CA2160248A1 - Pharmaceutical composition containing thymoctonan and azt - Google Patents
Pharmaceutical composition containing thymoctonan and aztInfo
- Publication number
- CA2160248A1 CA2160248A1 CA002160248A CA2160248A CA2160248A1 CA 2160248 A1 CA2160248 A1 CA 2160248A1 CA 002160248 A CA002160248 A CA 002160248A CA 2160248 A CA2160248 A CA 2160248A CA 2160248 A1 CA2160248 A1 CA 2160248A1
- Authority
- CA
- Canada
- Prior art keywords
- thymoctonan
- azt
- hiv
- treatment
- agent
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The combined use of thymoctonan and an antiretroviral agent such as AZT in the treatment of retroviral disease, notably AIDS and ARC (AIDS-related complex), is disclosed.
Description
w 095/23610 ~ ~ 6 0 2 4 ~ PCTAEPg5/00653 PHARMACEUTICAL COMPOSITION CONTAINING THYMOCTONAN AND AZT
This invention relates to the use of thymoctonan in comhination with other compounds that inhibit retro-virus replication in order to control immune system impairment in the treatment of Acquired Immunodeficiency Syndrome (AIDS) or ARC (AIDS related complex). Pharmaceutical compositions and their preparations useful in such treatment are also disclosed.
AIDS is caused by HIV, a human retrovirus of the lentivirus group. The four recognized human retroviruses belong to two distinct groups; the human T lymphotropic (or leukaemia) retro-viruses, HTLV-I and HTLV-II, and the human immunodeficiency viruses, HIV-1 and HIV-2. The former are transforming viruses, and the latter are cytopathic viruses. The most common cause of AIDS throughout the world is HIV-1. HIV-2 has about 40 percent sequence homology with HIV-1 and is more closely related to some members of a group of simian immunodeficiency viruses (SIV). HIV has the usual retroviral genes (env, qaq, and ~ol) and six extra genes involved in the replication and other biologic activities of the virus.
The common denominator of AIDS is a profound immunosuppression, predominantly of cell mediated immunity, that leads to a variety of opportunistic diseases, particularly certain infections and neoplasms. The main cause of immune defect in AIDS is a quantitative and qualitative deficiency in the subset of thymus-derived (T) WO95/23610 PCT~P95/00653 ~ 1 6 a 2 L~
lymphocytes termed the T4 population. This subset of cells is defined phenotypically by the presence of the CD4 surface cell molecule, which is the cellular receptor for HIV. Although the T4 cell is the major cell type infected with HIV, virtually any human cell that expresses the CD4 molecule on its surface is capable of binding to and being infected with HIV. Of particular importance are cells of monocyte-macrophage lineage.
The degree of relative contribution of each part of the immune system to the host's ability to control HIV
infection is not yet clear. Nevertheless, attempts have been made to augment the host's immune defense in HIV
infection with the hope of beneficially altering the progress of the disease. An immunomodulatory intervention is d'efined as a method or an agent believed to exert its primary effect on the host's immune system but not to have direct antiviral activity. In particular, an immunomodulant like thymoctonan that has been shown to play a major role in the differentiation and maturation of the T-lymphocytes, and to reverse the depression of cell-mediated immunity in severe viral infection, could exert a regulatory effect with an enhancement of immune response, leading to a decrease of viral burden and a slowing of dlsease progression.
Thymoctonan is a synthetic octapeptide originally isolated and characterized from fetal calf thymus, as described in US patent No. 4,621,135.
This invention relates to the use of thymoctonan in comhination with other compounds that inhibit retro-virus replication in order to control immune system impairment in the treatment of Acquired Immunodeficiency Syndrome (AIDS) or ARC (AIDS related complex). Pharmaceutical compositions and their preparations useful in such treatment are also disclosed.
AIDS is caused by HIV, a human retrovirus of the lentivirus group. The four recognized human retroviruses belong to two distinct groups; the human T lymphotropic (or leukaemia) retro-viruses, HTLV-I and HTLV-II, and the human immunodeficiency viruses, HIV-1 and HIV-2. The former are transforming viruses, and the latter are cytopathic viruses. The most common cause of AIDS throughout the world is HIV-1. HIV-2 has about 40 percent sequence homology with HIV-1 and is more closely related to some members of a group of simian immunodeficiency viruses (SIV). HIV has the usual retroviral genes (env, qaq, and ~ol) and six extra genes involved in the replication and other biologic activities of the virus.
The common denominator of AIDS is a profound immunosuppression, predominantly of cell mediated immunity, that leads to a variety of opportunistic diseases, particularly certain infections and neoplasms. The main cause of immune defect in AIDS is a quantitative and qualitative deficiency in the subset of thymus-derived (T) WO95/23610 PCT~P95/00653 ~ 1 6 a 2 L~
lymphocytes termed the T4 population. This subset of cells is defined phenotypically by the presence of the CD4 surface cell molecule, which is the cellular receptor for HIV. Although the T4 cell is the major cell type infected with HIV, virtually any human cell that expresses the CD4 molecule on its surface is capable of binding to and being infected with HIV. Of particular importance are cells of monocyte-macrophage lineage.
The degree of relative contribution of each part of the immune system to the host's ability to control HIV
infection is not yet clear. Nevertheless, attempts have been made to augment the host's immune defense in HIV
infection with the hope of beneficially altering the progress of the disease. An immunomodulatory intervention is d'efined as a method or an agent believed to exert its primary effect on the host's immune system but not to have direct antiviral activity. In particular, an immunomodulant like thymoctonan that has been shown to play a major role in the differentiation and maturation of the T-lymphocytes, and to reverse the depression of cell-mediated immunity in severe viral infection, could exert a regulatory effect with an enhancement of immune response, leading to a decrease of viral burden and a slowing of dlsease progression.
Thymoctonan is a synthetic octapeptide originally isolated and characterized from fetal calf thymus, as described in US patent No. 4,621,135.
2 1 ~ ~ 2 ~ ~ PCT~P95/00653 The present invention provides products containingthymoctonan and an antiretroviral agent as a combined preparation for simultaneous separate or sequential use in the treatment of a retroviral disease. The products of the invention may be used in particular to treat patients infected with HIV, especially HIV-l.
The anti-retroviral agent used in the present invention may be selected, for example, from reverse transcriptase inhibitors (RT inhibitors) such as nucleoside analogues or non-nucleoside inhibitors of HIV reverse transcriptase (NNRTI's); protease inhibitors; agents which block cell entry by HIV; nucleic acid-based therapeutics;
and Tat inhibitors (Tat is a regulatory protein required for HIV replication in cultured cells and is a positive transactivator which stimulates transcription: see, for instance, B.M. Peterlin et al, Proc. Natl. Acad. Sci USA 83 9734 (1986)). These classes of anti-retroviral agent, with particular reference to HIV, are discussed by Johnston and Hoth in Science vol 260, 1286-1293, 28 May 1993.
Examples of RT inhibitors include AZT (3'-azidothymidine, zidovudin, Retrovir); ddI (2',3'-dideoxyinosine, Didanosine, Videx); ddC (2',3'-dideoxycytidine, Zalcitabine, HIVID); 3TC (the (-)-enantiomer of 2'-deoxy-3'-thiacytidine, Lamivadine); d4T
(didehydrothymidine, Stavidine); 3'-halo-dideoxypyridine analogues such as FLT (3'-fluoro-thymidine); and PNEA (9-(2-phosphonomethoxyethyl)-adenine, an acylic nucleotide).
WO95/23610 PCT~P95/00653 ~16~2~8 Examples of non-nucleoside reverse transcriptase inhibitors (NNRTI's) include tetrahydro-imidazo [4,5,1-jk][1,4]-benzodiazepin-2(lH)-one; 11-cyclopropyl-7-methyl-dipyrido-[2,3-b: 3'3'-f] 1,4-diazepin-6H-5-one (BI-RG-587, nevirapine); and bis(heteroaryl)piperazines (BHAP's, U-87201E, Alevidine Mesylate, ATV : see, for example, D.L.
Romero et al Proc. Natl. Acad. Sci USA 88 8806 (1991)).
There are currently 3 anti-retroviral agents approved for HIV disease; 3'azidothymidine (AZT, Zidovudine),2',3',-didoxyinosine (ddI, Didanosine) and 2',3'-dideoxycytidine (ddC, Zalcitabine). Numerous others are in clinical trials, such as for example rIFN-alpha, rIFN-betaSerl7 and rIFN~ as cytokines, phosphonoformate as inhibitor of reverse transcription, ribavirin, amphotericin B and castanospermine with different modes of attack on the retrovirus. Any of these may be employed as the anti-viral agent in the present invention.
The combination comprising thymoctonan and anti-retroviral agent is administered to a patient in an amount sufficient to inhibit retro-viral replication; it is to be noted that thymoctonan can also control or reduce the side effects related to anti-retroviral agents such as AZT.
The invention also provides pharmaceutical compositions containing thymoctonan, as an immunostimulant, and an anti retro-viral agent. A pharmaceutically acceptable carrier or diluent is typically also included in the composition.
WOgS/23610 PCT/~5~00G53 ~60248 The results of the combined treatment showing a positive and beneficial effect are reported below.
The combined therapy of the present invention enhances the antiviral effect of the anti-retroviral agent and thus yields the most effective and least toxic treatment for ARC and AIDS.
A clinical study using an anti-retroviral agent in combination with thymoctonan has demonstrated that thymoctonan provides a synergistic complement in the treatment of HIV infections including ARC and AIDS, itself specifically. It was found that thymoctonan associated with an anti-retroviral agent may prolong survival in HIV-infected individuals.
The antiretroviral drugs preferred for use in the present invention are AZT, ddI and ddC, alone or in combination.
The amount of antiretroviral drug administered is from 10 to 1500 mg/daily, preferably from 50 to 1000 mg/daily. For example, AZT is administered orally at a dose from 600 to 1200 mg/daily and ddI at an oral dose of from 500 to 750 mg/daily.
The amount of thymoctonan administered is from 0.25 to 1000 ~g/weekly, preferably from 0.5 to 100 ~g/weekly, the route of administration being parenteral (i.m. or s.c.).
More preferably the antiretroviral drug is administered at conventional dosage, the thymoctonan at a WO95/23610 PCT~P95/00653 4 ~
dosage of 0.5, 4 or 40 ~g by i.m. injection, once daily for 15 days (induction period); then twice weekly for at least 12 months.
Thymoctonan was administered in particular in combination with AZT to a symptomatic HIV-infected individuals with a CD4 count less than 500/~1, showing suggestive evidence of a surprising favourable effect in terms of viral load decrease in comparison with the single treatment with AZT alone.
lo The combined administration, according to the present invention, of thymoctonan and an antiretroviral agent includes presentation in which both agents are administered together as a therapeutic mixture, and also procedures in which the two agents are administered separately, e.g.
thymoctonan through i.m. or s.c. injection and the anti-retroviral agent by the oral route. Combined administration further includes the separate administration of the drugs in which one of the drugs is given first followed shortly by the second.
Clinical data As a part of a multicenter controlled double-blind, clinical study we enrolled 12 patients (4 AIDS, 6CDC III
and 2 CDC II) that were treated for the first six months with either 4 or 40 ~g of thymoctonan or placebo (2 times a week by i.m. injection). After this period all the patients voluntarily received the highest dose of active WosS/23610 216 0~ PCT~P95/006~3 drug on open-label. Patients received since the beginning of the treatment AZT 5000 mg/day orally, too.
For the evaluation of open-label treatment we chose a case-control design. Patients in the control group were 24 (1:2 ratio) subjects, admitted in our service, who started AZT treatment in the same period of time and matched thymoctonan treated patients as to sex, age, CDC
classification of illness, number of CD4 + T-cells at admission (median 117.5 vs 165 cells/~l) and previous opportunistic infections. All cases and controls received PCP prophylaxis whenever CD4 +T-cell count fell below 200/~l. The groups were homogeneous for all considered entry variables.
They were followed for 19+5 months (cases) and 15+5 (controls). No case of death was observed in the thymoctonan treated group, while 9 subjects (37.5%) died in the control group (P=0.01 Fisher). No cases of disease progression (in terms of CDC group shift for patients in II
or III stage) was observed in the thymoctonan group but in 4 out of 16 patients in the control group, 3 of whom died.
Four patients in the thymoctonan group and 11 in the control group were hospitalized at least once during the observation period and 3 vs 12 presented AZT intolerance.
In addition, in the thymoctonan group patients stayed without AZT treatment or were in the hospital for a shorter proportion of time (P<0.0001 Kruskal-Wallis).
The anti-retroviral agent used in the present invention may be selected, for example, from reverse transcriptase inhibitors (RT inhibitors) such as nucleoside analogues or non-nucleoside inhibitors of HIV reverse transcriptase (NNRTI's); protease inhibitors; agents which block cell entry by HIV; nucleic acid-based therapeutics;
and Tat inhibitors (Tat is a regulatory protein required for HIV replication in cultured cells and is a positive transactivator which stimulates transcription: see, for instance, B.M. Peterlin et al, Proc. Natl. Acad. Sci USA 83 9734 (1986)). These classes of anti-retroviral agent, with particular reference to HIV, are discussed by Johnston and Hoth in Science vol 260, 1286-1293, 28 May 1993.
Examples of RT inhibitors include AZT (3'-azidothymidine, zidovudin, Retrovir); ddI (2',3'-dideoxyinosine, Didanosine, Videx); ddC (2',3'-dideoxycytidine, Zalcitabine, HIVID); 3TC (the (-)-enantiomer of 2'-deoxy-3'-thiacytidine, Lamivadine); d4T
(didehydrothymidine, Stavidine); 3'-halo-dideoxypyridine analogues such as FLT (3'-fluoro-thymidine); and PNEA (9-(2-phosphonomethoxyethyl)-adenine, an acylic nucleotide).
WO95/23610 PCT~P95/00653 ~16~2~8 Examples of non-nucleoside reverse transcriptase inhibitors (NNRTI's) include tetrahydro-imidazo [4,5,1-jk][1,4]-benzodiazepin-2(lH)-one; 11-cyclopropyl-7-methyl-dipyrido-[2,3-b: 3'3'-f] 1,4-diazepin-6H-5-one (BI-RG-587, nevirapine); and bis(heteroaryl)piperazines (BHAP's, U-87201E, Alevidine Mesylate, ATV : see, for example, D.L.
Romero et al Proc. Natl. Acad. Sci USA 88 8806 (1991)).
There are currently 3 anti-retroviral agents approved for HIV disease; 3'azidothymidine (AZT, Zidovudine),2',3',-didoxyinosine (ddI, Didanosine) and 2',3'-dideoxycytidine (ddC, Zalcitabine). Numerous others are in clinical trials, such as for example rIFN-alpha, rIFN-betaSerl7 and rIFN~ as cytokines, phosphonoformate as inhibitor of reverse transcription, ribavirin, amphotericin B and castanospermine with different modes of attack on the retrovirus. Any of these may be employed as the anti-viral agent in the present invention.
The combination comprising thymoctonan and anti-retroviral agent is administered to a patient in an amount sufficient to inhibit retro-viral replication; it is to be noted that thymoctonan can also control or reduce the side effects related to anti-retroviral agents such as AZT.
The invention also provides pharmaceutical compositions containing thymoctonan, as an immunostimulant, and an anti retro-viral agent. A pharmaceutically acceptable carrier or diluent is typically also included in the composition.
WOgS/23610 PCT/~5~00G53 ~60248 The results of the combined treatment showing a positive and beneficial effect are reported below.
The combined therapy of the present invention enhances the antiviral effect of the anti-retroviral agent and thus yields the most effective and least toxic treatment for ARC and AIDS.
A clinical study using an anti-retroviral agent in combination with thymoctonan has demonstrated that thymoctonan provides a synergistic complement in the treatment of HIV infections including ARC and AIDS, itself specifically. It was found that thymoctonan associated with an anti-retroviral agent may prolong survival in HIV-infected individuals.
The antiretroviral drugs preferred for use in the present invention are AZT, ddI and ddC, alone or in combination.
The amount of antiretroviral drug administered is from 10 to 1500 mg/daily, preferably from 50 to 1000 mg/daily. For example, AZT is administered orally at a dose from 600 to 1200 mg/daily and ddI at an oral dose of from 500 to 750 mg/daily.
The amount of thymoctonan administered is from 0.25 to 1000 ~g/weekly, preferably from 0.5 to 100 ~g/weekly, the route of administration being parenteral (i.m. or s.c.).
More preferably the antiretroviral drug is administered at conventional dosage, the thymoctonan at a WO95/23610 PCT~P95/00653 4 ~
dosage of 0.5, 4 or 40 ~g by i.m. injection, once daily for 15 days (induction period); then twice weekly for at least 12 months.
Thymoctonan was administered in particular in combination with AZT to a symptomatic HIV-infected individuals with a CD4 count less than 500/~1, showing suggestive evidence of a surprising favourable effect in terms of viral load decrease in comparison with the single treatment with AZT alone.
lo The combined administration, according to the present invention, of thymoctonan and an antiretroviral agent includes presentation in which both agents are administered together as a therapeutic mixture, and also procedures in which the two agents are administered separately, e.g.
thymoctonan through i.m. or s.c. injection and the anti-retroviral agent by the oral route. Combined administration further includes the separate administration of the drugs in which one of the drugs is given first followed shortly by the second.
Clinical data As a part of a multicenter controlled double-blind, clinical study we enrolled 12 patients (4 AIDS, 6CDC III
and 2 CDC II) that were treated for the first six months with either 4 or 40 ~g of thymoctonan or placebo (2 times a week by i.m. injection). After this period all the patients voluntarily received the highest dose of active WosS/23610 216 0~ PCT~P95/006~3 drug on open-label. Patients received since the beginning of the treatment AZT 5000 mg/day orally, too.
For the evaluation of open-label treatment we chose a case-control design. Patients in the control group were 24 (1:2 ratio) subjects, admitted in our service, who started AZT treatment in the same period of time and matched thymoctonan treated patients as to sex, age, CDC
classification of illness, number of CD4 + T-cells at admission (median 117.5 vs 165 cells/~l) and previous opportunistic infections. All cases and controls received PCP prophylaxis whenever CD4 +T-cell count fell below 200/~l. The groups were homogeneous for all considered entry variables.
They were followed for 19+5 months (cases) and 15+5 (controls). No case of death was observed in the thymoctonan treated group, while 9 subjects (37.5%) died in the control group (P=0.01 Fisher). No cases of disease progression (in terms of CDC group shift for patients in II
or III stage) was observed in the thymoctonan group but in 4 out of 16 patients in the control group, 3 of whom died.
Four patients in the thymoctonan group and 11 in the control group were hospitalized at least once during the observation period and 3 vs 12 presented AZT intolerance.
In addition, in the thymoctonan group patients stayed without AZT treatment or were in the hospital for a shorter proportion of time (P<0.0001 Kruskal-Wallis).
Claims (8)
1. Products containing thymoctonan and an antiretroviral agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a retroviral disease.
2. Products according to claim 1 for use in the treatment of HIV-infected patients.
3. Products according to claim 1 or 2 for use in the treatment of HIV-1 infected patients.
4. Products according to any one of claims 1 to 3 wherein the antiretroviral agent is AZT, ddI or ddC.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active agents, thymoctonan and an anti-retroviral agent.
6. A composition according to claim 5 wherein the anti-retroviral agent is AZT, ddI or ddC.
7. Use of thymoctonan and an antiretroviral agent in the preparation of a medicament for use in the treatment of HIV infected patients.
8. Use according to claim 7 wherein the anti-retroviral agent is AZT, ddI or ddC.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9403856A GB9403856D0 (en) | 1994-03-01 | 1994-03-01 | Combined treatment of human retroviral infections |
| GB9403856.9 | 1994-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2160248A1 true CA2160248A1 (en) | 1995-09-08 |
Family
ID=10751061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002160248A Abandoned CA2160248A1 (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing thymoctonan and azt |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0696202A1 (en) |
| JP (1) | JPH08509993A (en) |
| KR (1) | KR960701652A (en) |
| AU (1) | AU1759295A (en) |
| CA (1) | CA2160248A1 (en) |
| FI (1) | FI955181A0 (en) |
| GB (1) | GB9403856D0 (en) |
| HU (1) | HUT73178A (en) |
| IL (1) | IL112803A0 (en) |
| MX (1) | MX9504565A (en) |
| NO (1) | NO954171D0 (en) |
| PL (1) | PL311340A1 (en) |
| WO (1) | WO1995023610A1 (en) |
| ZA (1) | ZA951654B (en) |
-
1994
- 1994-03-01 GB GB9403856A patent/GB9403856D0/en active Pending
-
1995
- 1995-02-23 MX MX9504565A patent/MX9504565A/en unknown
- 1995-02-23 PL PL95311340A patent/PL311340A1/en unknown
- 1995-02-23 EP EP95910515A patent/EP0696202A1/en not_active Withdrawn
- 1995-02-23 HU HU9503432A patent/HUT73178A/en unknown
- 1995-02-23 JP JP7522672A patent/JPH08509993A/en active Pending
- 1995-02-23 KR KR1019950704771A patent/KR960701652A/en not_active Application Discontinuation
- 1995-02-23 CA CA002160248A patent/CA2160248A1/en not_active Abandoned
- 1995-02-23 WO PCT/EP1995/000653 patent/WO1995023610A1/en not_active Application Discontinuation
- 1995-02-23 AU AU17592/95A patent/AU1759295A/en not_active Abandoned
- 1995-02-27 IL IL11280395A patent/IL112803A0/en unknown
- 1995-02-28 ZA ZA951654A patent/ZA951654B/en unknown
- 1995-10-19 NO NO954171A patent/NO954171D0/en unknown
- 1995-10-30 FI FI955181A patent/FI955181A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUT73178A (en) | 1996-06-28 |
| ZA951654B (en) | 1995-12-08 |
| HU9503432D0 (en) | 1996-01-29 |
| FI955181A (en) | 1995-10-30 |
| JPH08509993A (en) | 1996-10-22 |
| NO954171L (en) | 1995-10-19 |
| FI955181A0 (en) | 1995-10-30 |
| WO1995023610A1 (en) | 1995-09-08 |
| IL112803A0 (en) | 1995-05-26 |
| EP0696202A1 (en) | 1996-02-14 |
| MX9504565A (en) | 1997-05-31 |
| KR960701652A (en) | 1996-03-28 |
| AU1759295A (en) | 1995-09-18 |
| GB9403856D0 (en) | 1994-04-20 |
| PL311340A1 (en) | 1996-02-05 |
| NO954171D0 (en) | 1995-10-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |