WO1995023610A1 - Pharmaceutical composition containing thymoctonan and azt - Google Patents
Pharmaceutical composition containing thymoctonan and azt Download PDFInfo
- Publication number
- WO1995023610A1 WO1995023610A1 PCT/EP1995/000653 EP9500653W WO9523610A1 WO 1995023610 A1 WO1995023610 A1 WO 1995023610A1 EP 9500653 W EP9500653 W EP 9500653W WO 9523610 A1 WO9523610 A1 WO 9523610A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- thymoctonan
- azt
- hiv
- treatment
- agent
- Prior art date
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
Definitions
- This invention relates to the use of thymoctonan in combination 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 ly photropic (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 ho ology 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, gag, and pol) and six extra genes involved in the replication and other biologic activities of the virus.
- T4 lymphocytes thymus-derived lymphocytes
- This subset of cells is defined phenotypically by the presence of the CD4 surface cell molecule, which is the cellular receptor for HIV.
- CD4 surface cell molecule which is the cellular receptor for HIV.
- 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.
- An immunomodulatory intervention is defined 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.
- 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 disease progression.
- Thymoctonan is a synthetic octapeptide originally isolated and characterized from fetal calf thymus, as described in US patent No. 4,621,135.
- the present invention provides products containing thymoctonan 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-1.
- 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 a_l, Proc. Natl. Acad. Sci USA 8J3 9734 (1986)) .
- 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 nucleic acid-based therapeutics
- Tat inhibitors Tat is a regulatory protein required for
- RT inhibitors include AZT (3'- azidothymidine, zidovudin, Retrovir) ; ddl (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 PMEA (9- (2-phosphonomethoxyethyl) -adenine, an acylic nucleotide).
- NRTI's non-nucleoside reverse transcriptase inhibitors
- NRTI's examples include tetrahydro-imidazo [4,5,1- jk] [l,4]-benzodiazepin-2 (IH) -one; ll-cyclopropyl-7-methyl- dipyrido-[2,3-b: 3'3'-f] l,4-diazepin-6H-5-one (BI-RG-587, nevirapine) ; and bis(heteroaryl)piperazines (BHAP's,
- 3 anti-retroviral agents approved for HIV disease 3'azidothymidine (AZT, Zidovudine) ,2' ,3' ,- didoxyinosine (ddl, Didanosine) and 2' ,3'-dideoxycytidine (ddC, Zalcitabine) .
- AZT Zidovudine
- ddl Didanosine
- ddC 2' ,3'-dideoxycytidine
- 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.
- thymoctonan 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.
- 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.
- 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.
- antiretroviral drugs preferred for use in the present invention are AZT, ddl 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.
- AZT is administered orally at a dose from 600 to 1200 mg/daily and ddl 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. ) .
- the antiretroviral drug is administered at conventional dosage, the thymoctonan at a 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/ ⁇ l, showing suggestive evidence of a surprising favourable effect in terms of viral load decrease in comparison with the single treatment with AZT alone.
- 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.
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- 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
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019950704771A KR960701652A (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing thymoctonan and AZT |
MX9504565A MX9504565A (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing thymoctonan and azt. |
AU17592/95A AU1759295A (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing thymoctonan and azt |
JP7522672A JPH08509993A (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing timoctonane and AZT |
EP95910515A EP0696202A1 (en) | 1994-03-01 | 1995-02-23 | Pharmaceutical composition containing thymoctonan and azt |
NO954171A NO954171D0 (en) | 1994-03-01 | 1995-10-19 | Pharmaceutical composition comprising thymoctonane and AZT |
FI955181A FI955181A (en) | 1994-03-01 | 1995-10-30 | Pharmaceutical compositions containing trymoctonane and ATZ |
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 |
---|---|
WO1995023610A1 true WO1995023610A1 (en) | 1995-09-08 |
Family
ID=10751061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1995/000653 WO1995023610A1 (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) | FI955181A (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 AU AU17592/95A patent/AU1759295A/en not_active Abandoned
- 1995-02-23 JP JP7522672A patent/JPH08509993A/en active Pending
- 1995-02-23 EP EP95910515A patent/EP0696202A1/en not_active Withdrawn
- 1995-02-23 PL PL95311340A patent/PL311340A1/en unknown
- 1995-02-23 HU HU9503432A patent/HUT73178A/en unknown
- 1995-02-23 MX MX9504565A patent/MX9504565A/en unknown
- 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
- 1995-02-27 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/FI955181A/en not_active Application Discontinuation
Non-Patent Citations (3)
Title |
---|
CALENDA V ET AL: "Effects of thymus humoral factor gamma-2 (THF-gamma-2) on lymphohaematopoietic progenitor cells: An in vitro study", RESEARCH IN IMMUNOLOGY, 144 (6-7). 1993. 395-406. * |
KOUTTAB N ET AL: "Phase I trial of intramuscular (IM) thymic humoral factor (THF) in combination with zidovudine (ZDV) in HIV infected individuals.", INT CONF AIDS, JUL 19-24 1992, 8 (2) PB161 (ABSTRACT NO. POB 3447) * |
TRAININ N: "Prospects of AIDS therapy by thymic humoral factor, a thymic hormone.", NAT IMMUN CELL GROWTH REGUL, 1990, 9 (3) P155-9, SWITZERLAND * |
Also Published As
Publication number | Publication date |
---|---|
HUT73178A (en) | 1996-06-28 |
FI955181A0 (en) | 1995-10-30 |
HU9503432D0 (en) | 1996-01-29 |
AU1759295A (en) | 1995-09-18 |
GB9403856D0 (en) | 1994-04-20 |
FI955181A (en) | 1995-10-30 |
JPH08509993A (en) | 1996-10-22 |
EP0696202A1 (en) | 1996-02-14 |
NO954171L (en) | 1995-10-19 |
IL112803A0 (en) | 1995-05-26 |
ZA951654B (en) | 1995-12-08 |
CA2160248A1 (en) | 1995-09-08 |
NO954171D0 (en) | 1995-10-19 |
PL311340A1 (en) | 1996-02-05 |
KR960701652A (en) | 1996-03-28 |
MX9504565A (en) | 1997-05-31 |
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