°C.
• the mouse was removed from the hot plate immediately upon the first sign of painful stimulus.
• the maximum latency time registered on the hot plate was 45 seconds.
• the second experiment was the abdominal constriction test.
• mice Male Swiss Webster mice weighing between 22 g and 30 g were used.
• the analgesia induced by the acetyl L-carnitine was determined in presence of some antagonists of some neurotransmission systems deeply involved in the regulation of pain threshold, and in particular the naloxone (opioid antagonist), the CGP-35348 (GABAg antagonist) and the alpha- methyl-p-tyrosine (inhibitor of the synthesis of cathecolamines).
• some antagonists of some neurotransmission systems deeply involved in the regulation of pain threshold and in particular the naloxone (opioid antagonist), the CGP-35348 (GABAg antagonist) and the alpha- methyl-p-tyrosine (inhibitor of the synthesis of cathecolamines).
• the doses used for any antagonist were the minimum required to prevent the analgesia induced by morphine (7 mg/kg SC) (1, 100 e 200 mg/kg IP), baclofen (4 mg/kg SC) and amphetamine (1 mg/kg SC) (non-reported data) respectively.
• Acetyl L-carnitine 100 mg/kg BID, SC for 7 days.
• Values are mean l standard error of at least 12 animals.
• oligonucleotides against the gene coding for the M- ⁇ aODN-anti M- j J receptor at a dose of 3 nanomoles for each single intracerebroventricular injection (ICV) was found to be capable to prevent the production of the antinociception induced by the repeated administration of acetyl L-carnitine (100 mg/kg BID,
• Acetyl L-carnitine 100 mg/kg BID, SC, for 7 days. aODN was injected via ICV on days 1, 4 and 7;
• the nociceptive response has been recorded 24 hours after the last injection of Acetyl L-carnitine. Values are mean l standard error of at least 10 animals.
• EXAMPLE 4 The following tests have been carried out to determine the effects that acetyl L-carnitine may have on the nervous system: the rota-rod test, the hole board test and the sleep induction test.
• mice Male Swiss Webster mice weighing between 22 g and 30 g were used.
• the rota rod test was carried out by means of an apparatus consisting of a platform and a 3 cm-diameter rotating rod (16-20 r.p.m.) with a non- slipping surface.
• the integrity of the animals' motor coordination was determined according to the capacity of the mice to keep their balance on the rotating rod.
• the parameter considered was the number of falls of the animal within a 30 second-observation (Vaught et a., Neuropha ⁇ nacol., 24: 211, 1985).
• the rat's movements were recorded by two separate photocell systems, which recorded both the movements on the board (spontaneous motility) and how many times the mouse put its head into the holes on the surface (exploratory activity). The mice were placed on the board one at a time and left free to explore both the surface and the holes for 5 minutes.
• the hyperalgesia induced by morphine withdrawal syndrome was assessed.
• Male Swiss Webster mice weighing between 22 g and 30 g together with male rats were used.
• the morphine was dissolved in the mice's bottle; the dose of morphine was increased every 48 hours.
• the solution of morphine was sweetened with 5% sucrose to hide the bitter taste and was prepared according to the following schedule: 1 st and 2 nd day 0.1 mg/ml; 3 rd and 4 th day 0.2 mg/ml; 5 th and 6 th day 0.3 mg/ml; 7* to 14* day 0.4 mg/ml.
• the 7-day treatment with acetyl L-carnitine started from day 7 of morphine treatment.
• mice so treated showed during the hot plate test, a significant reduction in the pain threshold which reached its peak after 6 hours (11.8+0.8 seconds licking latency compared with 15.7+ 1.1 seconds recorded in the control group).
• mice Male Swiss Webster mice weighing between 22 g and 30 g were used in the kainic acid-induced hyperalgesia and the test was carried out in compliance with the method described by Giovengo et al. in Pain, 83: 347-358, 1999.
• the hyperalgesia - determined in the mice through the hot plate test - is induced by a solution of kainic acid (20 mg/kg, IP).
• mice Male Swiss Webster mice weighing between 22 g and 30 g were used. This test was carried out in compliance with what described in the rats by Davies and Inturrisi in J. Pharmacol. Exp. Ther., 289: 1048- 1053, 1999, but was applied to the mice by us.
• the hyperalgesia assessed through the hot plate test, is to be induced by intrathecal administration of an NMDA solution (1.64 ⁇ g/mouse; administered around 15 minutes after the last administration of acetyl L-carnitine) .
• Figure 7 shows the anti- nociceptive effect exerted by the acetyl L-carnitine (100 mg/kg, BID, SC or IP for 7 days) in presence of the reduction in the pain threshold induced by NMDA.

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