PHARMACEUTICAL PREPARATION AND METHOD FOR INHIBITING REPLICATION OF HTLV-III (AIDS) VIRUS

PREPARATION PHARMACEUTIQUE ET METHODE PERMETTANT D'INHIBER LA REPLICATION DU HTLV-III (SIDA)

English Abstract

ABSTRACT

Dextran sulphate and salts thereof are used to inhibit
replication of HTLV-III (AIDS) virus both in vivo and in vitro. The
same compounds are used in solution to inhibit the destructive
action of HTLV-III virus upon human lymphocyte T helper cells.
Preferably the dextran sulphate or salts thereof have a molecular
weight in the range of 3000-500,000 and a sulphur content of 12-25%.

Claims

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The embodiments of the invention in which an exclusive property
or privilege is claimed are defined as follows.


1. A pharmaceutical preparation for inhibiting replication of
HTLV-III virus which comprises a compound selected from the class
consisting of dextran sulphate and the salts thereof.

2. A pharmaceutical preparation according to claim 1,
comprising sodium dextran sulphate.

3. A pharmaceutical preparation for inhibition of activity of
HTLV-III virus which comprises dextran sulphate or its salts
having a molecular weight in the range of 3000-500,000 and a
sulphur content of 12-15%.

4. A pharmaceutical preparation for inhibiting the destructive
action of HTLV-III or "AIDS" virus upon human lymphocyte T-
helper cells which comprises a pharmaceutically acceptable
formulation comprising dextran sulphate or salts thereof.


5. A pharmaceutical preparation according to claim 4 which
comprises sodium dextran sulphate.


6. A pharmaceutical preparation for inhibiting replication of
HIV viruses such as HTLV-III which comprises a compound selected
from the class consisting of dextran sulphate and the salts
thereof.





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7. A pharmaceutical composition for inhibiting replication of
HTLV-III virus by oral administration comprising:
an active ingredient selected from the group of dextran
sulphate and salts of dextran sulphate; and
a pharmaceutically acceptable carrier for oral
administration.


8. The pharmaceutical preparation according to claim 7 wherein
said active ingredient is the sodium salt of dextran sulphate.

Description

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This invention relates to a pharmaceutical preparation and
method for inhibiting replication of HTLV-III (AIDS) Virus.
Certain retrovirus infections have been known to depress
immune functions in animals. In recent years it has been discovered
that a family of T-lymphotropic retroviruses causes T-cell
proliferation leukemia, helper T-cell depletion, and
immunosuppression in humans infected by these viruses. These
viruses have become known as the HTLV family of retroviruses. A
group of these viruses designated as HTLV-III has been isolated from
patients with acquired immune deficiency syndrome (AIDS) and has
become considered to be responsible for the development of this
condition in humans.
A cell line representative of this group has been deposited
under ATCC No. CRL8543 by an agency of the U.S. Department of Health
and Human Services.
Up to the present there has been no effective treatment for
the damage to the human immune system created by the infection with
this virus, although certain drugs have been shown to have some
inhibitory effects upon replication. These effects are not
cumulative and appear to be of temporary duration.
One of such drugs is azidothymidine (AZT) which has the
disadvantage of numerous serious side effects, especially with long
term usage.

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03363-53


Dextran Sulphate is a product obtained by methods well
known to the art, such as by sulfation of dextran with
chlorsulfonic acid in pyridine (Ricketts, Biochem J. 51 210-233 -
1952) or by means of concentrated sulphuric acid (U.S. Patent No.
3,498,972) or by chlorsulfonic acid - formamide (U.S. Patent No.
3,141,014), etc.
Sodium dextran sulphate ~M.W. 7000-8000) has been
utilized as an anticoagulant and has been in chemical use in
Japan as an anti lipaemic agent for more than 20 years and has
been proven safe for human use by oral administration over long
term use.
Dextran sulphate of higher molecular weights has been
found to be useful in the treatment of peptic ulcers as an oral
drug and by in;ection for the treatment of Scrapie infection in
animals.
Applicant has now determined that dextran sulphate and
its salts, particularly the sodium salt thereof, can inhibit the
replication of HTLV-III virus in vitro and in vivo, particularly
in proper concentrations and in suitable molecular weights,
depending on whether topical, oral or intravenous application is
desired.
Accordingly, the present invention comprises a
pharmaceutical preparation for inhibiting replication of HTLV-
III virus which comprises a compound selected from the class
consisting of dextran sulphate and the salts thereof.

B

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03363-53


This invention provides for both a method of making and
an antiviral pharmaceutical composition comprising dextran
sulphate or its salts in admixture with a pharmaceutically
acceptable diluant or carrier suitable for topical use. Examples
of such diluants or carriers are white petrolatum, Glaxaltm base
and Unibasetm. The diluant or carrier may have a water base or
an oil base. The topical formulation of the antiviral composition
of the present invention may be a suspension, an emulsion, a
power, an ointment, a cream or other suitable topical
formulation.




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This invention further provides for both a method of making
and an antiviral pharmaceutical composition comprising dextran
sulphate or its salts in admixture with a pharmaceutically
acceptable diluant or carrier suitable for intravenous use.
Examples of such diluants or carriers are normal saline and dextrose
solution.
This invention still further provides for both a method of
making and an antiviral pharmaceutical composition comprising
dextran sulphate or its salts in admixture with a pharmaceutically
acceptable diluant or carrier suitable for oral use. Examples of
such diluants or carriers are lactose, dextrose and starch.
The antiviral composition (and method for making same) of
the present invention may also include zinc sulphate which has a
synergistic effect on dextran sulphate and its salts. The
proportion of zinc sulphate to dextran sulphate or its salts may be
in the ratio of 5-10:1 respectively.
Since dextran sulphate and its salts having molecular
weights in the range of 3000-40,000 are systematically absorbed they
may be utilized by oral administration. Higher molecular weights up
to about 500,000 or more may be utilized by injection. Sulphur
content may range from 12-25%.
In evaluating the effectiveness of dextran sulphate, the
following test procedures have been carried out.
Human T-lymphocyte cells were exposed to HTLV-III cells in



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culture and almost all cells were destroyed by the end of the sixth
day. Dextran sulphate (8,000 M.W. sulphur content 18%) was then
added to another sample of same human T-cell culture in the
proportion of 10 micrograms per milliliter. This sample was then
inoculated with HTLV-III cells and allowed to stand. On the sixth
day the target lymphocyte cells wera counted and found to be
essentially unaffected by the virus and continued to proliferate
thereafter. This clearly indicated substantially complete blockage
of the viral toxicity of HTLV-III. Although this procedure was
carried out in vitro, similar in vivo activity can be predicted.
Based upon prior studies relating to the action of anionic
polyelectrolyte drugs upon other types of viruses, it would appear
that the effectiveness of dextran sulphate upon this HTLV-III virus
stems from one or more of several different types of activity. The
inhibiting effect may be due to the fact that studies have shown
that dextran sulphate markedly enhances aggregation of virus cells
and thus can inhibit absorption and penetration into target cells.
Dextran sulphate and other similar polyelectrolytes tend to
complex with proteins and hence may react to a certain extent with
the cell walls of the virus to impair their activity. In addition,
prior data indicates that injections of high molecular weight
dextran sulphate appear to increase immune response and the
production in target cells of a viral inhibitor having
interferon-like activity.




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For use with animals, including human use, the selected
dextran sulphate or sodium salt thereof may be formulated in known
conventional manner into tablets or capsules for oral
administration, ointments and creams for topical application or may
be prepared in solution or suspension for injection. Dosage
requirements for animal or human use based upon the above data
indicate that administration of 1-5 grams daily would be sufficient
to produce the desired blood levels of dextran sulphate to produce
inhibition. Such dosages have been found to be safe for long term
use.