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
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the use of acetyl-leucine for the preparation of a medicament for the treatment of balance disorders.
• Acetyl-leucine in the form of racemate and its salts are known for their effectiveness in the treatment of vertigo of different origins, in particular Mérier's vertigo, vertigo of inflammatory origin.
• the vertiginous crisis is linked to an imbalance in the membrane potentials of the neurons of the median vestibular nuclei. This disruption of the system results in hyperpolarization or depolarization of neurons.
• a treatment for a vertiginous crisis therefore consists in reducing this imbalance by bringing the membrane potentials of these neurons back to their resting potential.
• Vestibular neurotomy is a surgical technique proposed in the treatment of disabling vertigo and resistant to any conservative therapy.
• the principle consists of disafferent the peripheral vestibular system by sectioning the vestibular nerve while respecting the integrity of the cochlear and facial nerves.
• acetyl-leucine which has no effect in a population of patients exhibiting a vestibular function abolished before the neurotomy, makes it possible to accelerate the compensation observed in a population. of patients with residual vestibular function.
• the present invention relates to the use of acetyl-leucine for the preparation of a medicament intended to treat acute deafferentiation syndromes in patients whose vestibular deficit is less than 88%, advantageously less than 75%. %, in caloric tests.
• the syndromes are acute intermittent deafferentiation syndromes resulting from an imbalance in the circulation of the predominantly unilateral nerve impulses in the auditory nerve.
• the syndromes are acute intermittent deafferentiation syndromes following any event leading to the unilateral disruption of the circulation of the nerve impulse in the auditory nerve accompanied by dizziness.
• Acute deafferentiation syndromes may be consecutive to unilateral surgical neurotomy and acute intermittent deafferentiation syndromes may be consecutive, especially to unilateral neurotomy selected from the group comprising traumatic unilateral neurotomies, unilateral neurotomies associated with acute auditory nerve ischemia , unilateral neurotomies due to extrinsic compressions, unilateral neurotomies due to structural edemas and unilateral neurotomies following endogenous viral attacks.
• the vestibular deficit is assessed by the caloric test which provides information on vestibular reflectivity, i.e. the ability of the vestibule to respond to stimulation (caused by irrigation of the external auditory canal with hot water and then cold).
• acetyl-leucine means (DL) -acetyl-leucine, (L) -acetyl-leucine and (D) -acetyl-leucine and the pharmaceutically acceptable salts of these various forms.
• f acetyl-leucine may be administered orally at doses between 500 mg and 10 g per day, advantageously between 1 and 2 g per day. It can also be administered intravenously at a rate of 500 mg to 1 g per day continuously.
• Example 1 Effect of Tanganil on the ability to maintain an erect posture 8 days after neurotomy
• the deficit is measured according to the methods described by Les vertiges and the practitioner of P. Tran Ba Huy and C. De Waele (Coll. Pathologie Sciences Formation, Ed. John Libbey Eurotext, Paris, 1996) and by Les Vertiges by G. Rancurel, 0. Sterkers, E. Vitte, Preface by G. Freyss (Ed. Méd. Spécia., 1989 ).
• the vestibular reflectivity is tested at Jo before the neurotomy by the caloric test to objectify a hyporeflexia or a vestibular areflexia.
• This test consists in successively irrigating the right and then left external auditory canal with hot and then cold water, causing a current of endolymph in the semicircular canal which displaces the ampullary crest.
• the caloric response results in the appearance of a beating nystagmus on the side of the stimulated ear when hot water is applied and on the opposite side when cold water is applied.
• the nystagmic response is recorded by videonystagmography by calculating its frequency, that is to say the number of nystagmic jerks occurring between the 60 th and the 90 th second after the start of the stimulation. This number quantifies the vestibular response.
• the difference in responses from one ear to the other reflects what is called hypovalence; it is the difference between the hot and cold responses on the left side and the hot and cold responses on the right side, divided by the total sum of the responses. In normal subjects it is less than 15%. Hypovalence is the major sign of damage to the peripheral vestibular apparatus.
• the results are analyzed on 56 subjects: 25 patients show a vestibular deficit greater than 75% and 31 patients a vestibular deficit less than or equal to 75%.
• the main criterion was "the possible standing position on D 8 " (YES / NO).
• Example 2 Effect of Tanganil on various symptoms evaluated by visual analogue scales (VAS).
• Example 3 Effect of Tanganil ® on the equilibration evaluated by static posturography.
• the tonic postural activity results in an overall attitude of the human body, fixing the different joints in determined positions, interdependent with each other, mainly in response to the forces of gravity.
• Vestibular afferents, extrinsic ocular musculature, proprioceptive afferents and finally visual afferents play a major role in maintaining the standing position. Standing, at rest, the subject is never perfectly still, he oscillates constantly.
• the static posturography (not done on D8 if the subject could not stand) was performed in a standing position, under 4 conditions (eyes open and eyes closed, with and without foam mat). With the foam mat and / or eyes closed, patients are placed in conditions that minimize the role of visual and proprio-receptive information.
• statokinesigram The movements of the subject's center of gravity during a given time are called the statokinesigram. This plot allows a study of the amplitudes of the oscillations, of the surface described by them. The "antero-posterior" oscillations can be separated from the “right-left” oscillations. 3.2. Results.
• Example 4 Effect in vitro of the (D) and (L) enantiomers of acetyl-leucine on the median vestibular neurons of mice.
• NVM median vestibular neurons
• L of acetyl-leucine (1 inM) were tested on the membrane properties of neurons in "impressed current" mode at different values of the membrane potential: normal membrane potential (approximately -45mV), potential maintained at a hyperpolarized level of about -70 mV or at a depolarized level of about -35 mV.
• Example 5 Effect in vivo of the (D) and (L) enantiomers of acetyl-leucine in the rat.

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• Bioinformatics & Cheminformatics (AREA)
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• Hospice & Palliative Care (AREA)
• Otolaryngology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2005
  • 2005-03-18 FR FR0502696A patent/FR2883180B1/fr not_active Expired - Lifetime
• 2006
  • 2006-03-17 CA CA002601101A patent/CA2601101A1/fr not_active Abandoned
  • 2006-03-17 WO PCT/EP2006/060841 patent/WO2006097527A1/fr not_active Ceased
  • 2006-03-17 US US11/886,419 patent/US20080108702A1/en not_active Abandoned
  • 2006-03-17 JP JP2008501329A patent/JP2008533102A/ja active Pending
  • 2006-03-17 EP EP06725137A patent/EP1865943A1/fr not_active Withdrawn
• 2013
  • 2013-04-09 JP JP2013081360A patent/JP2013173759A/ja active Pending

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