WO1993020824A1 - Pharmaceutical compositions containing monosialoganglioside derivatives suitable for the treatment of spinal cord injury - Google Patents
Pharmaceutical compositions containing monosialoganglioside derivatives suitable for the treatment of spinal cord injury Download PDFInfo
- Publication number
- WO1993020824A1 WO1993020824A1 PCT/EP1993/000894 EP9300894W WO9320824A1 WO 1993020824 A1 WO1993020824 A1 WO 1993020824A1 EP 9300894 W EP9300894 W EP 9300894W WO 9320824 A1 WO9320824 A1 WO 9320824A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- spinal cord
- monosialoganglioside
- cord injury
- agf
- ester
- Prior art date
Links
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
Definitions
- the present invention relates to pharmaceutical compositions containing monosialoganglioside derivatives suitable for the treatment of spinal cord injury.
- the incidence of said injury is high: for example, in the USA over
- Spinal cord injury may be defined as primary or secondary.
- the secondary injury seems to be the result of the combined action of delayed swelling, additional injuries to the already affected spinal segment, anoxia, reduced perfusion to the impaired medulla tract and/or release of endogenous factors.
- the investigations carried out so far have pinpointed some molecular bases of spinal injury and recovery, i.e.: a) "neuronal elements injury”: as known, secondary injury at least in part results from hypoxic-ischaemic processes damaging neuronal and axonal elements. It is to be stressed that spinal cord traumatic injury seldom causes spinal cord anatomic transection, even in case of total loss of the neurologic clinical function at the caudal portion level.
- the neurologic deficit is actually induced by a microscopic physical decay of the axons crossing the injury site, by ischaemia or hypoxia followed by local infarction, or by microhaemorrhages or oedema inside the spinal cord at the injury site,- which also affect neuronal impulses transmission;
- substantially alba tracts injury as known, clinical deficit after spinal cord injury results also from disorders to the substantia alba, including spinal cord ascending and descending tracts;
- neurotrophic agents as known, soluble trophic agents are released by glial cells and improve the survival, the spinal neurons morphofunctional properties and the axonal regeneration;
- microenvironmental conditions as known, one of the problems inherent in spinal cord injury recovery is the microenvironment not being “receptive" to neuronal regeneration.
- Methylprednisolone is the first drug which proved to be clinically effective , but only in the peracute phase and at high dosage levels (Bracken M . B . et al . : "A randomized , controlled trial of methylprednisolone or naloxone in the treatment of spinal-cord injury: results of the Second National Acute Spinal Cord Injury Study” , New Engl . J . of Med. , 322 , l405-l4ll , 1990) .
- Monosialoganglioside GM- ⁇ is the second drug which was found significantly to improve the patients ' neurologic functional recovery at one-year distance from injury , on condition that treatment had began within 2 hours from injury, followed by 18-32 i.v. doses of 100 mg/day (Geisler F.H . et al . : "Recovery of motor function after spinal-cord injury - a randomized, placebo-controlled trial with GM j ⁇ ganglioside" , New Engl . J . of Med. , 26, 324 , 1829- 1838; patent application PD 9- 0 023 dated 23rd Dec , 1991) .
- GM- ⁇ monosialoganglioside GM- ⁇ can produce a neuroprotective effect in the acute phase by limiting the secondary neuronal damage and can improve the functional recovery in the long run.
- GM ⁇ was clinically applied to treat cerebral ischaemic strokes (Argentino C. et al. : "G ⁇ ganglioside therapy in acute ischemic s roke", Stroke, 20, 1143- 1149. 1989; U.S. patent 4,940,694).
- the inner ester derivative of GM ⁇ (AGF2) and the small-dose fast- acting therapeutic efficacy of same in acute cerebral eschaemic models are also known (Cahn R.
- the inner esters of gangliosides are active in the treatment of nervous system disorders, in particular of the peripheral nervous system and of the central nervous system .
- the inner ester derivatives of the ganglioside mixture or of the monosialoganglioside GM- ⁇ fraction may be administered by the oral way to treat PNS and CNS disorders.
- the outer carboxylic esters of gangliosides and their therapeutic application to treat PNS and CNS disorders - as described above for inner ester derivatives - are also known (EP
- a recent patent application PD 91 A 000101 claims a different therapeutic application of GM-j methyl ester to patients affected by nervous system damages caused by excitatory amino acids (e.g. ischaemia, hypoxia, traumas, compressions, dysmetabolisms, epilepsy, neurodegenerative diseases, and chronic ache).
- excitatory amino acids e.g. ischaemia, hypoxia, traumas, compressions, dysmetabolisms, epilepsy, neurodegenerative diseases, and chronic ache.
- monosialoganglioside GM ⁇ derivatives i.e. the inner ester AGF2 and the methyl ester AGF/ j of said monosialoganglioside
- the present invention is, therefore, referred to said pharmaceutical compositions and to the therapeutic method envisaging the use of same for the treatment of spinal cord injury.
- Said derivatives are selected from the group consisting of the monosialoganglioside GM- ⁇ inner ester (AGF2) and the GM- ⁇ methyl ester (AGF 4 ).
- AGF2 and AGFj are pharmacologically active in the therapy of spinal cord injury and that AGF2 and AGF ⁇ efficacy is surprisingly higher than that of monosialoganglioside GM ⁇ .
- the experimentation was aimed at reducing the neurologic deficit in rabbit caused by secondary ischaemic spiral cord injury brought on by aortic obstruction.
- the results obtained are particularly interesting because of the high incidence (up to 50%) of spinal cord injury - i.e. paralysis and paraplegia - in patients having undergone surgical removal of aneurysms in thoracic or thoracicoabdominal aorta segments.
- spinal cord injury - i.e. paralysis and paraplegia -
- patients having undergone surgical removal of aneurysms in thoracic or thoracicoabdominal aorta segments In fact, even after 1 to 7 days from the aforesaid operation, which requires thoracic aorta obstruction and complete blood flow discontinuance through the aorta segment affected by the aneurysm, many patients suffer neurological deficit, e.g. paraplegia or paraparesls.
- said pharmaceutical approach is not only limited to this specific surgical situation but can also be applied to all spinal cord injury events directly brought on by a traumatic or hypoxic- ischaemic lesion.
- Two neurosensory electrostimulation electrodes were applied to the skin of the hind legs. The animals were stimulated every five seconds at a lower voltage than required for testing the neurologic functions (motor and sensory) .
- the spinal cord injury was treated pharmacologically with the following compounds:
- ALF2 monosialoganglioside GM ⁇ inner ester
- AGF /j monosialoganglioside GM ⁇ methyl ester
- AGF2 and AGFj j considerably delay the acute motor and sensory loss occurring during obstruction
- AGF2 and AGF ⁇ considerably increase the neurologic recovery: after 24 hrs the paralysis incidence is 15% - 18% in treated animals vs 63% in controls and after 7 hours the paralysis incidence is 36% - 38% in treated animals vs 91% in controls; - the effect of AGF 2 and AGF4 is greater than that of monosialoganglioside GM- ⁇ fraction.
- the monosialoganglioside derivatives considered herein are effective in preventing and/or recovering neurologic functional disorders, e.g. paralysis, caused by an ischaemic- ype secondary spinal cord injury.
- the efficacy of said compounds may be advantageously exploited for preventing and/or recovering acute spinal cord injuries brought on directly by traumatic or hypoxic-ischaemic causes, associated with an acute, subchronic and chronic symptomatology, as well as for preventing and/or recovering the secondary ischaemic spinal cord injury following vascular operations, e.g. the surgical operations to remove thoracic or thoracicoabdominal aneurysms, which must be performed under aorta obstruction conditions. Therefore, monosialoganglioside GMi derivatives, and precisely its inner ester derivative AGF 2 , and its methyl ester derivative AGF/ j can be used as active ingredients for the preparation of pharmaceutical compositions suitable for the treatment of spinal cord injury. Said compositions contain a pharmacologically effective quantity of said derivatives, mixed with pharmacologically acceptable excipients and diluents.
- compositions as per the present invention may have an active ingredient content of r 10 to 200 mg and are prepared as formulations that can be administered to man orally or parenterally, i.e. by intramuscolar or intravenous or subcutaneous injection.
- the dose of active ingredient to be administered will depend on the desired effects and on the way of administration: by parenteral injection, it may range from 0.1 to 15 mg/kg/day; by os, it may range from 0.5 to 150 mg/kg/day.
- compositions prepared according to this invention are reported below by way of example and not of limitation:
- One 2 ml ampoule contains - methyl ester AGF/ j 5-00 mg
- compositions prepared in two vials are prepared in two vials.
- One vial contains the active ingredient in the form of freeze-dried powder (10% to 90% by wt. ) , mixed with a pharmacologically acceptable exclpient, glyclne or mannitol.
- the other vial contains the solvent, as sodium chloride solution and a citrate buffer.
- the powder may be obtained either by freeze- drying, using water for injection or another solvent (e.g. tert- butanol) , or by direct partition under aseptic conditions of the sterile powder.
- System No. 1 a. one 2 ml vial of freeze-dried powder contains
- one vial contains
- one 4 ml ampoule of solvent contains - monobasic sodium phosphate 2 -0 1.00 mg
- one vial contains
- one vial contains
- One enteric coated tablet contains
- One immediate release tablet contains
- One controlled release tablet contains
- One hard gelatin capsule enclosing enteric granules contains
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93911460A EP0633782A1 (en) | 1992-04-10 | 1993-04-13 | Pharmaceutical compositions containing monosialoganglioside derivatives suitable for the treatment of spinal cord injury |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI92A000878 | 1992-04-10 | ||
ITMI920878A IT1258310B (en) | 1992-04-10 | 1992-04-10 | PHARMACEUTICAL COMPOSITIONS INCLUDING MONOSIAL-GANGLIOSIDIC DERIVATIVES FOR THE TREATMENT OF DAMAGE TO THE SPINAL CORD. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993020824A1 true WO1993020824A1 (en) | 1993-10-28 |
Family
ID=11362885
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/000894 WO1993020824A1 (en) | 1992-04-10 | 1993-04-13 | Pharmaceutical compositions containing monosialoganglioside derivatives suitable for the treatment of spinal cord injury |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0633782A1 (en) |
IT (1) | IT1258310B (en) |
WO (1) | WO1993020824A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476119A (en) * | 1981-08-04 | 1984-10-09 | Fidia S.P.A. | Method for preparing ganglioside derivatives and use thereof in pharmaceutical compositions |
EP0548406A1 (en) * | 1991-12-23 | 1993-06-30 | FIDIA S.p.A. | Therapeutic use of ganglioside GM1 in the treatment of spinal cord injury |
-
1992
- 1992-04-10 IT ITMI920878A patent/IT1258310B/en active IP Right Grant
-
1993
- 1993-04-13 WO PCT/EP1993/000894 patent/WO1993020824A1/en not_active Application Discontinuation
- 1993-04-13 EP EP93911460A patent/EP0633782A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476119A (en) * | 1981-08-04 | 1984-10-09 | Fidia S.P.A. | Method for preparing ganglioside derivatives and use thereof in pharmaceutical compositions |
EP0548406A1 (en) * | 1991-12-23 | 1993-06-30 | FIDIA S.p.A. | Therapeutic use of ganglioside GM1 in the treatment of spinal cord injury |
Non-Patent Citations (4)
Title |
---|
J.NEUROTRAUMA vol. 9SPL1, March 1992, pages S407 - 16 'GM-1 Ganglioside in Human Sopinal Cord Injury' * |
NEW ENGL.J.MED. vol. 324, no. 26, 1991, pages 1829 - 38 'Recovery of Motor Function after Spinal Cord Injury - A Randomized, Placebo-Controlled trial with GM-1 Ganglioside' * |
PROC.NATL.ACAD.SCI.USA vol. 84, 1987, pages 5459 - 63 'Astroglyal and fibroblast growth factors have neurotrophic function for cultured peripheral and central nervous system neurons' * |
STROKE vol. 20, no. 5, 1989, pages 652 - 6 'Influence of Monosialoganglioside Inner Ester on Neurologic Recovery After Global Cerebral Ischemia in Monkeys' * |
Also Published As
Publication number | Publication date |
---|---|
ITMI920878A0 (en) | 1992-04-10 |
ITMI920878A1 (en) | 1993-10-10 |
EP0633782A1 (en) | 1995-01-18 |
IT1258310B (en) | 1996-02-22 |
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