EP0674520A1 - Application of carbamazepine and oxcarbazepine in the treatment of neurological lesions related to traumatic injuries - Google Patents

Application of carbamazepine and oxcarbazepine in the treatment of neurological lesions related to traumatic injuries

Info

Publication number
EP0674520A1
EP0674520A1 EP19940902018 EP94902018A EP0674520A1 EP 0674520 A1 EP0674520 A1 EP 0674520A1 EP 19940902018 EP19940902018 EP 19940902018 EP 94902018 A EP94902018 A EP 94902018A EP 0674520 A1 EP0674520 A1 EP 0674520A1
Authority
EP
European Patent Office
Prior art keywords
treatment
mg
carbamazepine
trauma
oxcarbazepine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP19940902018
Other languages
German (de)
French (fr)
Inventor
Adam Doble
Erik Louvel
Jérémy Pratt
Jean-Marie Stutzmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhone Poulenc Rorer SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to FR9215148A priority Critical patent/FR2699077B1/en
Priority to FR9215148 priority
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Priority to PCT/FR1993/001228 priority patent/WO1994013298A1/en
Publication of EP0674520A1 publication Critical patent/EP0674520A1/en
Application status is Ceased legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Abstract

Application of an anticonvulsant selected from carbamazepine and oxcabarzepine or pharmaceutically acceptable salts thereof in the treatment of neurological lesions related to traumatic injuries, especially spinal, cranial or cranial-spinal injuries.

Description

Appl ication of carbamazepine and 1 Oxcarbazepine in the treatment of neurological lesions the ied to traumati sms.

The invention relates to a new application

5 therapeutic anticonvulsant chosen from carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts of these compounds.

Carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts of these compounds are described as anticonvulsants and antiepileptics 0 in particular in Patent EP 50,589.

It has now been surprisingly found that these compounds can also be used in the treatment of neurological lesions associated with trauma and in particular to spinal trauma, cranial or cranio-spinal.

5 The activity of these products on the spinal cord has been demonstrated either as cord injury model in the rat ventral compression technique described by EC Benzel et al., Journal of Spinal Disorders, 3 , 4, 334-338 (1990) or in the model traumatic tetraplegia induced by compression of the spinal cord with a 0 inflatable microballonnet according to the technique described by D. Martin et al., Journal of Neuroscience Research, 32, 539 -550 (1992).

In these tests, carbamazepine and oxcarbazepine reduce the neurological deficit of animals (paraplegia) related to the spinal cord as well as histopathological lesions (necrosis of the cord). 5 This decrease is generally equal to or greater than 5%.

The activity of these products is also demonstrated in the model of spinal cord injury on 15 rabbits "Fauve de Bourgogne" 4 kg (± 200 g). The rabbits were divided into three groups to receive varying importance trauma using the following protocol:

0 a) preparation of animals: rabbits are injected intramuscularly

5 mg of Valium and 1/16 mg of atropine. After 30 minutes, is placed an isotonic saline infusion and anesthetized rabbits by slow intravenous injection of 40 mg / kg Nesdonal®. then sets up a cardioscope because the animal may have, especially when reinjection Nesdonal® a lasting apnea with bradycardia.

b) recording of somatosensory evoked potentials (SEPs): these recordings specify the integrity of the sensory pathways of the cord. Stimulation is performed at the tibial nerve (SPI). The stimulation intensity is calculated to evoke a potential in sensory fibers of large caliber, which is carried at the motor stimulation threshold (minimum movement of the paw). The collection is done by means of an electrode planted in the scalp at the parietal cortex. A reference electrode is placed on the midline of the scalp to the front level (Fz). A PES is recorded before installation of the probe to serve as reference.

c) implementation of trauma: trauma is produced by inflating the balloon of a Fogarty French 3 probe placed in the spinal canal extradural position. For this, we realize a lower lumbar laminectomy. The opening of the yellow ligament allows the passage of the probe to the level of the first lumbar vertebra and the surgical wound is closed. A new PES is recorded to ensure the absence of functional lesion during the passage of the probe. The lesion is then produced by inflating the balloon with variable amounts of air (0.2, 0.4 and 0.55 ml of air) and then the probe is withdrawn. A new PES is carried out just after the trauma and is compared (amplitude and latency) to the reference PES.

d) The products are injected intraperitoneally one time daily for 5 days, at doses ranging between 1 and 8 mg / kg.

e) histology: a spine is taken-marrow block comprising the injured level that is set in 10% formalin. A week later, the marrow is extracted from the block (this fixing time appears necessary to avoid a post-mortem lesion). A visible bleeding area with the naked eye shows the level of trauma. Histological sections stepped specify the extent of the lesions. f) results: carbamazepine and oxcarbazepine possible to reduce the neurological deficit associated with the spinal cord, to protect sensitive neurological pathways and reduce hemorrhagic necrotic area within the gray matter of the spinal cord. These decreases are generally equal to or greater than 5%.

The activity of these products in head trauma has been shown in rats using the technique described by TK McINTOSH et al., Central Nervous System Trauma, 4, 2, 119-134 (1987).

In this test, carbamazepine and oxcarbazepine improve the neurological score of animals having undergone brain trauma and reduces the necrotic lesions. This decrease is generally equal to or greater than 5%.

Pharmaceutically acceptable salts may be mentioned in particular the addition salts with mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulphonate, isethionate, théophilline- acetate, salicylate, phenolphthalinate, methylene-bis-β-oxynaphthoate or substitution derivatives of these derivatives.

The medicinal products consist at least an anticonvulsant chosen from carbamazepine and oxcarbazepine in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or as a composition wherein it is combined with any other pharmaceutically compatible product which may be inert or physiologically active. The medicaments according to the invention may be employed orally or parenterally.

As solid compositions for oral administration may be used tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (dragees) or a varnish.

As liquid compositions for oral administration, one can use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.

The sterile compositions for parenteral administration may be preferably aqueous or nonaqueous solutions, suspensions or emulsions. As solvent or vehicle, there may be employed water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other organic solvents suitable. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating into the composition sterilizing agents, by irra- diation 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 other sterile injectable medium.

The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally between 50 and 800 mg per day orally for an adult with unit doses ranging from 25 to 200 mg of active compound and between 25 and 600 mg per day by intravenous route for an adult with unit doses ranging from 12.5 to 200 mg of active substance.

Generally, the doctor will determine the appropriate dosage depending on the age, weight and all other factors specific to the subject to be treated.

The following examples illustrate medicaments according to the invention: Example A

Are prepared according to the usual technique, tablets containing 50 mg of active product having the following composition:

- Active ingredient 50 mg - mannitol 64 mg

- microcrystalline cellulose 50 mg

- Polyvidone excipient 12 mg

- Sodium starch 16 mg

- Talc 4 mg - magnesium stearate 2 mg

- Colloidal anhydrous silica 2 mg

- Mixture of methylhydroxypropylcellulose, polyethylene glycol 6000, titanium dioxide (72-3,5-24,5) qs 1 finished film-coated tablet 245 mg

example B

Are prepared according to the usual technique, capsules containing 50 mg of active product having the following composition:

- Active ingredient 50 mg

- Cellulose 18 mg - 55 mg Lactose

- Colloidal silica 1 mg

- Sodium starch 10 mg

- Talc 10 mg

- Magnesium stearate 1 mg

example C

An injectable solution containing 10 mg of active product having the following composition:

- Active ingredient 10 mg

- Benzoic acid 80 mg - Benzyl alcohol 0.06 cm3 - Sodium benzoate 80 mg

- 95% ethanol 0.4 cm3

- Sodium hydroxide 24 mg

- Propylene glycol 1, 6 cm3 - Water qs 4 cm 3

The invention also relates to the process for the preparation of medicaments useful in the treatment of neurological lesions associated with trauma and, in particular, to spinal, cranial or cranial-spinal comprising mixing an anticonvulsant chosen from carbamazepine and oxcarbazepine or pharmaceutically acceptable salts of these compounds with one or more diluents and / or adjuvants compatible and pharmaceutically acceptable.

The invention also relates to a method of treating a mammal, including humans, with neurological lesions associated with trauma and, in particular, to spinal, cranial or cranial-spinal comprising administering a effective amount of an anticonvulsant chosen from carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts thereof.

Claims

1 - Application of an anticonvulsant chosen from carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment of neurological lesions associated with trauma.
2 - Use according to claim 1 for the preparation of medicaments for the treatment of neurological lesions associated with spinal trauma.
3 - Application according to claim 1 for the preparation of medicaments for the treatment of neurological lesions associated with cranial trauma.
4 - Use according to claim 1 for the preparation of medicaments for the treatment of neurological lesions associated with cranial-spinal injuries.
5 - Use according to one of claims 1 to 4 for obtaining a medicament useful orally comprising 25 to 200 mg of the anticonvulsant.
6 - Application according to one of claims 1 to 4 to obtain an intravenous medicament comprising 12.5 to 200 mg of the anticonvulsant.
7 - A process for preparing a medicament useful for the treatment of neurological lesions associated with trauma and, in particular, to spinal, cranial trauma or cranial-spinal characterized in that one mixes an anticonvulsant chosen from carbamazepine and oxcarbazepine or the pharmaceutically acceptable salts of these compounds with one or more diluents and / or adjuvants compatible and pharaceutiquement acceptable.
EP19940902018 1992-12-16 1993-12-10 Application of carbamazepine and oxcarbazepine in the treatment of neurological lesions related to traumatic injuries Ceased EP0674520A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
FR9215148A FR2699077B1 (en) 1992-12-16 1992-12-16 Application of anticonvulsants in the treatment of neurological lesions associated with trauma.
FR9215148 1992-12-16
PCT/FR1993/001228 WO1994013298A1 (en) 1992-12-16 1993-12-10 Application of carbamazepine and oxcarbazepine in the treatment of neurological lesions related to traumatic injuries

Publications (1)

Publication Number Publication Date
EP0674520A1 true EP0674520A1 (en) 1995-10-04

Family

ID=9436652

Family Applications (3)

Application Number Title Priority Date Filing Date
EP19940902019 Expired - Lifetime EP0674512B1 (en) 1992-12-16 1993-12-10 Application of riluzole in the treatment of neurological lesions related to traumatic injuries
EP19940902802 Withdrawn EP0674518A1 (en) 1992-12-16 1993-12-10 Application of lamotrigine in the treatment of neurological lesions related to traumatic injuries
EP19940902018 Ceased EP0674520A1 (en) 1992-12-16 1993-12-10 Application of carbamazepine and oxcarbazepine in the treatment of neurological lesions related to traumatic injuries

Family Applications Before (2)

Application Number Title Priority Date Filing Date
EP19940902019 Expired - Lifetime EP0674512B1 (en) 1992-12-16 1993-12-10 Application of riluzole in the treatment of neurological lesions related to traumatic injuries
EP19940902802 Withdrawn EP0674518A1 (en) 1992-12-16 1993-12-10 Application of lamotrigine in the treatment of neurological lesions related to traumatic injuries

Country Status (22)

Country Link
US (1) US5830907A (en)
EP (3) EP0674512B1 (en)
JP (3) JPH08504429A (en)
KR (2) KR950703968A (en)
AT (1) AT164067T (en)
AU (3) AU678795B2 (en)
CA (3) CA2151604C (en)
CZ (3) CZ154695A3 (en)
DE (2) DE69317578D1 (en)
DK (1) DK0674512T3 (en)
ES (1) ES2113635T3 (en)
FR (1) FR2699077B1 (en)
GR (1) GR3026403T3 (en)
HU (3) HU217133B (en)
IL (3) IL108051A (en)
MX (3) MX9307882A (en)
NO (3) NO952228D0 (en)
PL (3) PL309346A1 (en)
RU (1) RU2142800C1 (en)
SK (3) SK279759B6 (en)
WO (3) WO1994013288A1 (en)
ZA (3) ZA9309400B (en)

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CA2151604A1 (en) 1994-06-23
HU9501752D0 (en) 1995-08-28
US5830907A (en) 1998-11-03
JP3712239B2 (en) 2005-11-02
AU678795B2 (en) 1997-06-12
CZ154795A3 (en) 1995-11-15
CA2151601A1 (en) 1994-06-23
AU5702094A (en) 1994-07-04
ES2113635T3 (en) 1998-05-01
HU217133B (en) 1999-11-29
NO307027B1 (en) 2000-01-31
JPH08504429A (en) 1996-05-14
IL108052D0 (en) 1994-04-12
SK78795A3 (en) 1996-05-08
NO952229D0 (en) 1995-06-06
DK674512T3 (en)
CZ154595A3 (en) 1995-11-15
SK279759B6 (en) 1999-03-12
NO952228D0 (en) 1995-06-06
JPH08504428A (en) 1996-05-14
JPH08504430A (en) 1996-05-14
ZA9309399B (en) 1994-08-22
WO1994013298A1 (en) 1994-06-23
HUT71814A (en) 1996-02-28
ZA9309401B (en) 1994-08-19
FR2699077A1 (en) 1994-06-17
HU9501753D0 (en) 1995-08-28
RU2142800C1 (en) 1999-12-20
MX9307882A (en) 1994-06-30
EP0674512A1 (en) 1995-10-04
EP0674512B1 (en) 1998-03-18
EP0674518A1 (en) 1995-10-04
IL108051D0 (en) 1994-04-12
DE69317578T2 (en) 1998-07-23
NO952230L (en) 1995-06-06
FR2699077B1 (en) 1995-01-13
PL309346A1 (en) 1995-10-02
KR950703965A (en) 1995-11-17
DE69317578D1 (en) 1998-04-23
HUT71839A (en) 1996-02-28
KR950703954A (en) 1995-11-17
IL108053D0 (en) 1994-04-12
AU5654094A (en) 1994-07-04
CA2151603A1 (en) 1994-06-23
AU5653994A (en) 1994-07-04
WO1994013288A1 (en) 1994-06-23
PL309347A1 (en) 1995-10-02
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PL309348A1 (en) 1995-10-02
SK78595A3 (en) 1996-05-08
HU9501751D0 (en) 1995-08-28
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