WO2005037276A1 - Utilisation du riluzole dans le traitement des tremblements essentiels - Google Patents

Utilisation du riluzole dans le traitement des tremblements essentiels Download PDF

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Publication number
WO2005037276A1
WO2005037276A1 PCT/EP2004/012186 EP2004012186W WO2005037276A1 WO 2005037276 A1 WO2005037276 A1 WO 2005037276A1 EP 2004012186 W EP2004012186 W EP 2004012186W WO 2005037276 A1 WO2005037276 A1 WO 2005037276A1
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WIPO (PCT)
Prior art keywords
tremor
riluzole
treatment
harmaline
mpp
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PCT/EP2004/012186
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English (en)
Inventor
Fredericka C. Martin
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Aventis Pharma S.A.
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Publication date
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Publication of WO2005037276A1 publication Critical patent/WO2005037276A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • Riluzole (2-amino-6-trifluoromethoxy-benzothiazole) is marketed for the treatment of amyotrophic lateral sclerosis.
  • This compound is also useful as an anticonvulsant, an anxiolytic and a hypnotic (EP 50551 ), in the treatment of schizophrenia (EP 305276), in the treatment of sleep disorders and of depression (EP 305277), in the treatment of cerebrovascular disorders and as an anesthetic (EP 282971 ), in the treatment of spinal, cranial and craniospinal traumas (WO 94/13288), as a radio restorative (WO 94/15600), in the treatment of Parkinson's disease (WO 94/15601 ), in the treatment of neuro- AIDS (WO 94/20103), in the treatment of mitochondrial diseases (WO 95/19170), in the treatment of acoustic trauma (WO00/35447).
  • Essential tremor is up to four times more common than Parkinson's disease.
  • the tremor of ET can interfere with eating, drinking, writing, dressing, and other activities of daily living.
  • the condition was often referred to as "benign essential tremor".
  • Tremor is defined as an involuntary, rhythmic oscillatory movement of a part or parts of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles.
  • Tremor is the most common form of involuntary movement.
  • Tremors may result from normal (physiologic) or pathologic processes and may be characterized by their etiology or phenomenology (i.e., activation state, frequency, amplitude, waveform).
  • Descriptive terms used to describe the clinical phenomenology of tremor include rest tremors and action tremors. Rest tremor occurs when muscle is not voluntarily activated, whereas action tremor is present with voluntary contraction of muscle. Subtypes include postural, kinetic, and isometric tremor. Postural tremor is present while voluntarily maintaining a position against gravity. Kinetic tremor may occur during any form of voluntary movement. Intention or terminal tremor refers to exacerbation of kinetic tremor toward the end of a goal-directed movement. The invention includes all forms of ET as described herein. The classification of essential tremor by clinical phenomenology is as follows:
  • Rest tremor is present when skeletal muscles are not voluntarily activated and the relevant body part is fully supported against gravity. Associated with Parkinson's Disease, secondary parkinsonism, hereditary chin quivering, and severe ET. Often suppressed with voluntary muscle contraction.
  • Action tremor occurs upon any voluntary muscle contraction and may include any combination of postural, kinetic, task- or position-specific, or isometric tremor.
  • Postural tremor is an action tremor that is present while voluntarily maintaining a position against gravity. Associated with ET, primary orthostatic tremor, physiologic and enhanced physiological tremors, drug-induced and toxic tremors, neuropathic tremor, cerebellar head tremor (titubation), and dystonic tremor.
  • Kinetic tremor is an action tremor that occurs with any form of voluntary movement including visually- or nonvisuallv-guided actions, such as speaking, pouring water into a cup, or finger-to-nose testing.
  • Associated with ET. classic cerebellar tremor e.g.. seen in multiple sclerosis, infarction
  • dystonic tremor e.g.. seen in multiple sclerosis, infarction
  • drug-induced or toxic tremors e.g. seen in multiple sclerosis, infarction
  • midbrain lesions e.g. seen in multiple sclerosis, infarction
  • dynamic or terminal tremor which occurs with target-directed movements
  • simple kinetic tremor which is present with nontarget-directed actions.
  • Task- or position-specific tremor is a kinetic tremor that occurs during performance of highly specialized, complex movements, such as writing, speaking, or smiling.
  • Primary writing tremor and isolated voice tremor are included.
  • Isometric tremor is a kinetic tremor present during voluntary muscle contraction against a rigid stationary object, such as making a fist or flexing the wrist against a horizontal, flat surface.
  • Harmaline tremor is the most commonly used animal model of ET (Brain Research (2002), 945(2), 212-218). Harmaline is an alkaloid that induces a tremor, which shares many characteristics with ET. Both ET and harmaline tremor show a postural/kinetic tremor. Activation of the olivocerebellar system occurs in both, as shown by neuroimaging, and tremor reduction in both occurs in response to ethanol and octanol.
  • N-methyl-D-aspartate (NMDA) antagonists MK-801 and CPPene block harmaline-induced tremor, but are not suitable for clinical use.
  • NMDA N-methyl-D-aspartate
  • CPPene CPPene
  • a clinically acceptable drug which reduces activity at NMDA receptors would also reduce harmaline- induced tremor.
  • Riluzole was selected for testing on this basis. It was subsequently found that riluzole was highly effective for suppressing harmaline-induced tremor at doses which did not induce sedation or ataxia.
  • mice Female ICR mice (20-24 g) were provided with commercial rodent diet and water ad libitum.
  • Harmaline was dissolved in saline and administered subcutaneously at 20 mg/kg.
  • Riluzole was suspended in 0.5 % carboxymethylcellulose (CMC) in saline and administered i.p., while controls received vehicle.
  • Sedation/ataxia test Sedation and ataxia were tested by giving mice riluzole and subjecting them to the "hanging wire test" every 10 minutes for up to two hours. In this test a mouse is suspended by its front paws from a rigid, 2 mm diameter wire and the time it takes the mouse to bring a hind paw up to the wire noted. Normal mice always do so within 10 seconds, while sedated or ataxic mice usually fall off without bringing a hind paw up to the wire.
  • Tremor measuring equipment Tremor activity was measured with a Convuls- 1 system (Columbus Instruments; Columbus, Ohio), which is a metal platform with a load sensor beneath it, which was connected to an electrical amplifier (Grass Instruments, West Warwick, Rl) that transmitted the data to a computer acquisition system.
  • the filters were set to exclude input below 1 Hz or above 30 Hz.
  • Output power was recorded digitally and analyzed for change of frequency and power using a Datawave Technologies A/D converter and software (Longmont, CO). Calibration was performed on the platforms by dropping a weight from a set height and checking the peak height with an oscilloscope.
  • Mouse protocol A plastic cage (12.7 cm wide, 16.5 cm long, 17.8 cm tall, weight 248 g) with air holes in the top and no bottom was placed directly on the platform and the mouse put inside. Data were sampled at 68 Hz, collected in 30 second bins, and then exported to data analysis and graphing software Origin® 6.1 (OriginLab Corporation, Northampton, MA). In Origin, the total power for each 20 minutes epoch was calculated at 0-34 Hz (full spectrum of motion) and at 10-16 Hz (the harmaline tremor frequency bandwidth); and the motion power ratio (10-16Hz) power/(0-34 Hz) power calculated.
  • MPP motion power percentage
  • the motion power percentage (MPP), which represents the percent of the total motion power that falls within the tremor frequency bandwidth, was collected for each 20 minutes epoch.
  • MPP Motion power percentage
  • Statistical analysis was performed using a repeated measures ANOVA model followed by post-hoc t- tests under the model using the Tukey-Fisher significance criterion. This analysis was performed with statistical analysis software JMP (SAS Inc., Cary, NC).
  • MPPET is the MPP for the experimental group for a particular epoch
  • MPPCT is the MPP for the corresponding control group epoch
  • MPP E B is the MPP for the experimental group at pre-harmaline baseline
  • MPP C B is the corresponding control group value.
  • Riluzole was tested from 5 mg/kg to 10 mg/kg, and it was found that riluzole at 10 mg/kg was more effective than 5 mg/kg at suppressing harmaline- induced tremor whereas the lower dose was lilely to show less side effects.
  • Riluzole is highly effective at suppressing harmaline-induced tremor in mice at a dose that was at least four-fold smaller than the dose required to reliably induce sedation or ataxia. Therefore, these results show that Riluzole is useful in the clinical treatment of ET in human.
  • salts of riluzole are e.g. addition salts with inorganic acids such as hydrochloride, sulfate, nitrate, phosphate; or organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methane-sulfonate, isothionate, theophyllineacetate, salicylate, phenolphthalinate, methylene-bis- ⁇ -oxy-naphthoate; or derivatives of organic acid salts.
  • inorganic acids such as hydrochloride, sulfate, nitrate, phosphate
  • organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methane-sulfonate, isothionate, theophyllineacetate, salicylate, phenolphthalinate, methylene-bis- ⁇ -oxy-naphthoate; or derivatives of
  • the medicaments consist of at least riluzole in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in a pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active.
  • the medicaments according to the invention may be used by the oral, parenteral, rectal or topical route.
  • compositions for oral administration tablets, pills, powders, (gelatin capsules, cachets) or granules may be used.
  • the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, preferably under an argon stream.
  • these compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablets) and/or a glaze.
  • compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
  • inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
  • These compositions may comprise one or more substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • the sterile compositions for parenteral administration may preferably be solutions, which are aqueous or nonaqueous, suspensions or emulsions.
  • solvent or vehicle there may be used e.g. water; propylene glycol; polyethylene glycol; vegetable oils, in particular olive oil; injectable organic esters, for example ethyl oleate; or other suitable organic solvents.
  • These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and/or stabilizing agents.
  • the sterilization may be carried out in several ways, for example by aseptisizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • compositions for topical administration may be, for example, creams, lotions, collyria, mouthwash, nasal drops or aerosols.
  • the doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally between 25 and 1000 mg per day by the oral route for an adult with unit doses ranging from 10 to 200 mg of active substance.
  • the doctor will determine the appropriate dosage according to the age, weight and all the other factors specific to the subject to be treated.
  • Tablets containing a 50 mg dose of active product having the following composition are prepared according to the usual technique: - Riluzole 50 mg - Mannitol 64 mg - Microcrystalline cellulose 50 mg - Polyvidone excipient 12 mg - Sodium carboxymethylstarch 16 mg - Talc 4 mg - Magnesium stearate 2 mg - Anhydrous colloidal silica 2 mg - Mixture of methylhydroxypropylcellulose (72 % by weight), polyethylene glycol 6000 (3.5 % by weight), titanium dioxide (24.5 % by weight), 1 finished film-coated tablet weighing 245 mg.
  • Gelatin capsules containing a 50 mg dose of active product having the following composition are prepared according to the usual technique: - Riluzole 50 mg - Cellulose 18 mg - Lactose 55 mg - Colloidal silica 1 mg - Sodium carboxymethylstarch 10 mg - Talc 10 mg - Magnesium stearate 1 mg
  • An injectable solution containing 10 mg of active product having the following composition is prepared: - Riluzole 10 mg - Benzoic acid 80 mg - Benzyl alcohol 0.06 cm 3 - Sodium benzoate 80 mg - Ethanol at 95% 0.4 cm 3 - Sodium hydroxide 24 mg - Propylene glycol 1.6 cm 3 - Water 4 cm 3
  • the invention also relates to the method of preparing medicaments useful in the prevention and/or treatment of essential tremor consisting in mixing riluzole or the pharmaceutically acceptable salts of this compound with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants.
  • the invention also relates to the method of preventing and/or treating essential tremor consisting in administering riluzole or one of its pharmaceutically acceptable salts to the patient.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Psychology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)

Abstract

La présente invention concerne l'utilisation du riluzole ou d'un de ses sels acceptables d'un point de vue pharmaceutique dans la prévention et/ou le traitement des tremblements essentiels.
PCT/EP2004/012186 2003-10-09 2004-10-06 Utilisation du riluzole dans le traitement des tremblements essentiels WO2005037276A1 (fr)

Applications Claiming Priority (2)

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EP03022896.9 2003-10-09
EP03022896 2003-10-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010096869A1 (fr) * 2009-02-26 2010-09-02 Steven Michael Weiss Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur
CN111821289A (zh) * 2020-02-27 2020-10-27 鲁南制药集团股份有限公司 一种利鲁唑口崩片及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282971A2 (fr) * 1987-03-16 1988-09-21 Warner-Lambert Company 2-Aminobenzothiazoles et dérivés utile comme agents cérébrovasculaires
EP0516978A1 (fr) * 1991-05-03 1992-12-09 Hoechst Aktiengesellschaft Enantiomères de (aminophényl)-hétéroaryle éthylamines substitués, un procédé pour leur préparation et médicaments contenant ces composés
WO1994015601A1 (fr) * 1993-01-07 1994-07-21 Rhone-Poulenc Rorer S.A. Application du riluzole dans le traitement de la maladie de parkinson et des syndromes parkinsoniens
WO1997014415A1 (fr) * 1995-10-19 1997-04-24 F.H. Faulding & Co. Limited Composition pharmaceutique analgesique a liberation immediate et a liberation lente

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282971A2 (fr) * 1987-03-16 1988-09-21 Warner-Lambert Company 2-Aminobenzothiazoles et dérivés utile comme agents cérébrovasculaires
EP0516978A1 (fr) * 1991-05-03 1992-12-09 Hoechst Aktiengesellschaft Enantiomères de (aminophényl)-hétéroaryle éthylamines substitués, un procédé pour leur préparation et médicaments contenant ces composés
WO1994015601A1 (fr) * 1993-01-07 1994-07-21 Rhone-Poulenc Rorer S.A. Application du riluzole dans le traitement de la maladie de parkinson et des syndromes parkinsoniens
WO1997014415A1 (fr) * 1995-10-19 1997-04-24 F.H. Faulding & Co. Limited Composition pharmaceutique analgesique a liberation immediate et a liberation lente

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BEZARD E ET AL: "Riluzole delayed appearance of parkinsonian motor abnormalities in a chronic MPTP monkey model", EUROPEAN JOURNAL OF PHARMACOLOGY 1998 NETHERLANDS, vol. 356, no. 2-3, 1998, pages 101 - 104, XP001188104, ISSN: 0014-2999 *
EBLEN FRANK ET AL: "Effects of 7-nitroindazole, N-G-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 299, no. 1-3, 1996, pages 9 - 16, XP001188103, ISSN: 0014-2999 *
MIZOULE J ET AL: "2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--I. Anticonvulsant properties.", NEUROPHARMACOLOGY. ENGLAND AUG 1985, vol. 24, no. 8, August 1985 (1985-08-01), pages 767 - 773, XP001184798, ISSN: 0028-3908 *
MÜLLER JÖRG ET AL: "Riluzole therapy in cervical dystonia.", MOVEMENT DISORDERS: OFFICIAL JOURNAL OF THE MOVEMENT DISORDER SOCIETY. UNITED STATES JAN 2002, vol. 17, no. 1, January 2002 (2002-01-01), pages 198 - 200, XP008027194, ISSN: 0885-3185 *
TARIQ MOHAMMAD ET AL: "2-Deoxy-D-glucose attenuates harmaline induced tremors in rats.", BRAIN RESEARCH, vol. 945, no. 2, 2 August 2002 (2002-08-02), pages 212 - 218, XP001184797, ISSN: 0006-8993 (ISSN print) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010096869A1 (fr) * 2009-02-26 2010-09-02 Steven Michael Weiss Agent permettant d'améliorer l'inotropie et la lusitropie et de traiter des maladies provoquant ou provoquées par une contractilité ou un relâchement médiocre du cœur
CN111821289A (zh) * 2020-02-27 2020-10-27 鲁南制药集团股份有限公司 一种利鲁唑口崩片及其制备方法

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