Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-28
2004-06-15
Henley, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06750208
ABSTRACT:
The subject of the invention is a medicine for treating apoptosis dysfunctions.
The term <<apoptosis>> is intended to refer to programmed cell death or cell suicide.
This death corresponds to a self-elimination of cells according to a defined program.
It reveals itself, initially, through bulges in the plasma membrane, these bulges being accompanied by a structural change in the membrane, and then through a loss of volume of the cell, which appears to contract and to collapse in on itself.
The nucleus condenses and the DNA is cleaved into small fragments (Raff, <<
Nature>>,
356, 397, 1992; Bortner et al., <<
Trends in Cell. Biol.>>
5, 21, 1995).
In vivo, the cell undergoing apoptosis is recognized by macrophages which will phagocytose it and eliminate it without any inflammatory process.
Still in vivo, apoptosis is widely used by living organisms to control cell populations, in particular lymphocytes subsequent to their activation.
Moreover, during the development of organisms, apoptosis plays a fundamental role in the elimination of unnecessary embryonic tissues (lizard tail, rudiment of the genital organs of one sex or the other) and in the pattern of the organism (elimination of the interdigital webs between the future fingers etc.).
Some compounds which are present in living organisms specifically induce an apoptotic phenomenon. Thus, for example in mammals, the binding of the Fas ligand to the Fas membrane-bound receptor, which is also referred to as APO-1 or CD95, specifically induces an apoptosis; this apoptosis is used by the living organism to control lymphocyte populations, in particular T lymphocyte populations.
The abovementioned receptor and ligand represent an extremely advantageous physiological system which is involved in the specific elimination of cells which are no longer desired in the organism.
Mention may be made in particular of cell elimination during the maturation and activation of T lymphocytes. In fact, the Fas system, i.e. Fas ligand/Fas receptor, plays a fundamental role in the homeostasis of the immune system.
The Fas receptor is a member of a family of proteins which act as cell surface receptors and which also comprise the TNF (tumor necrosis factor) and NGF (nerve growth factor) receptors.
The Fas receptor is expressed in many cells; it is thought to accumulate in the Golgi apparatus.
The mechanism by which the Fas system induces cell death in unknown, but involves the activation of the proteases which are known under the designation ICE-like (<<interleukin-1 beta-converting enzyme>>) or caspases.
It may be noted that the Fas ligand can be secreted by cells in order to induce their own suicide; but given that this ligand is also found at the surface of activating cells, these cells will, as a result, induce the suicide of target cells by simple contact. Once it has been activated, the Fas receptor interacts with many intracellular proteins so as to transmit the apoptosis-triggering signal.
In vitro, other means exist for inducing apoptosis, for example by inhibiting the activity of certain kinases, and in particular kinase C; in this case, staurosporin may be used.
This product is very effective for inducing cell death by apoptosis.
It should, however, be noted that the signal transduction which is induced by staurosporin is different from that involving the Fas receptor.
However, while the means of activating apoptosis are different, the execution of the death program which is induced by these two modes of activation is equivalent and is characterized by an activation of the caspase cascade and a dysfunction of mitochondria, which releases compounds (for example, the cytochrome C) which will promote the programmed destruction of the cell. This phenomenon is energy-dependent, but does not require the synthesis of new proteins. In fact, in a cell, everything is ready for it to carry out its own destruction.
In vivo, the regulation of the apoptotic phenomenon has a considerable importance.
Specifically, many pathologies are associated with its dysfunction.
Mention may be made, for example, of two cases of apoptosis dysfunction in which the apoptosis is modified via the Fas system; they are autoimmune diseases in which apoptosis is deficient and the destruction of HIV-1-infected CD41 T lymphocytes in which apoptosis is too active.
In other cases such as the neuronal degeneration which is encountered, for example, in multiple sclerosis, apoptosis is activated via pathways which are as yet unknown.
Other pathologies exist in which apoptosis is deficient; in this respect, mention may be made of the accumulation of cancer cells in which apoptosis would appear to depend on the FAS system (<<
Green>>,
Science, vol. 278, 1246, 1997).
In light of the findings recalled above, the applicant company, to its credit, found that as a result of the availability of a medicine which is capable of modifying apoptosis dysfunctions both from the point of view of an activation, in the case of the pathologies of the group comprising autoimmune diseases and the pathologies such as cancer, and from the point of view of its inhibition, in the case of the pathologies of the group comprising AIDS, it became possible to combat these diseases.
It also found, to its no less great credit, that some oligosaccharide and monosaccharide substances which optionally comprise, on at least some of their individual units, at least one substituent of the group comprising sulfate, methyl and acetyl groups, were capable of modifying apoptosis dysfunctions.
A subject of the invention is thus a medicine, characterized in that it comprises, as an active principle, an effective amount of at least one oligosaccharide substance which is capable of modifying apoptosis dysfunctions and which optionally comprises, on at least some of its individual units, at least one substituent of the group comprising sulfate, methyl and acetyl groups, said substance being chosen from the group comprising:
the oligosaccharides which are derived, by enzymatic or chemical process, from the polymers of the group comprising (1→3)-&bgr;-glucans which optionally comprise (1→6)-&bgr;-branching,
the oligosaccharides which are derived, by enzymatic or chemical process, from sulfated galactans, in particular carrageenans, agars and porphyrans.
According to one advantageous embodiment, the medicine in accordance with the invention comprises, as an active principle, an effective amount of at least one oligosaccharide which is capable of modifying apoptosis dysfunctions and which satisfies the formula:
[
Gluc
→
1
3
β
Gluc
→
1
3
β
Gluc
Gluc
β
↓
1
5
]
n
(
I
)
in which n represents an integer from 1 to 50, preferably from 5 to 10, and in which the number of branches varies from 0 to 3 per repeat unit.
According to another advantageous embodiment, the medicine in accordance with the invention comprises, as an active principle, an effective amount of at least one repeat disaccharide which is capable of modifying apoptosis dysfunctions and which satisfies the formula:
[
Gal
→
1
3
α
Gal
→
1
4
β
]
n
Gal
(
II
)
in which n represents an integer from 1 to 50, preferably from 1 to 20, at least some of the repeat disaccharides of formula (II) possibly comprising one or more sulfate groups.
According to another advantageous embodiment, the medicine in accordance with the invention comprises, as an active principle, an effective amount of the product which is capable of at least partially inhibiting apoptosis and which is obtained by hydrolysis from sodium iota-carrageenate, this product consisting of a mixture of oligo-iota-carrageenans which is referred to as I
9
, which has a total saccharide content (determined according to Tillmans and Philippi) of 62%, and which has a distribution profile by size, which is estimated by electrophoresis on polyacrylamide gel according to Zabla
Arrigo Patrick
Cloarec Bernard
Cruz Florence
Descamps Valérie
Richard Christophe
Henley III Raymond J.
Kilpatrick & Stockton LLP
Laboratoires Goemar S.A.
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