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US20030125363A1 - Riluzole and alpha-tocopherol combination - Google Patents

Riluzole and alpha-tocopherol combination Download PDF

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US20030125363A1
US20030125363A1 US10/369,151 US36915103A US2003125363A1 US 20030125363 A1 US20030125363 A1 US 20030125363A1 US 36915103 A US36915103 A US 36915103A US 2003125363 A1 US2003125363 A1 US 2003125363A1
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riluzole
combination
patients
tocopherol
pharmaceutically acceptable
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Michel Dib
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the combination of ⁇ -tocopherol and of riluzole or of a pharmaceutically acceptable salt of this compound and the use of this combination for the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Amyotrophic lateral sclerosis also known by the name of CHARCOT's disease and LOU GEHRIG's disease, was described for the first time by CHARCOT in 1865.
  • ALS is a fatal disease resulting from degeneration of the motoneurons. The disease is accompanied by progressive paralysis, leading to the loss of motor and respiratory functions and then to death within a period of two to eight years after the appearance of the first symptoms.
  • riluzole (2-amino-6-trifluoromethoxybenzothiazole) is marketed under the name RILUTEK® for the treatment of amyotrophic lateral sclerosis.
  • Riluzole makes it possible mainly to slow down the progression of the disease.
  • group 1 145 patients treated with 100 mg/day of riluzole by the oral route and 1000 mg/day of ⁇ -tocopherol by the oral route,
  • group 2 144 patients treated with 100 mg/day of riluzole by the oral route and placebo.
  • the Munsat functional state A relates to patients in an average or mild state:
  • mild state average deficiency in 3 regions or mild to severe deficiency in one region while the other two regions are normal or slightly affected.
  • the Munsat functional state B relates to patients in the severe or final state:
  • final state nonfunctional use of at least 2 regions and mild or nonfunctional use of the third region.
  • Fatigability is measured according to the visual analog scale (VAS) on inclusion of the patients (M0) and at 3 months (M3).
  • VAS visual analog scale
  • the mean values obtained are the following: VAS VAS at M0 at M3 ⁇ M0-M3 (mm) (mm) (mm) RILUZOLE AND PLACEBO 48.4 65.7 17.3 (115 patients) RILUZOLE AND 46.4 58.6 12.2 ⁇ -TOCOPHEROL COMBINATION (118 patients)
  • the plasma concentration of malondialdehyde which is thought to be a predictive factor for the progression of ALS, was determined at the time of inclusion of the patients (M0) and at 3 months (M3).
  • the mean values of the concentrations obtained are the following: Concentration Concentration at at M0 M3 ⁇ ( ⁇ M) ( ⁇ M) M3-M0 ( ⁇ M) RILUZOLE 2.94 ⁇ 0.40 2.72 ⁇ 0.40 0.22 ⁇ 0.40 AND PLACEBO (65 patients) RILUZOLE AND 2.86 ⁇ 0.40 2.36 ⁇ 0.30 0.50 ⁇ 0.50 ⁇ -TOCOPHEROL COMBINATION (58 patients)
  • salts of riluzole there may be mentioned in particular the addition salts with inorganic acids such as hydrochloride, sulphate, nitrate and phosphate, or organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophilline acetate, salicylate, phenolphthalinate, methylene-bis- ⁇ -oxynaphthoate or substitution derivatives of these derivatives.
  • inorganic acids such as hydrochloride, sulphate, nitrate and phosphate
  • organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophilline acetate, salicylate, phenolphthalinate, methylene-bis- ⁇ -oxynaphthoate or substitution derivatives of these derivatives.
  • the combination may be used by the oral, parenteral or rectal route, either simultaneously or separately or spaced out over time.
  • the present invention also relates to the pharmaceutical compositions comprising the combination of riluzole and of ⁇ -tocopherol in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants and/or optionally in combination with another pharmaceutically compatible and physiologically active product.
  • compositions for oral administration use may be made of tablets, pills, powders (gelatin capsules, cachets) or granules.
  • the active ingredients are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream.
  • these compositions may also comprise substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating.(sugar-coated tablets) or a glaze.
  • compositions for oral administration use may be made of 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 substances other than the diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.
  • the sterile compositions for parenteral administration may be preferably solutions which are aqueous or nonaqueous, suspensions or emulsions.
  • solvent or vehicle use may be made of 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 stabilizing agents.
  • the sterilization may be performed in several ways, for example by asepticizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • the present invention also relates to the method of treating patients suffering from amyotrophic lateral sclerosis, which consists in administering to the patient a combination of ⁇ -tocopherol and of riluzole or of one of its pharmaceutically acceptable salts either simultaneously or separately or spaced out over time.
  • the doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally from 10 to 400 mg per day by the oral route for an adult with unit doses ranging from 10 to 200 mg of riluzole and from 250 to 4000 mg per day by the oral route for an adult with unit doses of 100 to 1000 mg of ⁇ -tocopherol.
  • the doctor will determine the appropriate dosage according to the age, weight and all the other factors specific to the subject to be treated.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fats And Perfumes (AREA)
  • External Artificial Organs (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Anti-Oxidant Or Stabilizer Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Cosmetics (AREA)
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  • Pyrane Compounds (AREA)

Abstract

The invention concerns a combination of alpha-tocopherol and riluzole or a pharmaceutically acceptable salt thereof and the use of said combination for treating amyotrophic lateral sclerosis.

Description

  • This application is a continuation of U.S. application Ser. No. 09/854,318, filed May 11, 2001, now allowed, which is a continuation of International application No. PCT/FR99/02,753, filed Nov. 9, 1999; which claims the benefit of priority of French Patent Application No. 98/14,250, filed Nov. 13, 1998.[0001]
  • The present invention relates to the combination of α-tocopherol and of riluzole or of a pharmaceutically acceptable salt of this compound and the use of this combination for the treatment of amyotrophic lateral sclerosis (ALS). [0002]
  • Amyotrophic lateral sclerosis, also known by the name of CHARCOT's disease and LOU GEHRIG's disease, was described for the first time by CHARCOT in 1865. ALS is a fatal disease resulting from degeneration of the motoneurons. The disease is accompanied by progressive paralysis, leading to the loss of motor and respiratory functions and then to death within a period of two to eight years after the appearance of the first symptoms. [0003]
  • To date, only riluzole (2-amino-6-trifluoromethoxybenzothiazole) is marketed under the name RILUTEK® for the treatment of amyotrophic lateral sclerosis. Riluzole makes it possible mainly to slow down the progression of the disease. [0004]
  • It has now been found that the combination of riluzole or one of its pharmaceutically acceptable salts and of α-tocopherol (vitamin E) makes it possible to slow down the disease more substantially than riluzole alone and also to reduce fatigue in patients and the plasma concentration of malondialdehyde. [0005]
  • The study was carried out in 289 patients in total aged over 18 years, who have been suffering from ALS for less than 5 years and in whom the vital capacity/theoretical normal vital capacity ratio is greater than or equal to 60% (the vital capacity is a routine conventional measurement of the respiratory function also called lung function test). [0006]
  • The patients are divided into 2 groups: [0007]
  • group 1: 145 patients treated with 100 mg/day of riluzole by the oral route and 1000 mg/day of α-tocopherol by the oral route, [0008]
  • group 2: 144 patients treated with 100 mg/day of riluzole by the oral route and placebo. [0009]
  • Some patients in the 2 groups no longer meeting, in a second evaluation, the inclusion criteria or who had not followed the treatment correctly, were not taken into account for the determination of the results. [0010]
  • The patients are monitored for a year. The results are measured on functional scales (Munsat's functional states (RIVIERE et al., Arch. Neurol., 55, 526 (1998)), a visual analog scale (VAS) for fatigability (LACOBLEZ et al., The Lancet, 347, 1425 (1996); BENSIMON et al., New England Journal of Medicine, 330, 585 (1994)) and plasma concentration of malondialdehyde, a biochemical marker for oxidative stress (FAVIER, Analysis of free radicals in biological systems, Birk Hauser, Basel/Switzerland, 1995 p. 100-117). [0011]
  • The Munsat functional state A relates to patients in an average or mild state: [0012]
  • average state: average deficiency in 3 regions (speech, arm and leg), functionally independent in speech, activities of the upper extremities in daily and ambulatory life, [0013]
  • mild state: average deficiency in 3 regions or mild to severe deficiency in one region while the other two regions are normal or slightly affected. [0014]
  • The Munsat functional state B relates to patients in the severe or final state: [0015]
  • severe state: need for assistance in 2 or 3 regions, dysarthric speech and/or patients requiring assistance to walk and/or requiring assistance for the activities of the upper extremities in daily life, [0016]
  • final state: nonfunctional use of at least 2 regions and mild or nonfunctional use of the third region. [0017]
  • The progression of the functional states A and B is determined at the time of inclusion (M0) and after 12 months of treatment (M12). The results obtained are the following: [0018]
    RILUZOLE AND RILUZOLE AND
    PLACEBO α-TOCOPHEROL
    (number of (number of
    patients) patients)
    Condition on inclusion (M0)
    state A 109 112
    state B 10 10
    Condition after treatment (M12)
    state A 56 73
    state B 63 49
  • These results demonstrate that, after 12 months of treatment with riluzole and placebo, 53 patients (44.5%) exhibited a worsening of the disease and 66 patients (55.3%) did not exhibit any change, whereas in the patients treated with the riluzole and α-tocopherol combination, only 39 patients (32%) exhibited a worsening and 83 patients (68%) did not exhibit any change. [0019]
  • The progression of the disease is therefore more reduced with the riluzole and α-tocopherol combination than with riluzole alone. [0020]
  • Fatigability is measured according to the visual analog scale (VAS) on inclusion of the patients (M0) and at 3 months (M3). [0021]
  • In this test, the mean values obtained are the following: [0022]
    VAS VAS
    at M0 at M3 Δ M0-M3
    (mm) (mm) (mm)
    RILUZOLE AND PLACEBO 48.4 65.7 17.3
    (115 patients)
    RILUZOLE AND 46.4 58.6 12.2
    α-TOCOPHEROL COMBINATION
    (118 patients)
  • These values clearly demonstrate that the patients treated with the riluzole and α-tocopherol combination are less tired than the patients treated with riluzole and placebo. [0023]
  • The plasma concentration of malondialdehyde, which is thought to be a predictive factor for the progression of ALS, was determined at the time of inclusion of the patients (M0) and at 3 months (M3). [0024]
  • The mean values of the concentrations obtained are the following: [0025]
    Concentration Concentration
    at at
    M0 M3 Δ
    (μM) (μM) M3-M0 (μM)
    RILUZOLE 2.94 ± 0.40 2.72 ± 0.40 0.22 ± 0.40
    AND PLACEBO
    (65 patients)
    RILUZOLE AND 2.86 ± 0.40 2.36 ± 0.30 0.50 ± 0.50
    α-TOCOPHEROL
    COMBINATION
    (58 patients)
  • These results demonstrate that the plasma concentration of malondialdehyde is increased in patients suffering from amyotrophic lateral sclerosis (concentrations at M0) and decreases during the treatment but more significantly with the riluzole and α-tocopherol combination than with riluzole alone. [0026]
  • As pharmaceutically acceptable salts of riluzole, there may be mentioned in particular the addition salts with inorganic acids such as hydrochloride, sulphate, nitrate and phosphate, or organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophilline acetate, salicylate, phenolphthalinate, methylene-bis-β-oxynaphthoate or substitution derivatives of these derivatives. [0027]
  • The combination may be used by the oral, parenteral or rectal route, either simultaneously or separately or spaced out over time.[0028]
  • The present invention also relates to the pharmaceutical compositions comprising the combination of riluzole and of α-tocopherol in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants and/or optionally in combination with another pharmaceutically compatible and physiologically active product. [0029]
  • As solid compositions for oral administration, use may be made of tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active ingredients are mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating.(sugar-coated tablets) or a glaze. [0030]
  • As liquid compositions for oral administration, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than the diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers. [0031]
  • The sterile compositions for parenteral administration may be preferably solutions which are aqueous or nonaqueous, suspensions or emulsions. As solvent or vehicle, use may be made of 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 stabilizing agents. The sterilization may be performed in several ways, for example by asepticizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium. [0032]
  • The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols. [0033]
  • The present invention also relates to the method of treating patients suffering from amyotrophic lateral sclerosis, which consists in administering to the patient a combination of α-tocopherol and of riluzole or of one of its pharmaceutically acceptable salts either simultaneously or separately or spaced out over time. [0034]
  • The doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally from 10 to 400 mg per day by the oral route for an adult with unit doses ranging from 10 to 200 mg of riluzole and from 250 to 4000 mg per day by the oral route for an adult with unit doses of 100 to 1000 mg of α-tocopherol. [0035]
  • In general, the doctor will determine the appropriate dosage according to the age, weight and all the other factors specific to the subject to be treated. [0036]

Claims (6)

1. A method of treating amyotrophic lateral sclerosis or diseases associated with degeneration of the motoneurons comprising administering to a patient in need of said treatment an effective amount of a combination of α-tocopherol and riluzole or of a pharmaceutically acceptable salt thereof, optionally in combination with the pharmaceutically acceptable carrier.
2. The method according to claim 1 wherein 10 to 400 parts by weight of riluzole are used per 250 to 4000 parts by weight of α-tocopherol.
3. The method according to claim 1 wherein the combination is used simultaneously, separately or spaced out over time.
4. The method according to claim 1 wherein the combination is used simultaneously.
5. The method according to claim 2 wherein the combination is used simultaneously, separately or spaced out over time.
6. The method according to claim 2 wherein the combination is used simultaneously.
US10/369,151 1998-11-13 2003-02-18 Riluzole and alpha-tocopherol combination Abandoned US20030125363A1 (en)

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FR9814250A FR2785808B1 (en) 1998-11-13 1998-11-13 RILUZOLE AND ALPHA-TOCOPHEROL ASSOCIATION
FRFR98/14250 1998-11-13
PCT/FR1999/002753 WO2000028992A1 (en) 1998-11-13 1999-11-09 Riluzole and alpha-tocopherol combination
US09/854,318 US6642262B2 (en) 1998-11-13 2001-05-11 Riluzole and alpha-tocopherol combination
US10/369,151 US20030125363A1 (en) 1998-11-13 2003-02-18 Riluzole and alpha-tocopherol combination

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FR2786101B1 (en) * 1998-11-24 2002-07-05 Aventis Laboratoire USE OF NICERGOLIN IN THE TREATMENT OF SPASTICITY
AU2006305309A1 (en) * 2005-10-18 2007-04-26 Ono Pharmaceutical Co., Ltd. Pharmaceutical for protection of motor nerve in patient with amyotrophic lateral sclerosis
US20070099156A1 (en) * 2005-10-28 2007-05-03 Jeff Wagner Self-etching dental primer compositions and methods and systems utilizing such compositions
FR2957077B1 (en) * 2010-03-02 2012-04-13 Univ Dauvergne Clermont I USE OF RILUZOLE FOR TREATING OR PREVENTING ADVERSE EFFECTS OF ANTI-CANCER AGENTS
WO2014145776A2 (en) * 2013-03-15 2014-09-18 Baylor College Of Medicine Msp and its receptors in the therapy of amyotrophic lateral sclerosis

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FR2688138B1 (en) * 1992-03-06 1995-05-05 Rhone Poulenc Rorer Sa APPLICATION OF AMINO-2 TRIFLUOROMETHOXY-6 BENZOTHIAZOLE TO OBTAIN A MEDICINE FOR THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS.
US5843641A (en) * 1993-02-26 1998-12-01 Massachusetts Institute Of Technology Methods for the daignosis, of familial amyotrophic lateral sclerosis
US6380252B1 (en) * 1996-07-05 2002-04-30 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Use of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine for increasing the levels of IGF-1
US5780489A (en) * 1996-08-21 1998-07-14 Brooks; Benjamin Rix Method for treating amyotrophic lateral sclerosis
JP3889844B2 (en) * 1997-02-10 2007-03-07 龍兒 梶 Amyotrophic lateral sclerosis therapeutic agent
FR2782008B1 (en) * 1998-08-07 2003-04-25 Sod Conseils Rech Applic USE OF GINKGO BILOBA EXTRACTS FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OF AMYOTROPHIC SIDE SCLEROSIS

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