WO1992004909A1 - Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation - Google Patents
Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation Download PDFInfo
- Publication number
- WO1992004909A1 WO1992004909A1 PCT/GB1991/001627 GB9101627W WO9204909A1 WO 1992004909 A1 WO1992004909 A1 WO 1992004909A1 GB 9101627 W GB9101627 W GB 9101627W WO 9204909 A1 WO9204909 A1 WO 9204909A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- agent
- hiv
- polyanionic
- virus
- effective dose
- Prior art date
Links
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 title claims abstract description 20
- 229940124411 anti-hiv antiviral agent Drugs 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 34
- 239000000463 material Substances 0.000 claims abstract description 24
- 241000700605 Viruses Species 0.000 claims abstract description 19
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 16
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 13
- 229920001282 polysaccharide Polymers 0.000 claims description 12
- 239000005017 polysaccharide Substances 0.000 claims description 12
- 229920001353 Dextrin Polymers 0.000 claims description 11
- 239000004375 Dextrin Substances 0.000 claims description 11
- 235000019425 dextrin Nutrition 0.000 claims description 11
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims description 10
- 150000004676 glycans Chemical class 0.000 claims description 9
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 4
- 230000036436 anti-hiv Effects 0.000 claims description 3
- -1 sulphat polysaccharide Chemical class 0.000 claims description 3
- 150000001720 carbohydrates Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims 1
- 229920000447 polyanionic polymer Polymers 0.000 claims 1
- 208000031886 HIV Infections Diseases 0.000 abstract description 8
- 208000037357 HIV infectious disease Diseases 0.000 abstract description 6
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 abstract description 6
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 108010041884 CD4 Immunoadhesins Proteins 0.000 description 1
- 241000518994 Conta Species 0.000 description 1
- 241000501458 Cultus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920000855 Fucoidan Polymers 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- GIXWDMTZECRIJT-UHFFFAOYSA-N aurintricarboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=CC1=C(C=1C=C(C(O)=CC=1)C(O)=O)C1=CC=C(O)C(C(O)=O)=C1 GIXWDMTZECRIJT-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
-
- 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
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- 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
-
- 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
Definitions
- This invention relates to pharmaceutically active compositi and to their use as agents against human immunodeficiency vi and related viruses.
- the HIV infection cycle includes a number of steps, each of th steps being a possible target for the use of chemotherapy hinder the infection.
- the first step in the infection cycle the attachment of the HIV virus to the host cell.
- the m receptor for the virus is believed to be the cell surf glycoprotein, designated CD4, which is present in some lymphocytes and in some macrophages. Much attention therefore been given to identifying agents which are capable blocking attachment of the virus to CD4.
- statin CD4 made by genetic engineering, can block attachment of H virus to cellular CD4, thereby inhibiting HIV infection in vitr
- CD4-li materials capable of binding to gpl20, such as CD4-Ig immunoadhesins, CD4 V1-V2 domains, and CD4-derived peptides, ha also been proposed as anti-HIV agents.
- CD4-Ig immunoadhesins CD4 V1-V2 domains
- CD4-derived peptides ha also been proposed as anti-HIV agents.
- the performan of CD4 and CD4-like materials in preventing the HIV virus fr binding to cells has until now been disappointing, a much high concentration of the agent being necessary than had been hoped.
- anti-HIV agents which block attachment of the virus cells are a number of polyanionic compounds which include Eva Blue, aurintricarboxylic acid (ATA), suramin, and certai sulphated polysaccharides. It might have been thought that i CD4 and such polyanionic anti-HIV agents were use simultaneously, the total anti-HIV activity would at best be th sum of their separate activities.
- CD4 which is used here an below, except where otherwise indicated, to include both CD4 an CD4-like materials
- a polyanionic anti-HIV agent such as a sulphated polysaccharide
- the invention provides an agent against HIV an related viruses, in dosage unit form, comprising CD4 or a CD4 like material and a polyanionic anti-HIV agent the content of CD and CD4-like material in the agent being less than the anti virally effective dose of the CD4 or CD4-like material alone.
- the agent according to the invention may contain substantiall less CD4 than the anti-virally effective dosage of CD4 alo i.e. in the absence of a polyanionic anti-HIV agent.
- reduction in the amount of CD4 required to achieve the same an viral effect as for CD4 alone may be such that less than o tenth (or, in favourable cases, less than one-hundredth) of amount of CD4 is needed.
- the invention offers possibility of using CD4 as a component of an anti-HIV agent i reduced and therefore safer and more economical amount than previously been feasible.
- the agent according to the invention may also contain less t the normally effective dose of the polyanionic compound. This advantageous because many of the known polyanionic anti- agents are significantly toxic. For example, sulphat polysaccharides have anti-coagulant activity. When t polyanionic anti-HIV agent is a sulphated polysaccharide, it m be present in the compositions of the invention in an amou which is less than that which would be required in an anti-H agent containing only the sulphated polysaccharide.
- compositions of the invention which conta sulphated polysaccharides may have a lower level of ant coagulant activity attributable to the sulphated polysacchari content than those previously known.
- the polyanionic anti-HIV agents used in the present invention a preferably sulphated polysaccharides. They include, for exampl dextran sulphate, pentosan polysulphate, fucoidan, and dextr sulphate. Other sulphated polysaccharides having anti-H activity (see, for example, EP specifications No's 240,098 a 293,826) may also be used.
- the sulphat polysaccharide contains at least one sulphate group p saccharide unit.
- the anti-HIV agent of the invention may administered enterally (including orally) or parenteral (including intravenously).
- administration via t peritoneum may be more effective in that it results in entry at least some of the anti-HIV agent directly into the lymphat system, within which system viral replication may be extensive.
- the invention also provides the use of the agent described abo against HIV-1 and relates viruses, the agent preferably bei administered peritoneally.
- the invention provides a pharmaceutical compositi containing the anti-HIV agent of the invention together with inert carrier or diluent and the agent of the invention for u in the manufacture of a pharmaceutical composition against HIV and related viruses.
- the invention additionally provides a method of treatment of human or animal subject carrying the HIV-1 virus or a rela virus, comprising administering to the subject a pharmaceutica effective amount of the agent of the invention.
- the CD4 or CD4-like material and the polyanionic anti-HIV ag may be administered to a subject one after the other, in order although preferably with the CD4 or CD4-like mater being administered before the polyanionic agent, when u against HIV-1 or a related virus.
- the invention thus provides CD4 or a CD4-like material, of amount less than its usual anti-virally effective dose, and polyanionic anti-HIV agent, for use in a method of treatment of human or animal subject carrying the HIV-1 virus or a relat virus in whic the CD4 or CD4-like material are administered the subject one after the other.
- T dextrin sulphate was produced by sulphation of a dextrin weight average molecular weight of about 20,000 daltons, using sulphur trioxide/trimethylamine complex, the degree substitution being approximately one sulphate group per gluco unit.
- the srCD4 was produced in a baculo virus system and w purchased from American Biotechnology Inc.
- Example 1
- T srCD4/HIV-l was then added to the dextrin sulphate pre-treat M8166 cells, and the plates read at 48 - 72 hours for t presence of syncytia, shown in the table below by +.
- srCD4 inhibited HIV infection of M8166 cells at 6 ug/ml (final concentration).
- dextrin sulphate inhibited HIV-1 infecti of M8166 cells at 5-10 ug/ml.
- 2 - 5.0 ug/ml of dextrin sulphate inhibited HIV-1 infection in t presence of srCD4 at a concentration of 0.05 - 0.09 ug/ml.
- Th represents a 10 ⁇ reduction in the quantity of srCD4 required prevent HIV-1 infection, and shows that the effect of the t drugs together is synergistic rather than simply additive.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Cell Biology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
L'invention se rapporte à un agent anti-VIH et virus apparentés, sous forme pharmaceutique unitaire, comprenant la glycoprotéine de surface cellulaire CD4 ou une substance similaire à CD4 et un agent polyanionique anti-VIH, la quantité de CD4 ou de substance similaire à CD4 dans l'agent étant inférieure à la dose anti-virale efficace de CD4 ou de substance similaire seule. On a découvert que, quand on utilise CD4 ou la substance similaire avec un agent polyanionique anti-VIH, la combinaison est plus efficace contre l'infection par VIH que ce ne serait le cas si l'effet anti-viral était uniquement additif.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3515281A JPH06502846A (ja) | 1990-09-25 | 1991-09-23 | Ｃｄ４及び抗ｈｉｖポリアニオン剤からなる薬剤組成体及びその利用方法 |
| AU86127/91A AU653962B2 (en) | 1990-09-25 | 1991-09-23 | Pharmaceutical composition comprising CD4 and a polyanionic anti-HIV agent and use thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9020872.9 | 1990-09-25 | ||
| GB909020872A GB9020872D0 (en) | 1990-09-25 | 1990-09-25 | Pharmaceutical compositions and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992004909A1 true WO1992004909A1 (fr) | 1992-04-02 |
Family
ID=10682731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1991/001627 WO1992004909A1 (fr) | 1990-09-25 | 1991-09-23 | Composition pharmaceutique contenant la glycoproteine cd4 et un agent polyanionique anti-vih et son utilisation |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0550529A1 (fr) |
| JP (1) | JPH06502846A (fr) |
| AU (1) | AU653962B2 (fr) |
| CA (1) | CA2092093A1 (fr) |
| GB (1) | GB9020872D0 (fr) |
| IE (1) | IE913341A1 (fr) |
| NZ (1) | NZ239909A (fr) |
| PT (1) | PT99058B (fr) |
| WO (1) | WO1992004909A1 (fr) |
| ZA (1) | ZA917596B (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993021943A1 (fr) * | 1992-05-07 | 1993-11-11 | M.L. Laboratories Plc | Agent antiviral comprenant la proteine cd4 et une histone h2 |
| US5272261A (en) * | 1989-01-11 | 1993-12-21 | Merrell Dow Pharmaceuticals Inc. | Preparation of sulfated polysaccharide fractions |
| FR2838649A1 (fr) * | 2002-04-19 | 2003-10-24 | Commissariat Energie Atomique | Composition anti-vih, procede de fabrication et medicament |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0293826A2 (fr) * | 1987-06-02 | 1988-12-07 | Stichting REGA V.Z.W. | Application thérapeutique et prophylactique des polysaccharides sulfatés contre le SIDA |
| EP0332952A2 (fr) * | 1988-03-12 | 1989-09-20 | BASF Aktiengesellschaft | Combinaisons d'héparines polysulfatées pour combattre les infections rétrovirales |
| WO1989011860A1 (fr) * | 1988-06-10 | 1989-12-14 | Biogen, Inc. | Combinaisons de proteines t4 solubles et d'agents anti-retroviraux, ainsi que procedes pour traiter ou prevenir l'infection par le sida, l'arc et le vih |
| WO1990000596A1 (fr) * | 1988-07-07 | 1990-01-25 | The Trustees Of The University Of Pennsylvania | Procede de modulation d'interactions entre des cellules hotes et un virus par l'utilisation d'hydrates de carbone et de derives d'hydrates de carbone |
-
1990
- 1990-09-25 GB GB909020872A patent/GB9020872D0/en active Pending
-
1991
- 1991-09-23 NZ NZ239909A patent/NZ239909A/xx unknown
- 1991-09-23 JP JP3515281A patent/JPH06502846A/ja active Pending
- 1991-09-23 EP EP91916829A patent/EP0550529A1/fr not_active Withdrawn
- 1991-09-23 WO PCT/GB1991/001627 patent/WO1992004909A1/fr not_active Application Discontinuation
- 1991-09-23 AU AU86127/91A patent/AU653962B2/en not_active Ceased
- 1991-09-23 CA CA002092093A patent/CA2092093A1/fr not_active Abandoned
- 1991-09-24 IE IE334191A patent/IE913341A1/en not_active Application Discontinuation
- 1991-09-24 ZA ZA917596A patent/ZA917596B/xx unknown
- 1991-09-25 PT PT99058A patent/PT99058B/pt not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0293826A2 (fr) * | 1987-06-02 | 1988-12-07 | Stichting REGA V.Z.W. | Application thérapeutique et prophylactique des polysaccharides sulfatés contre le SIDA |
| EP0332952A2 (fr) * | 1988-03-12 | 1989-09-20 | BASF Aktiengesellschaft | Combinaisons d'héparines polysulfatées pour combattre les infections rétrovirales |
| WO1989011860A1 (fr) * | 1988-06-10 | 1989-12-14 | Biogen, Inc. | Combinaisons de proteines t4 solubles et d'agents anti-retroviraux, ainsi que procedes pour traiter ou prevenir l'infection par le sida, l'arc et le vih |
| WO1990000596A1 (fr) * | 1988-07-07 | 1990-01-25 | The Trustees Of The University Of Pennsylvania | Procede de modulation d'interactions entre des cellules hotes et un virus par l'utilisation d'hydrates de carbone et de derives d'hydrates de carbone |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5272261A (en) * | 1989-01-11 | 1993-12-21 | Merrell Dow Pharmaceuticals Inc. | Preparation of sulfated polysaccharide fractions |
| US5861383A (en) * | 1989-01-11 | 1999-01-19 | Merrell Pharmaceuticals Inc. | Sulfated polysaccharide fractions having anti-HIV activity |
| WO1993021943A1 (fr) * | 1992-05-07 | 1993-11-11 | M.L. Laboratories Plc | Agent antiviral comprenant la proteine cd4 et une histone h2 |
| FR2838649A1 (fr) * | 2002-04-19 | 2003-10-24 | Commissariat Energie Atomique | Composition anti-vih, procede de fabrication et medicament |
| WO2003089000A3 (fr) * | 2002-04-19 | 2004-04-08 | Commissariat Energie Atomique | Composition anti-vih, comprenant un polyanion et un agent agissant sur gp120 de acon equivalent au cd4 |
| US7494975B2 (en) | 2002-04-19 | 2009-02-24 | Commissariat A L'energie Atomique | Anti-HIV composition, production method thereof and medicament |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2092093A1 (fr) | 1992-03-26 |
| AU653962B2 (en) | 1994-10-20 |
| JPH06502846A (ja) | 1994-03-31 |
| EP0550529A1 (fr) | 1993-07-14 |
| IE913341A1 (en) | 1992-02-25 |
| PT99058A (pt) | 1992-08-31 |
| PT99058B (pt) | 1999-02-26 |
| NZ239909A (en) | 1993-02-25 |
| ZA917596B (en) | 1992-05-27 |
| AU8612791A (en) | 1992-04-15 |
| GB9020872D0 (en) | 1990-11-07 |
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