Methods for increasing schwann cell survival

Details Methods for increasing schwann cell survival Methods for increasing schwann cell survival

1998-10-13

2002-07-09

Davenport, Avis M. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S654000, C530S300000, C530S303000

Reexamination Certificate

active

06417160

ABSTRACT:

BACKGROUND OF THE INVENTION
Deprenyl (also referred to herein as selegiline or R-(−)-N,&agr;-Dimethyl-N-2-propynyl phenethylamine) was first used as an adjunct to conventional drug therapy (L-dihydroxyphenylalanine (L-DOPA) plus a peripheral decarboxylase inhibitor) of Parkinson's disease (PD) in Europe over a decade ago on the basis that as a selective monoamine oxidase-B (MAO-B) inhibitor, it would elevate brain dopamine levels and potentiate the pharmacologic action of dopamine formed from L-DOPA, and yet prevent the tyramine-presser effect observed with non-selective MAO inhibitors. The combined drug therapy was reported to prolong the anti-akinetic effects of L-DOPA, resulting in the disappearance of on-off effects, reduced functional disability, and increased life-expectancy in PD patients (Bernheimer, H., et al., J. Neurolog. Sci., 1973. 20: 415-455, Birkmayer, W., et al., J. Neural Transm., 1975. 36:303-336, Birkmayer, W., et al., Mod. Prob. Pharmacopsychiatr., 1983. 19: 170-177, Birkmayer, W. and P. Riederer, Hassler, R. G. and J. F. Christ (Ed.) Advances In Neurology, 1984. 40(Y): p.0-89004, and Birkmayer, W., et al., J. Neural Transm., 1985. 64(2): p. 113-128).
Studies examining deprenyl as an adjunct to conventional L-DOPA therapy have reported a short term benefit which was usually lost by 1 year or less. Some, but not all, have reported that the levodopa dose can be decreased when taken in conjunction with deprenyl (Elizan, T. S., et al., Arch Neurol, 1989. 46(12): p. 1280-1283, Fischer, P. A. and H. Baas, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Golbe, L. I., Neurology, 1989.39: p. 1109-1111, Lieberman, A. N. et al., N.Y. State J. Med., 1987. 87: p. 646-649, Poewe, W., F.
Gerstenbrand, and G. Ransomayr, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Cedarbaum, J. M., M. Hoey, and F. H. McDowell, J. Neurol. Neurosurg. Psychiatry, 1989. 52(2): p. 207-212, and Golbe, L. I., J. W. Langston, and I. Shoulson, Drugs, 1990. 39(5): p. 646-651).
Increasingly, deprenyl is being administered to Parkinson's disease patients following reports (Parkinson, S. G. Arch Neurol 46, 1052-1060 (1989) and U.S.A., Parkinson, S. G. N. Engl. J. Med. 321, 1364-1371 (1989)) that it delays the disease progression; a mechanism has recently been proposed to explain its action (See, e.g., Tatton & Redman 1996).
Peripheral neuropathy is art-recognized and is a common neurological disorder resulting from damage to the peripheral nerves. It is a condition which is associated with several underlying conditions, including conditions such as inheritable neuropathies, diabetes, rheumatoid arthritis, acquired immunodeficiency syndrome (AIDS) and thyroid disease or associated side-effect of anti-cancer therapy, i.e., cisplatin treatment (see
J. Clinical Oncology
4(6): 1913 (1996),
B. J. Cancer
75(5):703 (1997) (for a review, see, e.g., Morgenlander, J. C.,
Postgrad. Med.
(1997) 102 (3): 71, and references cited therein).
Peripheral neuropathies can be debilitating, and treatment of such neuropathies is often difficult. Accordingly, methods of inhibiting or preventing the progression of peripheral neuropathies are needed.
SUMMARY OF THE INVENTION
It has now been discovered that certain compounds are capable of increasing survival of Schwann cells. The invention provides methods for increasing survival of Schwann cells both in vivo and in vitro, of preventing or inhibiting death of Schwann cells, of preventing or inhibiting the progression of peripheral neuropathy, and methods for treating a peripheral neuropathy.
In one aspect, the invention provides a method for increasing survival of Schwann cells. The method comprises administering to a subject in need thereof an effective amount of a compound selected from the group consisting of a deprenyl compound, N-acetylcysteine, and an insulin-dependant growth factor (IGF), such that survival of Schwann cells is increased. In certain embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
R
2
is hydrogen or alkyl;
R
3
is a single bond, alkylene, or —(CH
2
)
n
—X—(CH
2
)
m
;
in which X is O, S, or N-methyl; m is 1 or 2; and n is 0,1, or 2;
R
4
is alkyl, alkenyl, alkynyl, heterocyclyl, aryl or aralkyl; and
R
5
is alkylene, alkenylene, alkynylene and alkoxylene; and
R
6
is C
3
-C
6
cycloalkyl or
 —C≡CH;
or
R
2
and R
4
-R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group;
and pharmaceutically acceptable salts thereof. In certain embodiments: R
1
is a group that can be removed in vivo; R
1
is hydrogen; R
1
is alkyl; R
1
is methyl; R
2
is methyl; R
3
is methylene; wherein R
4
is aryl; R
4
is phenyl; R
5
is methylene; R
6
is
—C≡CH
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
R
2
is hydrogen or alkyl;
R
3
is a bond or methylene; and
R
4
is aryl or aralkyl; or
R
2
and R
4
—R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
2
is hydrogen or alkyl;
R
3
is a bond or methylene; and
R
4
is aryl or aralkyl; or
R
2
and R
4
—R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group; and
R
5
is alkylene, alkenylene, alkynylene and alkoxylene;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
A is a substituent independently selected for each occurence from the group consisting of halogen, hydroxyl, alkyl, alkoxyl, cyano, nitro, amino, carboxyl, —CF
3
, or azido;
n is 0 or an integer from 1 to 5;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the patient is a human. In a particularly preferred embodiment, the deprenyl compound is (−)-desmethyldeprenyl (DMD).
In another aspect, the invention provides a method for inhibiting peripheral neuropathy, comprising administering to a patient an effective amount of a compound selected from the group consisting of a deprenyl compound, N-acetyl cysteine and IGF-1, such that peripheral neuropathy is inhibited. In a preferred embodiment, the deprenyl compound is (−)-desmethyldeprenyl (DMD). In certain embodiments, the neuropathy is selected from the group consisting of diabetic neuropathy and AIDS-related neuropathy. In certain embodiments, the patient is a human.
In another aspect, the invention provides a method for increasing Schwann cell survival in vitro, comprising contacting Schwann cells with an effective amount of a compound selected from the group consisting of a deprenyl compound, N-acetyl cysteine and IGF-1, such that Schwann cell survival is increased.
In another aspect, the invention provides a method for increasing Schwann cell survival in a patient, comprising contacting a Schwann cell with a compound selected from the group consisting of a deprenyl compound, N-acetyl cysteine and IGF-1, such that Schwann cell survival increases. In preferred embodiments, the patient is a human; the deprenyl compound is (−)-desmethyldeprenyl; and/or the (−)-desmethyldeprenyl is administered transdermally to the patient.
In another aspect, the invention provides a composition comprising N-acetylcysteine in a pharmaceutically acceptable carrier.


REFERENCES:
patent: 4522811 (1985-06-01), Eppstein et al.
patent: 5374548 (1994-12-01), Caras
patent: 5399331 (1995-03-01), Kasai et al.
patent: 5416016 (1995-05-01), Low et al.
patent: 5444095 (1995-08-01), Talton
patent: 92/17169 (1992-10-01), None

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