CA2066134C - Complexes of polyadenylic acid with polyuridylic acid - Google Patents
Complexes of polyadenylic acid with polyuridylic acid Download PDFInfo
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- CA2066134C CA2066134C CA002066134A CA2066134A CA2066134C CA 2066134 C CA2066134 C CA 2066134C CA 002066134 A CA002066134 A CA 002066134A CA 2066134 A CA2066134 A CA 2066134A CA 2066134 C CA2066134 C CA 2066134C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Abstract
The invention relates to a therapeutical composition for the treatment of Acquired Immuno Deficiency Syndrome (Aids) and related infections, said composition comprising of from 1 to 100 % of complex of Poly(A).cndot.Poly(U), optionally associated to an other anti-Aids agent acting on the HIV virus according to a different mechanism of the one of the complex of Poly(A).cndot.Poly(U), and pharmaceutically acceptable diluents or carriers.
Description
The invention relates to pharmaceutical compositions containing complexes of polyadenylic acid with polyuridylic acid (hereinafter referred to as "the complex of Poly(A).Poly(U)" or "PoIyA.PolyU"), optionally associated with another anti-AIDS
drug, and also to the use of such complexes for the treatment of Acquired Immuno Deficiency Syndrome (AIDS) and related infections.
British Patent No. 2 211 847, which corresponds to U.S. patent No. 4 927 755, describes a process for the preparation of homopolymers and copolymers of polynucleotides and complexes thereof. Although these products were previously known, previous processes were not able to produce them at an economically acceptable cost without toxic impurities which made them unsuitable for pharmaceutical use.
The process described in the aforesaid British patent leads to products of sufficient purity for pharmaceutical use, namely for the treatment of tumors.
The complex of Poly(A).Poly(U) has been described as a poor anti-viral agent (cf "Effects of polynucleotides on monkeys and man", CLINICAL ASPECTS OF
INTERFERONS, 1988, pages 319-331). Even though viruses and retroviruses behave somewhat differently, one of skill in the art would not expect that Poly(A).Poly(U) might be an efficient anti-retroviral agent. Contrary to that which would be expected, the applicants have found Poly(A).Poly(U) to be effective in the treatment of AIDS.
It has been found that a complex of Poly(A).Poly(U) is also a potent inhibitory agent of various HIV viruses, by blocking the entry of the virus. The invention thus provides a therapeutic agent for the treatment of AIDS and HIV, wherein the major active ingredient is Poly(A).Poly(U). Preferably, the Poly(A).Poly(U) is prepared by the process described in said British Patent No. 2 211 847.
It has been found that Poly(A).Poly(U) is especially effective when administered with other anti-AIDS drugs, notably 3'-azido-3'-deoxythymidine (AZT), Dideoxyinosine (DDI) or Dideoxycytidine (DDC). Of particular interest is that fact that the complex of Poly(A).Poly(U) has been found to synergistically enhance the effect of AZT, DDI and DDC. Accordingly, a further aspect of the invention is directed to a pharmaceutical composition comprising pharmaceutically acceptable diluents or carriers and a S combination of Poly(A).Poly(U) and another anti-AIDS drug acting according to a different mechanism from that of the complex of Poly(A).Poly(U), the amount of each component of the combination being selected so that the combination is effective in the treatment of AIDS and/or in the inhibition of HIV.
The invention also provides a method for the treatment of AIDS, the method comprising administering an effective amount of Poly(A).Poly(U), alone or in combination with another anti-AIDS agent, to a patient suffering from AIDS.
Accordingly, this invention provides a therapeutic composition for the treatment of Acquired Immuno Deficiency Syndrome (AIDS) and related infections, said composition comprising as an active ingredient from about 0.1 to 100 °lo of a complex of Poly(A).Poly(U), optionally associated with another anti-AIDS agent acting on HIV
viruses according to a different mechanism from that of the complex of Poly(A).Poly(U), and pharmaceutically acceptable diluents or Garners.
According to a preferred embodiment of the invention, the anti-AIDS coagent acting on the HIV virus is selected from the group consisting of AZT, DDI, DDC and combinations of the foregoing. The weight ratio of Poly(A).Poly(U) to the anti-AIDS
coagent is suitably from about 1 : 10-1 to about 1 : 10-x, but is preferably from about 1 : 10-1 to about 1 : 10-2.
The interest of Poly(A).Poly(U) in the treatment of AIDS will appear clearly from the various experiments hereafter described.
These and other aspects of the present invention may be more fully understood from the following detailed discussion and the drawing, with the drawing showing the viral proteins synthesized during incubation.
_ 3_ 2066134 Two batches of CEM cells (T cells rich in CD4 receptors) were infectcd with Human Immunodeficiency Virus HIV-1 Bru (LAI) and were treated with Poly(A).Poly(U) 24 hours after infection. Two similar batches of HIV infected CEM cells were used as controls, i.e. they were not treated. The cell cultures were regularly inspected under a microscope to observe the onset of cytopathic effects (fusion of cells and formation of syncitia) resulting from the HIV.
The experimental protocols were as follows : 5 x 106 CEM cells were incubated with 1 ml of supernatent containing HIV with a reverse transcriptase activity of 1.0 x 106 cpm. One hour afterwards, the cells were centrifuged and the cellular residue (0.5 x 106 cells) was suspended in RMP1 medium containing 10 % fetal serum and 2 ~.g/ml polybrene. Twenty-four hours later, Poly(A).Poly(U) was added at a concentration of 200 ~.g/ml. The cell cultures were maintained without further addition of Poly(A).Poly(U).The results were as follows Table 1 Da 6 Da 7 Da 8 Da 11 Controls ++ ++++ ++++ cells dead Treated Cells- + + ++
The symbol "+" indicates the appearance of cytopathic effects ; the number of such symbols used is an approximate quantification. These results show that the cytopathic effects are significantly reduced by the treatment.
Cultures were prepared as above described, and during the night of days 7 and were incubated with 35S-methionine for electrophoretic analysis on SDS of the viral proteins synthesized, both in the cellular mass and in the supernatent. The results are shown in the accompanying drawing. In the drawing, "-" indicates a sample from an untreated control and "+" a sample from a culture treated with Poly(A).Poly(U). The identifiers on the right of the indicators shown are as follows gp 120 the envelope protein p68 reverse transcriptase p55 precursor of the core protein -4- 236~~.3~
p40 precursor of the core protein, partially cleaved p32 endonuclease p25 the major core pmtein The xesults show an almost total reduction of the presence of viral proteins in the cells and supernatants of the cultures treated with Poly(A).Poly(U).
The quantity of p24/p25 antigen in the supernatant was measured 8 days after infection, by the ELISA test. These results are as follows Controls Treated Cells 1.01 ml 0.03 ml 1.27 ml 0.07 ml This shows suppression of 96.5 % of the HIV production in the cultures treated by Poly(A).Poly(U).
The action of Poly(A).Poly(U) on the inhibition of the production of HIV has been confirmed by the following experiments.
1. Effect of variation of the dose of Pol f~~~) CEM cells were infected with HIV. Twenty-four hours later, different concentrations of Poly(A).Poly(U) were added. The production of the virus in the supernatant of the culture was determined on day 5 after infection, by quantifying the amount of p24/p25 antigen present. Control cells, which had been infected but to which Poly(A).Poly(U) had not been added, had by then ruptured. The obtained results were as follows ~ossl~4 Poly(A).Poly(U) p24/p25 1) m1 0 1.10 25 0.53 50 0.14 100 0.10 200 0.07 2. Effect of Repeated Treatment The operating procedure was similar to that described in experiment 1, but addition of Poly(A).Poly(U) was at a concentration of 200 p.g/ml at 24 and 96 hours after infection. An untreated control was also run ; as before, the cells in the control had ruptured by day 5.
The concentration (pg/ml) of p24/p25 at the days 4, 5, 6 and 7 after infection was measured in the untreated control and in the cells treated at days 1 and 4.
The obtained results were as follows Table 4 4 Day 5 Day 6 Day 7 Controls 0.72 1.25 Treated cells-. I 0.05 0.10 0.20 0.26 3. The effe.~t of Poi (v_,Al Poly~,1 is at an early t-ten in viros infection HIV infected cells were treated with 200~tg/ml of Poly(A).Poly(In at different times before, during and after infection with 1-IIV. On day 6 after infection, the number of syncitia were counted. On day 7, the level of p25 in the culture medium was assayed -6- zossl3~
Pol A .Pol ~ncida % 25 n ml Control (untreated)90 1320 Cells treated at . 3 days before 85 121 S
. 2 days before 72 965 . 1 day before 45 280 . 1 hour before <5 6 . Together with <5 5 HIV
. 1 hour after 10 110 . 4 hours after 10 120 STUDY OF USE OF POLY(A).POLY(U) WITH AZT
Cells were infected with HIV 24 hours before a single treatment with (a) Poly(A).Poly(U) alone, at a concentration of 100 pg/ml ;
(b) AZT alone, at concentrations of 100, 250, 1 000, 5 000 and 10 000 ng/ml, (5 samples) ;
(c) a combination of (i) AZT at concentrations of 100, 250, 1 000, 5 000 and ng/ml, and (ii) in each instance, Poly(A).Poly(U) at a concentration of 100 ug/ml.
A control (non-treated) was also maintained ; the cells culture in the control dies progressively after day ?. So, no figure appears in day 12 and day 14 columns.
The levels of antigen p25 in the supernatents were measured at days 7, 12 and 14 after infection. The results, expressed in itg/ml, were as follows -7- 2oss~~~
p25 Da 7 Da 12 Da Control 1250 Pol A).Pol ) 135 980 1200 '~ 1~ 16 75 900 Pol A).Pol ) Pol (A).Pol (U) AZT 1000 <5 52 590 '~'~ 1~ <5 17 200 Pol (A).Pol (U) AZT 5000 <5 27 275 <5 10 48 Pol (A).Pol (LT) AZT 10 000 <5 20 220 AZT 10 000 <5 8 39 Pol (A).Pol (U) These results show that the combination of Poly(A).Poly(U) with AZT is more effective than either alone.
The results show that Poly(A).Poly(U) has an inhibitory effect on HIV. This has been observed in different tests A) metabolic synthesis of viral proteins in infected cells B) activity of reverse transcriptase in the culture medium of infected cells C) amounts of the major core protein p25 of HIV in the culture medium of infected cells ; and D) cell fusion 2oss~3~
In all of the experiments presented above, the HIV-1 Bru isalate (commonly referred to as HIV-1 LAI) was employed. In order to demonstrate that the inhibitory action of Poly(A).Poly(U) is not restricted to the HIV-1 species used, another species of HIV-1 referred to as ELI (31) and two different HIV-2 species, ROD and EHO, were tested. Poly(A).Poly(U) added 6 hours before infestation of CEM cells with these viruses resulted in more than 90 % inhibition of virus production.
In all these tests, Poly(A).Poly(U) at a dosage of 200 p.g/ml exercises an inhibitory action which is between about 85 and about 90 %. For human beings, an amount per single injection of from about 100 to 4 000 mg is considered suitable ; doses of from about 150 to 1000 mg can be efficiently injected into human beings. It is preferred that treatment be as close as possible to the time of infection ; however, treatment before of after infection is also effective. The treatment is suitably repeated at intervals of about 3 to 5 days.
The compounds of the present invention are suitably administered by injection in water solution. The active ingredient is added to the water solution.
Poly(A).Poly(U) is suitably added at about 0.2 to about 1.0 g per 100 ml water solution.
Coagents, such as AZT, DDI and DDC, can suitably be added. The weight ratio of Poly(A).Poly(U) to the anti-AIDS coagent is suitably from about 1 : 10-1 to about 1 : 10-4. A
preferred water solution for use in the present invention is NaH2P04-H20 0.100 g NaCI 0.068 g NaOH to neutralize (pH
7) H2O q.v. to 100 ml In each 100 ml of water solution there is dissolved Poly(A).Poly(U) 0.40 g Mannitol 1.84 g NaCI 0.48 g If one or more coagents is desired, they are cumulatively added to the water solution, i.e. nothing is removed to account for the addition of the coagent.
A suitable amount of a coagent, notably AZT, is from about 0.04 mg to about 4 mg per 100 ml of water solution. For example, 150 mg of Poly(A).Poly(U) associated with 15 mg of AZT, may be administered by injection of 38 ml of a water solution as above described.
It has been demonstrated that the complex of Poly(A).Poly(U) has a potent anti-retroviral action. However, using Poly(A).Poly(U) in combination with another anti-retroviral agent such as AZT, DDI or DDC gives far better results than use of either alone.
An explanation for this may be that Poly(A).Poly(U) works at the level of penetration of the virus into the cell, whereas AZT, DDI and DDC work at the level of infra-cellular transcription. Whether or not this is the correct theory for the manner in which the combination of Poly(A).Poly(U) and another anti-retroviral drug is effective, the fact remains that the combination is superior to the use of either agent alone.
It will be understood that the claims are intended to cover all changes and modifications of the preferred embodiments of the invention herein chosen for the purpose of illustration which do not constitute a departure from the spirit and scope of the invention.
drug, and also to the use of such complexes for the treatment of Acquired Immuno Deficiency Syndrome (AIDS) and related infections.
British Patent No. 2 211 847, which corresponds to U.S. patent No. 4 927 755, describes a process for the preparation of homopolymers and copolymers of polynucleotides and complexes thereof. Although these products were previously known, previous processes were not able to produce them at an economically acceptable cost without toxic impurities which made them unsuitable for pharmaceutical use.
The process described in the aforesaid British patent leads to products of sufficient purity for pharmaceutical use, namely for the treatment of tumors.
The complex of Poly(A).Poly(U) has been described as a poor anti-viral agent (cf "Effects of polynucleotides on monkeys and man", CLINICAL ASPECTS OF
INTERFERONS, 1988, pages 319-331). Even though viruses and retroviruses behave somewhat differently, one of skill in the art would not expect that Poly(A).Poly(U) might be an efficient anti-retroviral agent. Contrary to that which would be expected, the applicants have found Poly(A).Poly(U) to be effective in the treatment of AIDS.
It has been found that a complex of Poly(A).Poly(U) is also a potent inhibitory agent of various HIV viruses, by blocking the entry of the virus. The invention thus provides a therapeutic agent for the treatment of AIDS and HIV, wherein the major active ingredient is Poly(A).Poly(U). Preferably, the Poly(A).Poly(U) is prepared by the process described in said British Patent No. 2 211 847.
It has been found that Poly(A).Poly(U) is especially effective when administered with other anti-AIDS drugs, notably 3'-azido-3'-deoxythymidine (AZT), Dideoxyinosine (DDI) or Dideoxycytidine (DDC). Of particular interest is that fact that the complex of Poly(A).Poly(U) has been found to synergistically enhance the effect of AZT, DDI and DDC. Accordingly, a further aspect of the invention is directed to a pharmaceutical composition comprising pharmaceutically acceptable diluents or carriers and a S combination of Poly(A).Poly(U) and another anti-AIDS drug acting according to a different mechanism from that of the complex of Poly(A).Poly(U), the amount of each component of the combination being selected so that the combination is effective in the treatment of AIDS and/or in the inhibition of HIV.
The invention also provides a method for the treatment of AIDS, the method comprising administering an effective amount of Poly(A).Poly(U), alone or in combination with another anti-AIDS agent, to a patient suffering from AIDS.
Accordingly, this invention provides a therapeutic composition for the treatment of Acquired Immuno Deficiency Syndrome (AIDS) and related infections, said composition comprising as an active ingredient from about 0.1 to 100 °lo of a complex of Poly(A).Poly(U), optionally associated with another anti-AIDS agent acting on HIV
viruses according to a different mechanism from that of the complex of Poly(A).Poly(U), and pharmaceutically acceptable diluents or Garners.
According to a preferred embodiment of the invention, the anti-AIDS coagent acting on the HIV virus is selected from the group consisting of AZT, DDI, DDC and combinations of the foregoing. The weight ratio of Poly(A).Poly(U) to the anti-AIDS
coagent is suitably from about 1 : 10-1 to about 1 : 10-x, but is preferably from about 1 : 10-1 to about 1 : 10-2.
The interest of Poly(A).Poly(U) in the treatment of AIDS will appear clearly from the various experiments hereafter described.
These and other aspects of the present invention may be more fully understood from the following detailed discussion and the drawing, with the drawing showing the viral proteins synthesized during incubation.
_ 3_ 2066134 Two batches of CEM cells (T cells rich in CD4 receptors) were infectcd with Human Immunodeficiency Virus HIV-1 Bru (LAI) and were treated with Poly(A).Poly(U) 24 hours after infection. Two similar batches of HIV infected CEM cells were used as controls, i.e. they were not treated. The cell cultures were regularly inspected under a microscope to observe the onset of cytopathic effects (fusion of cells and formation of syncitia) resulting from the HIV.
The experimental protocols were as follows : 5 x 106 CEM cells were incubated with 1 ml of supernatent containing HIV with a reverse transcriptase activity of 1.0 x 106 cpm. One hour afterwards, the cells were centrifuged and the cellular residue (0.5 x 106 cells) was suspended in RMP1 medium containing 10 % fetal serum and 2 ~.g/ml polybrene. Twenty-four hours later, Poly(A).Poly(U) was added at a concentration of 200 ~.g/ml. The cell cultures were maintained without further addition of Poly(A).Poly(U).The results were as follows Table 1 Da 6 Da 7 Da 8 Da 11 Controls ++ ++++ ++++ cells dead Treated Cells- + + ++
The symbol "+" indicates the appearance of cytopathic effects ; the number of such symbols used is an approximate quantification. These results show that the cytopathic effects are significantly reduced by the treatment.
Cultures were prepared as above described, and during the night of days 7 and were incubated with 35S-methionine for electrophoretic analysis on SDS of the viral proteins synthesized, both in the cellular mass and in the supernatent. The results are shown in the accompanying drawing. In the drawing, "-" indicates a sample from an untreated control and "+" a sample from a culture treated with Poly(A).Poly(U). The identifiers on the right of the indicators shown are as follows gp 120 the envelope protein p68 reverse transcriptase p55 precursor of the core protein -4- 236~~.3~
p40 precursor of the core protein, partially cleaved p32 endonuclease p25 the major core pmtein The xesults show an almost total reduction of the presence of viral proteins in the cells and supernatants of the cultures treated with Poly(A).Poly(U).
The quantity of p24/p25 antigen in the supernatant was measured 8 days after infection, by the ELISA test. These results are as follows Controls Treated Cells 1.01 ml 0.03 ml 1.27 ml 0.07 ml This shows suppression of 96.5 % of the HIV production in the cultures treated by Poly(A).Poly(U).
The action of Poly(A).Poly(U) on the inhibition of the production of HIV has been confirmed by the following experiments.
1. Effect of variation of the dose of Pol f~~~) CEM cells were infected with HIV. Twenty-four hours later, different concentrations of Poly(A).Poly(U) were added. The production of the virus in the supernatant of the culture was determined on day 5 after infection, by quantifying the amount of p24/p25 antigen present. Control cells, which had been infected but to which Poly(A).Poly(U) had not been added, had by then ruptured. The obtained results were as follows ~ossl~4 Poly(A).Poly(U) p24/p25 1) m1 0 1.10 25 0.53 50 0.14 100 0.10 200 0.07 2. Effect of Repeated Treatment The operating procedure was similar to that described in experiment 1, but addition of Poly(A).Poly(U) was at a concentration of 200 p.g/ml at 24 and 96 hours after infection. An untreated control was also run ; as before, the cells in the control had ruptured by day 5.
The concentration (pg/ml) of p24/p25 at the days 4, 5, 6 and 7 after infection was measured in the untreated control and in the cells treated at days 1 and 4.
The obtained results were as follows Table 4 4 Day 5 Day 6 Day 7 Controls 0.72 1.25 Treated cells-. I 0.05 0.10 0.20 0.26 3. The effe.~t of Poi (v_,Al Poly~,1 is at an early t-ten in viros infection HIV infected cells were treated with 200~tg/ml of Poly(A).Poly(In at different times before, during and after infection with 1-IIV. On day 6 after infection, the number of syncitia were counted. On day 7, the level of p25 in the culture medium was assayed -6- zossl3~
Pol A .Pol ~ncida % 25 n ml Control (untreated)90 1320 Cells treated at . 3 days before 85 121 S
. 2 days before 72 965 . 1 day before 45 280 . 1 hour before <5 6 . Together with <5 5 HIV
. 1 hour after 10 110 . 4 hours after 10 120 STUDY OF USE OF POLY(A).POLY(U) WITH AZT
Cells were infected with HIV 24 hours before a single treatment with (a) Poly(A).Poly(U) alone, at a concentration of 100 pg/ml ;
(b) AZT alone, at concentrations of 100, 250, 1 000, 5 000 and 10 000 ng/ml, (5 samples) ;
(c) a combination of (i) AZT at concentrations of 100, 250, 1 000, 5 000 and ng/ml, and (ii) in each instance, Poly(A).Poly(U) at a concentration of 100 ug/ml.
A control (non-treated) was also maintained ; the cells culture in the control dies progressively after day ?. So, no figure appears in day 12 and day 14 columns.
The levels of antigen p25 in the supernatents were measured at days 7, 12 and 14 after infection. The results, expressed in itg/ml, were as follows -7- 2oss~~~
p25 Da 7 Da 12 Da Control 1250 Pol A).Pol ) 135 980 1200 '~ 1~ 16 75 900 Pol A).Pol ) Pol (A).Pol (U) AZT 1000 <5 52 590 '~'~ 1~ <5 17 200 Pol (A).Pol (U) AZT 5000 <5 27 275 <5 10 48 Pol (A).Pol (LT) AZT 10 000 <5 20 220 AZT 10 000 <5 8 39 Pol (A).Pol (U) These results show that the combination of Poly(A).Poly(U) with AZT is more effective than either alone.
The results show that Poly(A).Poly(U) has an inhibitory effect on HIV. This has been observed in different tests A) metabolic synthesis of viral proteins in infected cells B) activity of reverse transcriptase in the culture medium of infected cells C) amounts of the major core protein p25 of HIV in the culture medium of infected cells ; and D) cell fusion 2oss~3~
In all of the experiments presented above, the HIV-1 Bru isalate (commonly referred to as HIV-1 LAI) was employed. In order to demonstrate that the inhibitory action of Poly(A).Poly(U) is not restricted to the HIV-1 species used, another species of HIV-1 referred to as ELI (31) and two different HIV-2 species, ROD and EHO, were tested. Poly(A).Poly(U) added 6 hours before infestation of CEM cells with these viruses resulted in more than 90 % inhibition of virus production.
In all these tests, Poly(A).Poly(U) at a dosage of 200 p.g/ml exercises an inhibitory action which is between about 85 and about 90 %. For human beings, an amount per single injection of from about 100 to 4 000 mg is considered suitable ; doses of from about 150 to 1000 mg can be efficiently injected into human beings. It is preferred that treatment be as close as possible to the time of infection ; however, treatment before of after infection is also effective. The treatment is suitably repeated at intervals of about 3 to 5 days.
The compounds of the present invention are suitably administered by injection in water solution. The active ingredient is added to the water solution.
Poly(A).Poly(U) is suitably added at about 0.2 to about 1.0 g per 100 ml water solution.
Coagents, such as AZT, DDI and DDC, can suitably be added. The weight ratio of Poly(A).Poly(U) to the anti-AIDS coagent is suitably from about 1 : 10-1 to about 1 : 10-4. A
preferred water solution for use in the present invention is NaH2P04-H20 0.100 g NaCI 0.068 g NaOH to neutralize (pH
7) H2O q.v. to 100 ml In each 100 ml of water solution there is dissolved Poly(A).Poly(U) 0.40 g Mannitol 1.84 g NaCI 0.48 g If one or more coagents is desired, they are cumulatively added to the water solution, i.e. nothing is removed to account for the addition of the coagent.
A suitable amount of a coagent, notably AZT, is from about 0.04 mg to about 4 mg per 100 ml of water solution. For example, 150 mg of Poly(A).Poly(U) associated with 15 mg of AZT, may be administered by injection of 38 ml of a water solution as above described.
It has been demonstrated that the complex of Poly(A).Poly(U) has a potent anti-retroviral action. However, using Poly(A).Poly(U) in combination with another anti-retroviral agent such as AZT, DDI or DDC gives far better results than use of either alone.
An explanation for this may be that Poly(A).Poly(U) works at the level of penetration of the virus into the cell, whereas AZT, DDI and DDC work at the level of infra-cellular transcription. Whether or not this is the correct theory for the manner in which the combination of Poly(A).Poly(U) and another anti-retroviral drug is effective, the fact remains that the combination is superior to the use of either agent alone.
It will be understood that the claims are intended to cover all changes and modifications of the preferred embodiments of the invention herein chosen for the purpose of illustration which do not constitute a departure from the spirit and scope of the invention.
Claims (20)
1- A therapeutic composition for the treatment of Acquired Immuno Deficiency Syndrome (AIDS) and related infections, said composition comprising from about 0.1 to 100% of a complex of Poly(A).Poly(U) and pharmaceutically acceptable diluents or carriers.
2 - The composition of claim 1 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 100 mg to about 4 000 mg per unitary dose.
3 - The composition of claim 1 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 150 mg to about 1 000 mg per unitary dose.
4 - The composition of claim 1 further comprising an anti-AIDS coagent which acts on the HIV virus according to a different mechanism from that of the complex of Poly(A).Poly(U).
5 - The composition of claim 4 wherein the weight ratio of Poly(A).Poly(U) to the anti-AIDS coagent is from about 1:10 -1 to about 1:10 -4.
6 - The composition of claim 5 wherein the said ratio is from about 1:10 -1 to about 1:10 -2.
7 - A therapeutic composition according to claim 6 wherein the anti-AIDS
coagent acting on the HIV virus according to a mechanism different from that one of the Poly(A).Poly(U) complex is selected from the group consisting of AZT, DDI, DDC
and combinations of the foregoing.
coagent acting on the HIV virus according to a mechanism different from that one of the Poly(A).Poly(U) complex is selected from the group consisting of AZT, DDI, DDC
and combinations of the foregoing.
8 - The composition of claim 7 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 100 mg to about 4 000 mg per unitary dose.
9- The composition of claim 7 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 150mg to about 1 000 mg per unitary dose.
10 - The composition of claim 4 wherein the anti-AIDS coagent is AZT and wherein the weight ratio of Poly(A).Poly(U) to AZT is from about 1:10 -1 to about 1:10 -4.
11 - The composition of claim 10 wherein the said ratio is from about 1:10 -1 to about 1:10 -2.
12 - The composition of claim 11 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 100 mg to about 4 000 mg per unitary dose.
13 - The composition of claim 11 wherein the complex of Poly(A).Poly(U) is present in the amount of from about 150 mg to about 1000 mg per unitary dose.
14 - The composition of claim 11 wherein an unitary dose contains 150 mg of the complex Poly(A).Poly(U) associated with 15 mg of AZT.
15- Use of a complex of Poly(A).Poly(U) to prepare a medicament intended to treat Acquired Immuno Deficiency Syndrome (AIDS) or related infection.
16- Use of a complex of Poly(A).Poly(U) and an anti-AIDS coagent which acts on the HIV virus according to a difference mechanism from that of the complex of Poly(A).Poly(U) to prepare a medicament intended to treat Acquired Immuno Deficiency Syndrome (AIDS) or related infections.
17- Use according to claim 16, characterised in that the anti-AIDS coagent is selected from the group consisting of AZT, DDI, DDC and combinations of the foregoing.
18- Use according to claim 17, characterised in that the anti-AIDS coagent is AZT.
19- Use according to claim 18, characterised in that the weight ratio of Poly(A).Poly(U) to AZT used is from about 1:10 -1 to about 1:10 -4.
20- Use according to claim 19, characterised in that the weight ratio of Poly(A).Poly(U) to AZT used is from about 1:10 -1 to about 1:10 -2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9108085-3 | 1991-04-16 | ||
| GB919108085A GB9108085D0 (en) | 1991-04-16 | 1991-04-16 | Complexes of polyadenylic acid with polyuridylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2066134A1 CA2066134A1 (en) | 1992-10-17 |
| CA2066134C true CA2066134C (en) | 2002-11-19 |
Family
ID=10693367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002066134A Expired - Fee Related CA2066134C (en) | 1991-04-16 | 1992-04-15 | Complexes of polyadenylic acid with polyuridylic acid |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US5756477A (en) |
| EP (1) | EP0509906A1 (en) |
| JP (1) | JPH05262653A (en) |
| KR (1) | KR100233393B1 (en) |
| AU (1) | AU656574B2 (en) |
| BE (1) | BE1004857A3 (en) |
| CA (1) | CA2066134C (en) |
| CH (1) | CH684521A5 (en) |
| DK (1) | DK51192A (en) |
| DZ (1) | DZ1570A1 (en) |
| FR (1) | FR2675384B1 (en) |
| GB (2) | GB9108085D0 (en) |
| IE (1) | IE921208A1 (en) |
| LU (1) | LU88102A1 (en) |
| MY (1) | MY108106A (en) |
| NO (1) | NO921513L (en) |
| OA (1) | OA09577A (en) |
| SE (1) | SE509801C2 (en) |
| ZA (1) | ZA922699B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6734192B1 (en) * | 1999-08-23 | 2004-05-11 | Mp-1 Inc. | Treatment of viral infections |
| US7875283B2 (en) * | 2000-04-13 | 2011-01-25 | Advanced Cardiovascular Systems, Inc. | Biodegradable polymers for use with implantable medical devices |
| US7186789B2 (en) * | 2003-06-11 | 2007-03-06 | Advanced Cardiovascular Systems, Inc. | Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings |
| US20060135253A1 (en) * | 2004-09-10 | 2006-06-22 | Jeffrey George | Gaming system and method for providing entry to a contest |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS4940954B1 (en) * | 1970-02-16 | 1974-11-06 | ||
| US3796631A (en) * | 1970-11-09 | 1974-03-12 | Choay Sa | Processes for preparing polynucleotides |
| IL37076A (en) * | 1971-06-16 | 1974-05-16 | Littauer U | A method for stepwise synthesis of oligoribonucleotides of defined sequence using 2'(3')-o-acyl-nucleoside diphosphates and polynucleotide phosphorylase |
| US4124702A (en) * | 1971-07-06 | 1978-11-07 | Merck & Co., Inc. | Polynucleotides active as inducers of interferon production in living animal cells |
| JPS524633B2 (en) * | 1972-07-21 | 1977-02-05 | ||
| GB1435571A (en) * | 1973-04-02 | 1976-05-12 | Searle & Co | Polynucleotides |
| DE2319495C2 (en) * | 1973-04-17 | 1985-01-10 | Yeda Research And Development Co., Ltd., Rehovot | Method for the selective, reversible binding of biomolecules to an adsorbent in a chromatographic column |
| US4024222A (en) * | 1973-10-30 | 1977-05-17 | The Johns Hopkins University | Nucleic acid complexes |
| FR2252350A1 (en) * | 1973-11-22 | 1975-06-20 | Choay Sa | Polynucleotide phosphorylase - extraction from E coli, fixation on sepharose, and use in preparing polynucleotides |
| JPS50107187A (en) * | 1974-02-08 | 1975-08-23 | ||
| US4006059A (en) * | 1974-07-29 | 1977-02-01 | Purdue Research Foundation | Hydrophobic noncovalent binding of proteins to support materials |
| US4000098A (en) * | 1974-08-16 | 1976-12-28 | Palo Alto Medical Research Foundation | Separation of proteins by hydrophobic adsorption |
| US4024241A (en) * | 1974-09-27 | 1977-05-17 | The United States Of America As Represented By The Secretary Of Health, Education And Welfare | Nuclease-resistant hydrophilic complex of polyriboinosinic-polyribocytidylic acid |
| US4075195A (en) * | 1976-08-31 | 1978-02-21 | Kraft, Inc. | Debittered protein product and method for manufacture |
| SU619508A1 (en) * | 1976-12-07 | 1978-08-15 | Предприятие П/Я Г-4740 | Method of obtaining polynucleotides possessing polyribonucleotidephosphorylase activity |
| JPS5519239A (en) * | 1978-07-28 | 1980-02-09 | Green Cross Corp:The | Interferon-producing attractant |
| JPS5618597A (en) * | 1979-07-23 | 1981-02-21 | Mitsubishi Chem Ind Ltd | Production of oligonucleotide |
| US4379843A (en) * | 1981-01-26 | 1983-04-12 | Peter Cashion | Immobilization of polynucleotides and polypeptides with tritylated polysaccharides |
| US4400375A (en) * | 1981-11-23 | 1983-08-23 | Eli Lilly And Company | Tobramycin-double stranded RNA complex suitable for inducing interferon |
| EP0113162B1 (en) * | 1982-09-16 | 1989-07-19 | Hem Research, Inc. | Anti-proliferative action of dsnras on tumor cells |
| US4617376A (en) * | 1985-07-01 | 1986-10-14 | Eli Lilly And Company | Process for recovering glucagon from pancreas glands |
| US4945082A (en) * | 1985-08-26 | 1990-07-31 | Hem Research, Inc. | Controlled dsRNA therapy for human viral infections |
| CA1326450C (en) * | 1985-08-26 | 1994-01-25 | William A. Carter | Modulation of aids virus-related events by double stranded rnas (dsrnas) |
| US4795744A (en) * | 1986-07-17 | 1989-01-03 | Hem Research, Inc. | Modulation of AIDS virus-related events by double-stranded RNAS |
| US4820696A (en) * | 1985-08-26 | 1989-04-11 | Hem Research, Inc. | Modulation of aids virus-related events by double-stranded RNAS |
| US5063209A (en) * | 1985-08-26 | 1991-11-05 | Hem Research, Inc. | Modulation of aids virus-related events by double-stranded RNAs |
| US4771128A (en) * | 1986-10-10 | 1988-09-13 | Cetus Corporation | Method of purifying toxin conjugates using hydrophobic interaction chromatography |
| US4950652A (en) * | 1987-03-23 | 1990-08-21 | Hem Research, Inc. | dsRNAs for combination therapy in the treatment of viral diseases |
| US5091374A (en) * | 1987-07-17 | 1992-02-25 | Hem Research Inc. | Double-stranded RNA correction of abnormalities in circulating immune complexes and monocyte function |
| AU1820588A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double-stranded rna correction of abnormalities in circulating immune complexes and monocyte function |
| AU1820388A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double stranded rna correction of aberrant metabolic pathways associated with uncontrolled tumor cell and virus growth cycles |
| GB8725606D0 (en) * | 1987-11-02 | 1987-12-09 | Soc D Etudes Prod Chimique | Preparation polynucleotides |
| US4963532A (en) * | 1987-11-25 | 1990-10-16 | Hem Research, Inc. | dsRNA-based prevention of viral escape |
| ES2066847T3 (en) * | 1988-07-07 | 1995-03-16 | Hem Pharma Corp | DIAGNOSIS AND TREATMENT OF CHRONIC FATIGUE SYNDROME. |
| JP2619710B2 (en) * | 1989-02-27 | 1997-06-11 | 日本製紙 株式会社 | Method for producing 2 ', 3'-dideoxypurine nucleosides |
-
1991
- 1991-04-16 GB GB919108085A patent/GB9108085D0/en active Pending
-
1992
- 1992-04-09 GB GB9207798A patent/GB2255504A/en not_active Withdrawn
- 1992-04-10 CH CH1177/92A patent/CH684521A5/en not_active IP Right Cessation
- 1992-04-12 DZ DZ920036A patent/DZ1570A1/en active
- 1992-04-13 ZA ZA922699A patent/ZA922699B/en unknown
- 1992-04-15 AU AU14909/92A patent/AU656574B2/en not_active Ceased
- 1992-04-15 CA CA002066134A patent/CA2066134C/en not_active Expired - Fee Related
- 1992-04-15 EP EP92401045A patent/EP0509906A1/en not_active Withdrawn
- 1992-04-15 SE SE9201207A patent/SE509801C2/en not_active IP Right Cessation
- 1992-04-15 IE IE120892A patent/IE921208A1/en unknown
- 1992-04-15 FR FR9204606A patent/FR2675384B1/en not_active Expired - Fee Related
- 1992-04-15 DK DK051192A patent/DK51192A/en not_active Application Discontinuation
- 1992-04-15 MY MYPI92000650A patent/MY108106A/en unknown
- 1992-04-15 JP JP4095140A patent/JPH05262653A/en not_active Ceased
- 1992-04-15 BE BE9200348A patent/BE1004857A3/en not_active IP Right Cessation
- 1992-04-15 KR KR1019920006270A patent/KR100233393B1/en not_active IP Right Cessation
- 1992-04-15 NO NO92921513A patent/NO921513L/en unknown
- 1992-04-16 LU LU88102A patent/LU88102A1/en unknown
- 1992-04-16 OA OA60187A patent/OA09577A/en unknown
-
1996
- 1996-01-04 US US08/582,658 patent/US5756477A/en not_active Expired - Fee Related
-
1997
- 1997-03-13 US US08/816,643 patent/US5736525A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| FR2675384B1 (en) | 1995-09-15 |
| MY108106A (en) | 1996-08-15 |
| US5756477A (en) | 1998-05-26 |
| GB9207798D0 (en) | 1992-05-27 |
| US5736525A (en) | 1998-04-07 |
| JPH05262653A (en) | 1993-10-12 |
| KR100233393B1 (en) | 1999-12-01 |
| IE921208A1 (en) | 1992-10-21 |
| FR2675384A1 (en) | 1992-10-23 |
| DZ1570A1 (en) | 2002-02-17 |
| AU656574B2 (en) | 1995-02-09 |
| NO921513L (en) | 1992-10-19 |
| BE1004857A3 (en) | 1993-02-09 |
| SE9201207D0 (en) | 1992-04-15 |
| LU88102A1 (en) | 1992-10-15 |
| GB2255504A (en) | 1992-11-11 |
| OA09577A (en) | 1993-01-31 |
| DK51192A (en) | 1992-10-17 |
| AU1490992A (en) | 1992-10-22 |
| KR920019363A (en) | 1992-11-19 |
| DK51192D0 (en) | 1992-04-15 |
| GB9108085D0 (en) | 1991-06-05 |
| SE9201207L (en) | 1992-10-17 |
| CA2066134A1 (en) | 1992-10-17 |
| EP0509906A1 (en) | 1992-10-21 |
| SE509801C2 (en) | 1999-03-08 |
| NO921513D0 (en) | 1992-04-15 |
| ZA922699B (en) | 1992-12-30 |
| CH684521A5 (en) | 1994-10-14 |
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| EEER | Examination request | ||
| MKLA | Lapsed |