CA1307740C - Pharmaceutical preparation and method for inhibiting replication of htlv-iii (aids) virus - Google Patents
Pharmaceutical preparation and method for inhibiting replication of htlv-iii (aids) virusInfo
- Publication number
- CA1307740C CA1307740C CA000543641A CA543641A CA1307740C CA 1307740 C CA1307740 C CA 1307740C CA 000543641 A CA000543641 A CA 000543641A CA 543641 A CA543641 A CA 543641A CA 1307740 C CA1307740 C CA 1307740C
- Authority
- CA
- Canada
- Prior art keywords
- dextran sulphate
- htlv
- iii
- pharmaceutical preparation
- virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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%.
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%.
Description
13077~0 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.
~3()7740 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
13~7740 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.
- 2a -jm7-3363d53 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 jm7-3363d53 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.
13077~0 jm7-3363d53 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.
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.
~3()7740 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
13~7740 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.
- 2a -jm7-3363d53 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 jm7-3363d53 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.
13077~0 jm7-3363d53 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.
Claims (8)
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.
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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000543641A CA1307740C (en) | 1987-08-05 | 1987-08-05 | Pharmaceutical preparation and method for inhibiting replication of htlv-iii (aids) virus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000543641A CA1307740C (en) | 1987-08-05 | 1987-08-05 | Pharmaceutical preparation and method for inhibiting replication of htlv-iii (aids) virus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1307740C true CA1307740C (en) | 1992-09-22 |
Family
ID=4136200
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000543641A Expired - Lifetime CA1307740C (en) | 1987-08-05 | 1987-08-05 | Pharmaceutical preparation and method for inhibiting replication of htlv-iii (aids) virus |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1307740C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006003521A1 (en) * | 2004-02-06 | 2006-01-12 | Monash University | High dose, short interval use of sulfated polysaccharides for the treatment of infections |
-
1987
- 1987-08-05 CA CA000543641A patent/CA1307740C/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006003521A1 (en) * | 2004-02-06 | 2006-01-12 | Monash University | High dose, short interval use of sulfated polysaccharides for the treatment of infections |
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| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |