WO1992001467A1 - Method for treating viral infections using oxidized lipoproteins - Google Patents
Method for treating viral infections using oxidized lipoproteins Download PDFInfo
- Publication number
- WO1992001467A1 WO1992001467A1 PCT/US1991/004913 US9104913W WO9201467A1 WO 1992001467 A1 WO1992001467 A1 WO 1992001467A1 US 9104913 W US9104913 W US 9104913W WO 9201467 A1 WO9201467 A1 WO 9201467A1
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- WO
- WIPO (PCT)
- Prior art keywords
- lipoproteins
- blood
- oxidized
- lipoprotein
- patient
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/775—Apolipopeptides
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to treating viral infections and particularly Acquired Immunodeficiency Syndrome (AIDS) in a living patient using oxidized lipoproteins, preferably peroxidized low density lipoproteins (p-LDL) .
- oxidized lipoproteins preferably peroxidized low density lipoproteins (p-LDL) .
- Lipoproteins as a group include chylomicrons, chylomicron remnants, very low density lipoproteins, intermediate density lipoproteins, low density lipoproteins and high density lipoproteins. All of these can serve as a source of oxidized lipoproteins.
- this invention relates to a method and an apparatus for producing and administering effective doses of oxidized lipoproteins into a patient's bloodstream in order to kill the Human Immunodeficiency Virus (HIV) and HIV-infected cells, leaving most healthy cells intact.
- HIV Human Immunodeficiency Virus
- oxidized lipids are cytotoxic to a majority of cell types, it is therefore desirable to find an agent which will be effective against viruses such as HIV and which will preferentially target virus-infected cells, particularly HIV-infected cells.
- the lipoprotein chosen must be one that the viruses and/or diseased cells have an enhanced ability, compared to normal cells of similar type, to take up or transport across their membranes. Also, the lipoprotein must be capable of being oxidized and preferably peroxidized with hydrogen peroxide.
- virus-infected cells are more susceptible than healthy cells to the cytotoxic effect of oxidized lipoproteins as defined herein. It was also discovered that p-LDL kills the virus as well. The mechanism by which this preferrential cytotoxicity occurs is not understood. It appears, that viruses and virus-infected cells have an enhanced ability to take up lipoproteins or an enhanced ability to transport lipoproteins across their membranes or an increased susceptibility to oxidized lipoproteins. According to the Fossel reference cited above, some diseased cells may take up more oxidized lipoproteins through an increased number of lipoprotein receptors. However, we are not aware of any evidence that viruses or virus-infected cells have been demonstrated to have an increased number of lipoprotein receptors.
- One important method for treating viral infections such as AIDS, with peroxidized lipoproteins involves administering p-LDL directly to the patient. Such administration may be accomplished by introducing p-LDL enriched blood directly into a patient's blood stream.
- Hydrogen peroxide or organic peroxides are capable of generating free-radicals which in turn can peroxidize LDL to kill the virus or virus-containing cells.
- a second method for treating viral infections, such as AIDS, using oxidized lipoproteins comprises introducing a therapeutic dose of organic peroxide into a diseased patient which makes p-LDL more cytotoxic to diseased cells infected with the virus.
- Administering non-oxidized but modified LDL should enhance the effect of the organic peroxides.
- Modified LDL is prepared by enriching the content of natural LDL with specific triglycerides, phospholipids, or cholesterol esters which are more easily oxidized or which result in more cytotoxic peroxidation products.
- a third method for producing peroxidized lipoproteins involves subjecting blood fluid lipids directly to hydrogen peroxide or organic peroxides alone or in the presence of an enzyme such as peroxidase.
- An apparatus for accomplishing the latter method comprises an extracorporeal module for installation in an AV (atrioventricular) shunt or arterial bypass, which includes a peroxidizing module and an inlet from a means, such as a pump, which can slowly and precisely introduce a flow of peroxide.
- blood is removed from a patient and treated under peroxidizing conditions to oxidize or peroxidize the lipoproteins present in the blood.
- the blood can be monitored for oxidized lipoprotein level by proton and carbon-13 nuclear magnetic resonance (NMR) spectroscopy and returned to the patient where the oxidized lipoproteins will come in contact with high metabolism virus-infected cells, where the peroxidized lipoprotein will be taken up by such cells and the cells will be killed.
- NMR nuclear magnetic resonance
- a patient's blood or blood from a donor source can be treated as described above, but in addition, the blood can be enriched with lipoproteins from other sources and then oxidized.
- an agent known to increase a cell's uptake of lipoproteins can be administered to the patient as a pretreatment in addition to further enriching the blood with a peroxide.
- a patient can receive blood from a donor which is superenriched with oxidized lipoproteins, which contains an agent to increase the virus or virus-in ected cell's ability to take up such lipoproteins and which further contains an oxidant to oxidize those lipoproteins already present in the patient.
- the lipid oxidation processes of the body may be further augmented by increasing the oxygen level in the blood via inhalation of increased levels of elemental oxygen during breathing.
- Perfluorocarbon fluosal may also be used to increase the oxygen level in the blood.
- FIG. 1 shows the apparatus of the invention where by means of an extracorporeal peroxidizing module, a patient's lipoproteins are peroxidized directly;
- FIG. 2 is a schematic diagram of the general method for using p-LDL cytotoxicity to treat virus infections in humans in accordance with the claimed invention
- FIG. 3 shows a procedure and apparatus for oxidizing the lipoproteins of a patient
- FIG. 4 shows an apparatus for oxidizing the lipoproteins in a blood supply
- FIG. 5 shows an apparatus for oxidizing the lipoproteins in a blood supply.
- this invention is a method of treating virus infections such as AIDS which is a disease state characterized by the presence of diseased cells with an enhanced ability to take up lipoproteins or an increased susceptibility to oxidized lipoproteins.
- virus infections such as AIDS which is a disease state characterized by the presence of diseased cells with an enhanced ability to take up lipoproteins or an increased susceptibility to oxidized lipoproteins.
- the treatment consists of the absorption of oxidized lipoproteins, preferably peroxidized low density lipoproteins, by viruses or infected cells with an enhanced ability to take up lipoproteins.
- virus relies on its host cell for viability.
- oxidized or peroxidized lipoproteins will preferentially kill virus-infected cells such as HIV-infected cells.
- the present invention is directed to methods and apparatus for the purpose of increasing the likelihood that oxidized lipoproteins will be taken up by virus-infected cells in order to destroy such cells.
- SUBSTITUTESHEET Table II shows the titration results for HIV-1 antigen in CR10 culture supernatant fluids at Day 2 of treatment.
- This antibody-antigen precipitation * experiment is designed using a titration dilution.
- the titration ratio was carried out to 1:64 to eliminate the antibody-antigen response.
- the titration ratio only needed to reach 1:16 for pLDL dilution of 1:10 and 1:32 for more dilute pLDL.
- Lipoproteins circulating in the blood take various forms including chylomicrons, chylomicron remnants, very low density lipoproteins, intermediate density lipoproteins, low density lipoproteins, and high density lipoproteins. Certain lipids associate with specific proteins to form lipid/protein systems in which the specific physical properties of these two classes of biomolecules are blended. There are two major types, transport lipoproteins and membrane systems. In the membrane systems, the lipids and proteins are not covalently joined but are held together largely by hydrophobic interactions between the nonpolar portions of the lipid and the protein components.
- the plasma transport lipoproteins are complexes in which the lipids and proteins occur in a relatively fixed ratio. They carry water-insoluble lipids between various organs via the blood, in a form with a relatively small and' s constant particle diameter and weight. Human plasma lipoproteins occur in four major classes that differ in density as well as particle size as shown in the table below. TABLE III Major Classes of Human Plasma Lipoproteins
- the plasma lipoproteins contain varying proportions of protein and different types of lipid.
- the very low-density lipoproteins contain four different types of polypeptide chains having distinctive a ino acid sequences.
- the high-density lipoproteins have two different types of polypeptide chains, of molecular weight 17,500 and 28,000.
- the polypeptide chains of the plasma lipoproteins are believed to be arranged on the surface of the molecules, thus conferring hydrophilic properties.
- the very low-density lipoproteins and chylomicrons there is insufficient protein to cover the surface; presumably the polar heads of. the phospholipid components also contribute hydrophilic groups on the surface, with the nonpolar triacylglycerols in the interior. Biochemistry, Lehninger, Worth Publishers, Inc., New York, 1975, pp.301.
- LDL low density lipoproteins
- lipoprotein chosen be one which the diseased cells have an enhanced ability to take-up or transport across their membrane or to which they have an increased susceptibility.
- Another important characteristic of the lipoprotein is that it be capable of being oxidized, ⁇ preferably peroxidized by reaction with hydrogen peroxide.
- lipoproteins are oxidized by reaction with horseradish peroxidase and hydrogen peroxide.
- one method of the present invention for treating virus infections such as AIDS a disease state characterized by diseased cells with an enhanced ability to take-up lipoproteins or an increased susceptibility to oxidized lipoproteins, using p-LDL, is as follows.
- Therapeutic doses of an oxidant such as an organic peroxide, or more specifically such as ditertiarybutyl peroxide are introduced into patients diagnosed as having a viral infection such as AIDS by methods well known in the art. The progress of the disease is monitored by conventional methods and the organic peroxide dose adjusted accordingly.
- Administering modified lipoproteins should enhance the effect of these peroxides.
- Modified lipoproteins are prepared by enriching the content of ⁇ natural lipoproteins with specific triglycerides, phospholipids, or cholesterol esters.
- Other enzymes and oxidants such as flavins and riboflavin and oxidases such as peroxidase and lipoxidase may also be used in this embodiment.
- the lipoproteins in a patient's blood are peroxidized directly by the method and apparatus of the invention.
- the apparatus consists of an extracorporeal peroxidizing module 50 (FIG. 1) which is installed through an A-V shunt or arterial bypass 51.
- the module 50 includes an immobilized enzyme 52 such as peroxidase or lipoxidase and an inlet 54 from a pump 56 which can very slowly and precisely introduce a flow of hydrogen peroxide into the blood.
- the lipid peroxidation process of the body may be further augmented by increasing the oxygen level in the blood via inhalation of increased levels of elemental oxygen during breathing.
- Perfluorocarbon fluosal may also be used to increase the oxygen level in the blood.
- patients with virus infections such as AIDS, a disease state characterized by diseased cells with an enhanced ability to take up lipoproteins or an increased susceptibility to oxidized lipoproteins, are treated by direct administration of peroxidized lipoproteins. Peroxidized low density lipoproteins produce the best results.
- LDL will be converted directly to p-LDL by exposure to a chemical agent 40 as described below.
- the agent 40 is ditertiarybutyl peroxide.
- the agent 40 is peroxidase together with peroxide. HIV-infected cells 36 will die in preference to normal cells.
- FIG. 3 depicts another embodiment of this invention in which blood is transferred from a patient 50 to a container 52 the interior walls of which are coated with an immobilized enzyme such as a lipoxidase or a peroxidase such as horseradish peroxidase.
- an immobilized enzyme such as a lipoxidase or a peroxidase such as horseradish peroxidase.
- a peroxide 54 is added to the container resulting in the formation of oxidized lipoproteins which are then transferred back to the patient 50.
- FIG. 4 depicts still another embodiment of this invention wherein a blood supply 58 is secured. It may be from a patient, a donor or any other compatible blood source.
- the blood 58 and an oxidant 60 such as hydrogen peroxide, are introduced into a container 62 thus forming oxidized lipoproteins.
- the oxidized lipoprotein-containing blood is then transferred to a storage container 64 until needed for treatment.
- peroxidized lipoproteins are injected intravenously.
- the progress of the HIV infection is monitored by conventional methods and the peroxidized low density lipoprotein dose is adjusted accordingly.
- the extent of lipid peroxidation is measured by performing a proton and carbon-13 (128/130 ppm ratio) NMR analysis of the oxidized low density lipoprotein solution.
- peroxidized low density lipoprotein is administered orally or intravenously.
- the progress of the HIV infection is monitored by conventional methods and the peroxidized low density lipoprotein dose is adjusted accordingly.
- ditertiarybutyl peroxide is administered by i.v. (intravenous) injection.
- the progress of the HIV infection is monitored by conventional methods and the ditertiarybutyl peroxide dose adjusted accordingly.
- the patient's blood oxygen supply may also be augmented by inhalation of elemental oxygen or by i.v. injection of perfluorocarbon fluosal.
- the patient's supply of lipoproteins may be augmented by intravenous injection of lipoproteins enriched with triglycerides, phospholipids or cholesterol esters.
- the ditertiarybutyl peroxide of this procedure may be replaced with any of the following in its proper dose: riboflavin, peroxidase, lipoxidase or other flavins, peroxides, organic peroxides or oxidases.
- the extent of lipid peroxidation is measured by performing a proton and carbon-13 (128/130 ppm ratio) NMR analysis of the oxidized low density lipoprotein-containing blood.
- an AV shunt or arterial bypass is attached to the patient.
- An extracorporeal peroxidizing module is attached to the AV shunt or arterial bypass. It has an inlet fluid connection from a pump which introduces hydrogen peroxide into the module which contains peroxidase or lipoxidase which in turn peroxidizes the plasma lipoproteins.
- a supply of blood is secured.
- the blood supply source may be from the diseased patient, a donor, a blood bank or any other compatible blood supply source. Blood from sources other than the diseased patient have the advantage of being from apparently healthy donors.
- the lipoproteins of the blood supply are then oxidized by adding an oxidant to the blood, thus producing oxidized lipoproteins.
- a second approach to increasing the blood's ' level of oxidized lipoproteins involves adding oxidized lipoproteins to the blood.
- the first two approaches may be combined, that is an oxidant as well as the oxidized lipoproteins are added to the same blood supply.
- the oxidized lipoprotein-containing blood may be stored until needed.
- the patient's blood it may be reintroduced to the patient at the most advantageous time for treatment.
- the oxygen available in the blood may be further increased by adding elemental oxygen or perfluorocarbon fluosal to the blood.
- the lipoprotein content of the blood could also be augmented by adding lipoproteins enriched with triglycerides, phospholipids or cholesterol esters.
- One embodiment of this invention involves providing a blood supply which may include the diseased patient's blood, a blood bank or any other compatible blood supply.
- Heparinized blood 66 is added to the bottom of a container 68, shown in FIG. 5, the walls of which confine a source of an immobilized enzyme such as horseradish peroxidase coated beads 70.
- Hydrogen peroxide 72 is introduced to the bottom of the container resulting in the formation of oxidized lipoproteins 74 in the blood which
- SUBSTITUTESHEET exits from the top of the container.
- the oxidized lipoprotein-containing blood 74 is then introduced to the patient 76 when treatment of the disease state is desired.
- This procedure may be further enhanced by introducing an oxidant to the blood prior to administering it to the patient.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP91513333A JPH05508159A (en) | 1990-07-18 | 1991-07-11 | How to treat viral infections using oxidized lipoproteins |
FI930123A FI930123A (en) | 1990-07-18 | 1993-01-12 | FOERFARANDE FOER ANVAENDNING AV OXIDERADE LIPOPROTEINER I VIRUSARTADE INFEKTIONER |
NO93930144A NO930144L (en) | 1990-07-18 | 1993-01-15 | PROCEDURE FOR TREATING VIRUS INFECTIONS BY USING OXIDATED LIPOPROTEIN |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55480790A | 1990-07-18 | 1990-07-18 | |
US554,807 | 1990-07-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992001467A1 true WO1992001467A1 (en) | 1992-02-06 |
Family
ID=24214788
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/004913 WO1992001467A1 (en) | 1990-07-18 | 1991-07-11 | Method for treating viral infections using oxidized lipoproteins |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0539506A4 (en) |
JP (1) | JPH05508159A (en) |
AU (1) | AU8305691A (en) |
CA (1) | CA2086921A1 (en) |
FI (1) | FI930123A (en) |
IE (1) | IE912498A1 (en) |
PT (1) | PT98373A (en) |
WO (1) | WO1992001467A1 (en) |
ZA (1) | ZA915639B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4336641A1 (en) * | 1993-10-22 | 1995-04-27 | Deutsches Rheuma Forschungszen | Use of superoxide dismutase (SOD) for producing pharmaceuticals with an antiviral action |
EP1994941A3 (en) * | 2000-10-20 | 2012-07-25 | Hamburger Stiftung zur Förderung von Wissenschaft und Kultur | Medicine containing at least one oxidised protein |
-
1991
- 1991-07-11 EP EP19910914013 patent/EP0539506A4/en not_active Withdrawn
- 1991-07-11 JP JP91513333A patent/JPH05508159A/en active Pending
- 1991-07-11 AU AU83056/91A patent/AU8305691A/en not_active Abandoned
- 1991-07-11 WO PCT/US1991/004913 patent/WO1992001467A1/en not_active Application Discontinuation
- 1991-07-11 CA CA002086921A patent/CA2086921A1/en not_active Abandoned
- 1991-07-17 IE IE249891A patent/IE912498A1/en unknown
- 1991-07-18 ZA ZA915639A patent/ZA915639B/en unknown
- 1991-07-18 PT PT98373A patent/PT98373A/en not_active Application Discontinuation
-
1993
- 1993-01-12 FI FI930123A patent/FI930123A/en not_active Application Discontinuation
Non-Patent Citations (2)
Title |
---|
Artheriosclerosis, Volume 3, No. 3, issued June 1983, J.R. HESSLER et al., "Lipoprotein Oxidation and Lipoprotein Induced Cytotoxicity", pages 215-222, see entire document. * |
Journal of Lipid Research, Volume 24, issued 1983, D.W. MOREL et al., "Low Density Lipoprotein Cytotoxicity Induced by Free Radical Pevexidation of Lipid", pages 1076-1077, see entire document. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4336641A1 (en) * | 1993-10-22 | 1995-04-27 | Deutsches Rheuma Forschungszen | Use of superoxide dismutase (SOD) for producing pharmaceuticals with an antiviral action |
EP1994941A3 (en) * | 2000-10-20 | 2012-07-25 | Hamburger Stiftung zur Förderung von Wissenschaft und Kultur | Medicine containing at least one oxidised protein |
AP2781A (en) * | 2000-10-20 | 2013-10-31 | Hamburger Stiftung Zur Forderung Van Wissenschaft Und Kultur | Oxidized proteins, their biological activity, and therapeutic and diagnostic measures, which are derived from the active mechansim, from the use of these porteins or from the inhibition thereof |
Also Published As
Publication number | Publication date |
---|---|
AU8305691A (en) | 1992-02-18 |
EP0539506A1 (en) | 1993-05-05 |
IE912498A1 (en) | 1992-01-29 |
FI930123A0 (en) | 1993-01-12 |
ZA915639B (en) | 1992-04-29 |
FI930123A (en) | 1993-01-12 |
CA2086921A1 (en) | 1992-01-19 |
EP0539506A4 (en) | 1993-11-24 |
PT98373A (en) | 1992-06-30 |
JPH05508159A (en) | 1993-11-18 |
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