WO2005037276A1

WO2005037276A1 - Use of riluzole for the treatment of essential tremor

Info

Publication number: WO2005037276A1
Application number: PCT/EP2004/012186
Authority: WO
Inventors: Fredericka C. Martin
Original assignee: Aventis Pharma S.A.
Priority date: 2003-10-09
Filing date: 2004-10-06
Publication date: 2005-04-28

Abstract

The present invention relates to the use of riluzole or one of its pharmaceutically acceptable salts for the prevention and/or treatment of essential tremor.

Description

USE OF RILUZOLE FOR THE TREATMENT OF ESSENTIAL TREMOR

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 (ET) 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. In the past, 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, drug-induced or toxic tremors, and midbrain lesions. Includes dynamic or terminal tremor, which occurs with target-directed movements, and 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.

There are currently only a few treatments for ET and many patients are either unable to tolerate them or are not helped by them. A new treatment for ET could be a highly beneficial option for these patients. The physiopathology and the mechanism of ET are unknown up to now.

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.

The N-methyl-D-aspartate (NMDA) antagonists MK-801 and CPPene block harmaline-induced tremor, but are not suitable for clinical use. However, based on these findings it was anticipated that 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.

The evaluation of Riluzole in the Harmaline tremor model was performed as follows:

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. The procedure for each mouse was to allow 10 minutes for habituation to the "tremor cage" before the collection of 20 minutes of pre-harmaline baseline motion power. Harmaline was then administered, and motion power measurement initiated again 10 minutes later when tremor had emerged. A five minute recording of harmaline tremor was performed to determine whether the mouse had an adequate response to the harmaline, defined as an absolute increase of 20 percentage points in the motion power percentage compared to pre-harmaline baseline (for example, and increase from 30 % to 50 %). The 5 minute harmaline recording was then followed by administration of riluzole or vehicle and motion power was recorded in successive 20- minutes epochs for the next 100 minutes. Data from mice which failed to show an adequate response to harmaline were not used. In addition, data from mice whose baseline motion power ratio was outside the 95 % confidence interval (16 % to 48 %) were not used.

Definition of motion power percentage (MPP): MPP is defined as the ratio of the harmaline tremor frequency bandwidth divided by overall motion power. MPP for mice is defined as 100x (10-16 Hz power)/ (0-34 Hz power). This ratio is expressed as motion power percentage (MPP) throughout these experiments. In untreated normal mice the MPP is approximately 30 percent. This motion power in untreated animals does not correspond to any visible tremor, and represents normal motion within these bandwidths.

Statistical analysis: 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. 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).

The descriptive statistic percent change in tremor was calculated using the formula:

100 x {1 -[(MPPET - MPP_EB) / (MPP_Cτ - MPP_CB) ] }

MPPET is the MPP for the experimental group for a particular epoch, while MPPCT is the MPP for the corresponding control group epoch. MPP_EB is the MPP for the experimental group at pre-harmaline baseline, and MPP_CB is the corresponding control group value. We assumed that, during harmaline exposure, random non-tremor motion power was unchanged from pre- harmaline baseline.

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.

The results are shown in figure 1. Riluzole reduces tremor by 87 % at 30 min and 74 % at 50 min.

Figure 1 : Figure 1 shows the suppression of harmaline-induced tremor by riluzole. Mice were recorded for a pre-harmaline baseline, and then administered 20 mg/kg harmaline followed 15 minutes later by 5 mg/kg riluzole (N = 7) or 0.5 % CMC vehicle (N = 6). The time courses of MPP collected from successive 20-minute epochs after drug treatment are shown. These results demonstrate marked suppression of harmaline-elevated MPP, i.e. at 30 and 50 minutes after riluzole administration. ^* p < 0.05, ** p < 0.005.

Therefore 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.

Pharmaceutically acceptable 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-β-oxy-naphthoate; or derivatives of organic acid salts.

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.

As solid compositions for oral administration, tablets, pills, powders, (gelatin capsules, cachets) or granules may be used. In these compositions 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.

As liquid 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. 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. As 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. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or in any other injectable sterile solvent or vehicle as defined above. The 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.

The 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.

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.

The following examples illustrate medicaments according to the invention:

Example A

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.

Example B

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

Example C

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 cm³ - Sodium benzoate 80 mg - Ethanol at 95% 0.4 cm³ - Sodium hydroxide 24 mg - Propylene glycol 1.6 cm³ - Water 4 cm³ 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.

Claims

1. Use of riluzole or one of its pharmaceutically acceptable salts for the preparation of medicaments for the prevention and/or treatment of essential tremor.

2. Use of riluzole or one of its pharmaceutically acceptable salts for the preparation of medicaments for the prevention and/or treatment of postural tremor.

3. Use of riluzole or one of its pharmaceutically acceptable salts for the preparation of medicaments for the prevention and/or treatment of kinetic tremor.

4. Use according to one of claims 1 to 3, for the preparation of a medicament comprising 10 to 200 mg of riluzole.