Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1993-06-22
1995-08-08
Griffin, Ronald W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 60, 514885, 536103, A61K 31725, A61K 4736, C08B 3106
Patent
active
054398924
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutically active materials and compositions and in particular to the use of such materials and compositions as agents against human immunodeficiency virus type I (HIV-1) and related viruses.
It is known that some sulphated polysaccharides have anti-HIV activity; see, for example, European Patent Specification No. 240,098. This specification discloses highly sulphated oligosaccharides obtained by sulphation of dextrins of relatively low molecular weight.
According to the present invention there is provided an agent against HIV-1 and related viruses, the agent being or including dextrin sulphate containing at most two sulphate groups per glucose unit. Dextrin is a mixture of polymers of glucose and the glucose units may be substituted in one or more of the 2, 3 and 6 positions by sulphate groups.
The present invention also provides compositions containing such an agent. In addition, the invention provides the use of such an agent or compositions against HIV-1 and related viruses.
A dextrin sulphate of use in the present invention may have up to two sulphate groups per glucose unit and preferred dextrin sulphates are those having about 1, or between 0.5 and 1.5, preferably up to 1.2, sulphate groups per glucose unit. More preferably, the agent is the 2- or 6-sulphate of dextrin or a mixture thereof.
We have found that dextrin 2-sulphate has about the same activity against the HIV-1 virus as the dextrin 6sulphate. However, the latter has a greater anti-coagulant activity and for this reason dextrin 2-sulphate is a particularly preferred agent.
We have also found that dextrin 3-sulphates have relatively poor anti-HIV activity, by comparison with dextrin 2- and 6-sulphates. It follows that for a given sulphate content the anti-HIV activity of a dextrin sulphate is inversely related to the proportion of 3-sulphation. Under most reaction conditions the 3-OH group of the glucose residue in a dextrin has been found to be less reactive than the 2-OH and 6-OH groups. Therefore, enhanced anti-HIV activity per sulphate group can be achieved by keeping the degree of sulphation relatively low, thereby reducing the extent of 3sulphation.
However, in selecting particular sulphated dextrin as an anti-HIV agent conflicting factors are encountered. Thus, generally speaking:
It has seemed that dextrin sulphates might in fact be unusable in practice as anti-HIV agents because satisfactory anti-HIV activity appeared to go hand-in-hand with unacceptable toxicity, either because the molecular weight was too high or because the sulphate content was too high.
By restricting the degree of substitution to a maximum of 2 the present invention makes it possible to produce a dextrin sulphate having adequate anti-HIV activity while keeping toxicity within acceptable limits. With a relatively low degree of of substitution the proportion of 3-sulphation can be kept low, so that the toxicity imported into the dextrin sulphate by 3-substitution is avoided. If a dextrin is fully substituted, i.e. to give the 2,3,6-sulphate, one-third of the sulphate groups are 3-sulphate groups, which give rise to additional toxicity out of all proportion to the extent to which they enhance the anti-HIV activity. The extent to which 3-sulphation occurs when the degree of substitution is kept below 2 varies with the nature of the sulphation process, but is normally substantially less than that of 2-sulphation or 6-sulphation. Presently available analytical techniques do not easily permit accurate analysis of the extent of sulphation at the three available sites, but an examination of the n.m.r. spectrum of a dextrin sulphate gives a sufficient indication of this for practical purposes. The total sulphate content can of course be evaluated by conventional analytical methods, normally by determining the sulphur content.
The molecular weight of dextrin sulphate of use in this invention may vary over a wide range. By way of example, dextrin sulphate of use in the present invention may have a weight average molecular weight of from 15
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Sandstrom et al., "Anti-viral Therapy in AIDS", AIDS Press Limited, pp. 373-390, Sep. 1987.
Mitsuya et al., Retroviruses In Human Lymphoma/Leukemia, "Protection of T Cells Against Infectivity and Cytopathic Effect of HTLV-III in Vitro", pp. 277-288 (1985), Japan Sci. Soc. Press, Tokyo/VMU Science Press, Utrecht.
Biesert et al., "Inhibition of HIV and virus replication by polysulfphated polyxylan: HOE/BAY 946, a new antiviral compound", AIDS, vol. 2, No. 6, pp. 449-457 (1988).
Ito et al., "Potent and selective activity of dextrin sulfphate against human immunodeficiency virus type 1 in vitro", Antiviral Chemistry & Chemothreraphy, vol. 2, No. 1, pp. 41-44 (1991).
Griffin Ronald W.
ML Laboratories
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