Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1994-09-12
2003-09-16
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C514S061000
Reexamination Certificate
active
06620792
ABSTRACT:
TECHNICAL FIELD
This invention relates to pharmaceutical compositions containing onosialoganglioside GM
1
or a derivative thereof suitable for the treatment of Parkinson's disease.
PRIOR ART
Parkinson's disease is a neurodegenerative disease, which has a high rate of incidence (20 persons in 100,000 in the U.S.A.) and generally affects people older than 45-years.
Parkinson's disease is characterized by a dopaminergic deficit, which brings about a series of neuronal events resulting in akinesia, muscle rigidity, and tremors.
Symptomatology is believed to manifest itself with the loss of at least 85% of the striatal dopaminergic innervation, consequent to the degeneration of the neurons producing DA (dopamine) in the substantia nigra and pars compacta (Kish S. J. et al., The New England J. of Med:, 318, 876, 1988).
It is to be stressed that although pharmacological therapy for Parkinson's disease has been studied for over 25 years, the disease is still a critical problem especially due to the slow and progressive degeneration of the dopaminergic system (McGeer P. L. et al., Ann. Neurol., 24, 574, 1988).
As known, the therapy based on L-dopa, associated with peripheral decarboxylase inhibitors (carbidopa or benserazide) , with monamine oxidase inhibitors (Shoulson I. et al.: “Effect of Deprenyl on the progression of disability in early Parkinson's disease”, The New England J. of Med., 16, 1364-1371, 1989), as well as the therapy based on long-acting direct dopaminergic agonists (pergolide, cabergoline), in the great majority of early-stage cases considerably improves the clinical picture and, in some cases, provides a total control of symptoms. However, after some years treatment, i.e. from 2-3 years min. to generally 10 years max. or even more, symptoms—mainly characterized clinically by fluctuation and dyskinesias of various types—appear anew in most patients (80-90%).
Said motor fluctuations (in particular on-off phenomena) and hyperkinesias deeply upset the patient who, after years of well-being resulting from the disease being compensated by the therapy, relapses into a decompensated condition that prevents him/her from enjoying an adequate family, social, and work life.
With a view to solving the main problem to be faced by Parkinson's disease therapy, i.e. the decompensated phase, present clinical practice uses slow-release compositions based on levodopa associated with benserazide or carbidopa, long-acting direct dopaminergic agonists (pergolide, cabergoline), as well as infusion methods (lisuride and apomorphine subcutaneous infusion). However, no therapy has so far proved to be effective in slowing down or stopping the progression of the disorder, which is at the base of all complications occurring in the advanced phase of the disease.
As known, L-dopa and its hydroxylated metabolite (TOPA) may produce neurotoxic effects and worsen the disabling neurodegenerative pathology progression (Only J. W. et al.: “Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases”, Exp. Neurol., 108, 268-272, 1990; Rosenberg P. A. et al.: “2,4,5-Trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxin”, Proc. Natl. Acad. Sci. USA, 88, 4865-4869, 1991; Newcomer T. A. et al.: “Detection of TOPA (6-OH-DOPA) and TOPA quinone by HPLC reveals a spontaneous DOPA to TOPA conversion in aqueous solutions”. Excitatory Amino Acids: Excito-toxicity I p. 83).
With a view to developing new pharmacological treatments capable of modifying the evolution of Parkinson's disease, by slowing down or inhibiting the progression of same, several experimental investigations on animals were carried out, especially aimed at identifying the neurobiological mechanisms that in parkinsonism cause cell death, in particular the death of substantia nigral cells.
Of great importance is the information obtained by using methylphenyltetrahydropyridine (MPTP), a toxic substance capable of producing a neuropathologic and neuropharmacological picture very similar to that of Parkinson's disease (Langston J. W.: “MPTP and Parkinson's disease”, Trends in Neurosciences, 8, 2, 79-83, 1985). MPTP neurotoxicity was attributed to its oxidation, catalysed by monamine oxidase B, to the ionic species MPP
+
, which is actively taken up by dopaminergic cell terminals and has a inhibitory effect on the mitochondrial oxidation of NADH-dependent substrates. This results in a loss of the substantia nigra and pars compacta dopaminergic neurons as well as of the striatum-innervating dopaminergic fibres, with consequent biochemical and behavioural deficiencies.
It is also known that gangliosides, i.e. the complex sialoglycosphingolipids that are present in neuronal membranes (Ando S.: “Gangliosides in the nervous system”, Neuroch. Int., 5, 507-537, 1983) improve the neurologic course in the CNS of several experimental models of acute damage. On the basis of said results, GM
1
was clinically applied to treat cerebral ischemic stroke (U.S. Pat. No. 4,940,694 dated Jul. 10th, 1990; Argentino C. et al.: “GM
1
ganglioside therapy in acute ischemic stroke”, Stroke, 20, 1143-1149, 1989) and traumatic spinal cord injury (patent application PD 91 000234 dated Dec. 23rd, 1991; Geisler F. H.: “Recovery of motor function after spinal-cord injury—a randomized placebo-controlled trial with GM
1
ganglioside”, The New England J. of Med., 324, 1829-1838, 1991).
The inner ester derivative of GM
1
(AGF2) and the low-dose and fast-acting therapeutic efficacy of same, especially in acute ischemia models, is also known (Cahn R. et al.: “Influence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeys”, Stroke 20, 652-656, 1989).
Furthermore, the pharmacokinetic advantages offered by GM
1
ester derivatives over their precursor, GM
1
, have already been described (Bellato P. et al.: “Disposition of exogenous tritium labelled GM
1
lactone in the rat”, Neurochem., pp. 1-6, 1991; EP patent 85401291.1).
SUMMARY
It has surprisingly been found that the compounds selected out of the group consisting of monosialoganglioside (GM
1
), its inner ester derivative (AGF2), its methyl ester (AGF4) and N-dicholoroacetyl lyso GM
1
can be successfully applied to chronic Parkinson's disease treatment for preventing or reversing the neuronal degeneration induced by a long-term L-DOPA treatment.
In fact said compounds produce a neutralizing effect on the neurotoxicity of L-Dopa metabolites such as TOPA.
Therefore, the present invention is referred to the use of the claimed compounds for the preparation of pharmaceutical compositions active in Parkinson's disease treatment and to the relevant therapeutic method.
REFERENCES:
patent: 4713374 (1987-12-01), della Valle et al.
patent: 5229373 (1993-07-01), della Valle
patent: 0167449 (1986-01-01), None
patent: 0373039 (1990-06-01), None
patent: 93/03049 (1983-02-01), None
Seren et al.Stroke1990, 21(11), 1607-1612.*
Bianchi et al.Diabet. Res. Clin. Prac.1991, 12, 107-111.*
Skaper et al.Neurosci. Lett.1990, 117, 154-159.*
Olney et al.Exp. Neurol.108, 269-272.*
Favaraon et al.Proc. Natl. Sci. USAOct. 1988, 85, 7351-7355.*
N.E.J. Med., “Uneven Pattern of Dopamine Loss in the Striatum of Patients with Idiopathic Parkinson'Disease”, pp. 876-880, Apr. 7, 1988.
Amer. Neurol., “Rate of Cell Death in Parkinsonism Indicates Active Neuropathological Process”, vol. 24, pp. 574-576, 1988.
N.E.J. Med., “Effect of Deprenyl on the Progression of Disability in Early Parkinson's Disease”, vol. 321, No. 20, pp. 1364-1371, Nov. 16, 1989.
Experimental Neurology, “Excitotoxicity of L-DOPA and 6-OH-DOPA: Implications for Parkinson's and Huntington's Diseases”, vol. 108, pp. 269-272, 1990.
Proc. Nat'l. Acad Sci., “2,4,5-Trihydroxyphenylalanine in Solution Forms a Non-N-Methyl-D-Aspartate Glutamatergic Agonist and Neurotoxin”, vol. 88, pp; 4865-4869, Jun. 1991.
Tins, “MPTP and Parkinson's Disease”, pp. 79-83, Feb. 1985.
Neurochemistry
Romeo Aurelio
Skaper Stephen Drake
Toffano Gino
Fidia S.p.A.
Fonda Kathleen K.
Hedman & Costigan ,P.C.
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