WO1991004744A1 - Methods and apparatus for treating disease states using oxidized lipoproteins - Google Patents
Methods and apparatus for treating disease states using oxidized lipoproteins Download PDFInfo
- Publication number
- WO1991004744A1 WO1991004744A1 PCT/US1990/005680 US9005680W WO9104744A1 WO 1991004744 A1 WO1991004744 A1 WO 1991004744A1 US 9005680 W US9005680 W US 9005680W WO 9104744 A1 WO9104744 A1 WO 9104744A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lipoproteins
- blood
- oxidized
- lipoprotein
- diseased cells
- Prior art date
Links
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- 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
- A61K31/02—Halogenated hydrocarbons
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to treating disease states in a living patient using oxidized lipoproteins., preferably peroxidized low density lipoproteins (p-LDL) . More particularly, it relates to a method for increasing the quantity of oxidized or peroxidized lipoproteins, which, includes chylomicrons, chylomicron remnants, very low density lipoproteins, intermediate density lipoproteins, low density lipoproteins and high density lipoproteins; taken up by diseased cells. All of these can serve as a source of oxidized lipoprotein. It also relates to a method and an apparatus for producing and administering effective doses of oxidized lipoproteins into a patient's bloodstream. The invention also relates to novel classes of oxidized lipoproteins which can be used to treat disease states.
- p-LDL peroxidized low density lipoproteins
- C-13 spectra provide a further basis for classifying persons with high triglyceride levels (above 190 g/dl) into two groups; cancerous or non-cancerous.
- the sample used to generate the H-1 NMR spectrum can be used to generate a C-13 NMR spectrum.
- the olefinic region of the spectrum is diagnostic.
- a ratio of the.signal at 128 ppm of resonance frequency to that at 130 ppm was obtained.
- A. ratio of greater than 0.9 indicates that the initial characterization from the proton NMR diagnosis was a false.- positive.
- a 128/130 ratio of less than 0.9 confirms the positive diagnosis.
- a complete evaluation comprising analysis of both H-1 and C-13. NMR spectra is more accurate than the proton test alone.
- the resonance peak at 128 ppm is due to linoleic acid, an eighteen carbon polyunsaturated fatty acid with two double bonds. It must be supplied via ones' diet as the body cannot synthesize such fatty acids.
- the resonance peak at 130 ppm is due both to polyunsaturated fatty acids such as linoleic acid and monounsatura ed fatty acids such as oleic acid, an eighteen carbon fatty acid produced by the body. The relative height of these peaks is affected by the cancerous state of the patient.
- linoleic acid contains a double bond pair capable of delocalizing an electron when in the radical state, its radical intermediate has a lower free energy than the oleic acid radical. Free-radical induced oxidation therefore results in a decreased proportion of polyunsaturated fatty acids such as linoleic to monounsaturated fatty acids such as oleic acid and consequently of the resonance peak at 128 ppm relative to that at 130 ppm.
- Linoleic acid is a constituent of triglycerides, cholesterol esters and phospholipids which, are components of. low density lipoproteins (LDL) , the major carrier of cholesterol in the blood. Much of the cholesterol carried by LDL is esterified, principally to linoleic acid. In addition, LDL is made up of phospholipids and a large core protein of 514 kD, protein B-100. All together, LDL is about 22 nm in diameter and has a mass of approximately 3 million daltons. LDL carries cholesterol to peripheral tissues. LDL receptors in coated pits on cell membranes bind protein B-100 and internalize the LDL particles. LDL is broken down inside the cell, and the LDL receptor is returned to the cell membrane.
- LDL low density lipoproteins
- the cholesterol may be incorporated into the cell membrane or stored in the cell in esterified form. Cells which have enough cholesterol stop producing LDL receptors which have a lifespan of about one day.
- TNF tumor necrosis factor
- TNF In addition to its production in response to cancer, TNF is released in response to a variety of other relatively rare and easily definable disease states including malaria, gram negative endotoxin shock, uncontrolled diabetes, AIDS, and organ rejection. Since the 1890's, when TNF-like activities were first described, several TNFs have been isolated and characterized. TNF-a, the original TNF, is the TNF referred to in this application.
- TNF produces very toxic side effects. It has, therefore, been difficult to use TNF for fighting- cancer in humans. It is desirable to find a chemotherapeutic agent which will target cancer cells preferentially.
- the present invention provides several methods for oxidizing lipoproteins for the purpose of treating disease states and photoperoxidation is one of these methods. It is believed, that by adding a photosensitizer such as 8-methoxypsoralen to blood and then irradiating the blood with ultraviolet light, radical intermediates may be produced resulting in generation of hydroxyl radicals. It is believed that these hydroxyl radicals in turn oxidize lipoproteins.
- a photosensitizer such as 8-methoxypsoralen
- diseased cells with an increased number of lipoprotein receptors or an enhanced ability to take up lipoproteins are more susceptible than healthy cells t ⁇ .the cytotoxic effect of oxidized lipoproteins as defined herein.
- One important method for treating diseased states characterized by diseased cells with an increased number of lipoprotein receptors, or an enhanced ability to take up lipoproteins, 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.
- Organic peroxides are capable of generating free-radicals which in turn can peroxidize LDL to fight disease states characterized by diseased cells with an increased number of lipoprotein receptors or an enhanced ability to take up lipoproteins, such as cancer, malaria and viral infections such as acquired immunodeficiency syndrome (AIDS) .
- a second method for treating such disease states using oxidized lipoproteins comprises introducing a therapeutic dose of organic peroxide into a diseased patient together with a chemotherapeutic effector agent, such as taurine or lovastatin, which makes p-LDL more cytotoxic to diseased cells, by further increasing the..number of lipoprotein receptors on a. diseased cell or.
- a chemotherapeutic effector agent such as taurine or lovastatin
- Modified LDL are 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 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.
- the latter method may additionally comprise adding a chemical effector agent as well.
- 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 carbo ⁇ -13 NMR and returned to the patient where the oxidized lipoproteins will come in contact with high metabolism diseased cells, such as cancer cells, where the peroxidized lipoprotein will be taken up by such cells and the cell will be killed.
- a patient's blood, or for that matter., 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, and which contains an agent to increase the diseased 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 oxygen during breathing.
- Perflurocarbon fluosal may also be used to increase the oxygen level in the blood.
- diseased states such as cancer, malaria and viral infections
- AIDS which are characterized by diseased cells with an increased number of lipoprotein receptors or an enhanced ability to take up lipoprotein by increasing the level of oxidized lipoprotein taken up by diseased cells.
- FIG. 1A shows the olefinic region of a C-13 spectrum of a normal human plasma sample
- FIG. IB shows the olefinic region of a C-13 spectrum of a human plasma sample from a person with untreated cancer
- FIG. 2A shows the olefinic region of a 125.8 MHz proton decoupled spectrum from normal human plasma
- FIG. 2B shows the olefinic region of a 125.8 MHz proton decoupled spectrum of the same plasma as in FIG. 1A following the addition of peroxidase (2 mg/ml) , and after 3 aliquots of 3% hydrogen peroxide (100 1/ml) were added at hourly intervals;
- FIG. 3A shows the olefinic region of the spectrum from mouse plasma control
- FIG. 3B shows the olefinic region of a spectrum from a mouse plasma sample treated with tumor necrosis factor
- FIG. 4 shows the free radical intermediates in lipid peroxidation of mono- and diunsaturated fatty acids
- FIG. 5A shows an electron micrograph of a cultured prostate adenocarcinoma cell
- FIG. 5B shows an electron micrograph of a cultured prostate adenocarcinoma cell 1.5 hours after treatment with a 1:40 dilution of peroxidized low density .lipoproteins
- FIG. 5C shows an electron micrograph of a cell as in FIG. 6B, 4 hours after treatment
- FIG. 6 shows the apparatus of the invention
- FIG. 7A is a schematic diagram of the mechanism for producing peroxidized low density lipoproteins as carried out by the human body in response to malignancy;
- FIG. 7B is a schematic diagram of the general method for treating cancer in accordance with the claimed invention.
- FIG. 8 shows a procedure and apparatus for oxidizing the lipoproteins of a patient
- FIG. 9 shows another embodiment of the apparatus for oxidizing the lipoproteins in a blood supply.
- FIG. 10 shows a furt ⁇ ter embodiment of the apparatus far oxidizing the lipoproteins in a blood supply.
- the invention is described in its broadest overall aspects, with a more detailed description following.
- the invention is a method of treating a disease state characterized by the presence of diseased cells with an increased number of lipoprotein receptors or an enhanced ability to take up lipoproteins by absorbing an oxidized lipoprotein, preferably a peroxidized low density lipoprotein, to the diseased cells.
- an oxidized lipoprotein preferably a peroxidized low density lipoprotein
- viruses and virus infections that may be treated by the administration of oxidized lipoproteins include retr ⁇ viruses including HIV, hepatitis, cytomegalovirus, herpes, pneumonia, varicella zooster virus, influenza virus, and others.
- the likely reason for the increased number of- receptors is that these cells have a large appetite and thus require - fuel. Lipids in the lipoproteins are fuel... In accordance with the present invention, it has been discovered that cells with lipoprotein receptors can be destroyed by oxidized lipoproteins.
- the present invention is directed to the many different ways to increase the likelihood that oxidized lipoproteins will be taken up by diseased cells and destroy them. As part of its response to diseases such as cancer, malaria and viral infections such as AIDS, a human host oxidizes lipoproteins circulating in the blood.
- Lipoproteins take various forms in the blood 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 these 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 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 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. Major Classes of Human Plasma Lipoproteins
- any of the four classes can be administered but it is the peroxidized low density lipoproteins that are most effective.
- 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 amino 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.
- Another important characteristic of the lipoprotein is that it be capable of being oxidized, preferably peroxidized by reaction with hydrogen peroxide.
- LDL, HDL and VLDL may be oxidized for the purpose of treatment of disease states.
- whole blood, plasma and serum may be used in accordance with the present invention.
- lipoproteins are oxidized by reaction with horseradish peroxidase and hydrogen peroxide.
- one method for treating disease states such as cancer, malaria and viral infections such as AIDS which are characterized by diseased cells with an increased number of lipoprotein receptors or an enhanced ability to take-up 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 cancer or malaria or 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 such as trilinoleal triglyceride, phospholipids such as dilinoleal phosphatidylcholine, or cholesterol esters such as cholesterol ester of linolei acid.
- Other enzymes and oxidants such as flavins and riboflavin; oxidases such as peroxidase and lipoxidase may also be used per this embodiment.
- FIG.6 illustrates the second embodiment where 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 which is installed through an A-V shunt or arterial bypass.
- 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.
- an immobilized enzyme 52 such as peroxidase or lipoxidase
- an inlet 54 from a pump 56 which can very slowly and precisely introduce a flow of hydrogen peroxide into the blood.
- Blood 53 from the patient's artery enters the module and returns to the patient's vein via 51.
- Both methods of the invention may also include using additional chemical effector agents.
- Taurine NH 2 CH 2 CH 2 S0 3 H/ethanolaminesulfonic acid
- one of the drugs used for reducing cholesterol such as lovastatin (MEVACOR R , C 24 H 36 0 5 , [1S-L1 ,3 ,7 ,8 ,8a 1]-1,2,3,7,8,8a -hexahydro-3,7-dimethyl—8—[2-(tetrahydro—4—hydroxy— 6—oxo—2H— -pyran-2-yl) ethyl]-1-napthale ⁇ yl 2-methylbuta ⁇ ate) may be introduced.
- lovastatin MEVACOR R , C 24 H 36 0 5 , [1S-L1 ,3 ,7 ,8 ,8a 1]-1,2,3,7,8,8a -hexahydro-3,7-dimethyl—8—[2-(tetrahydr
- Such drugs function by increasing the number of lipoprotein receptors on the cell membrane in a known fashion. Increasing the number of lipoprotein receptors increases the lipoprotein intake.
- the p-LDL_ particles are taken up by normal cells as well, but normal cells have a higher tolerance, presumably due to the lower rate of uptake.
- malignant cells are constantly growing, dividing, and synthesizing new membranes and therefore have a much greater intake of LDL.
- p-LDL particles are taken into malignant cells in greater numbers, where they have a cytotoxic effect.
- 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 oxygen during breathing.
- Perflurocarbon fluosal may also be used to increase the oxygen level in the blood.
- patients with disease states characterized by diseased cells with an increased number of lipoprotein receptors are treated by direct administration of peroxidized lipoproteins.
- Peroxidized low density lipoproteins produce the best results.
- This treatment may be further supplemented by administering a chemotherapeutic effector agent, such as taurine or lovastatin, to further increase the number- of lipoprotein receptors on the diseased cells.
- a chemotherapeutic effector agent such as taurine or lovastatin
- FIG. 8 depicts another embodiment of .this invention in. which blood is transferred from a patient 57 to a container 58 the interior walls of which are coated with an immobilized enzyme, such as a lipoxidase, ⁇ r a peroxidase such as horseradish peroxidase.
- a peroxide 59 is added to the container resulting in the formation of oxidized lipoproteins which are then transferred back to the patient 57.
- FIG. 9 depicts still another embodiment of this invention wherein a blood supply 60 is secured. It may be from a patient, a donor or any other compatible blood source.
- the blood 60 and an oxidant 61, 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 63 until needed for treatment.
- FIG. 7A illustrates how the cytotoxicity of p-LDL helps to fight cancer in humans.
- a cancer cell 30 is sensed by a macrophage 32 which secretes TNF 34.
- the TNF 34 induces PMN to undergo a respiratory burst to release superoxide, 0 2 *
- the superoxide causes the formation of hydroxyl free-radicals, 'OH which in turn oxidize LDL 33 to p-LDL 35 while being converted into hydroxide ions, OH.
- the p-LDL 35 exert their cytotoxic effect on malignant cells 36 leading to cell death.
- the malignant cells 36 killed,by p-LDL 35 may be the same or different than the originally sensed tumor cell 30.
- FIG. 7B illustrates the method of the present invention.
- Low density lipoproteins 33 will be converted: directly to p-LDL by exposure to a chemical agent 40.
- the agent 40 is ditertiarybutyl peroxide.
- the agent 40 is peroxidase together with peroxide.
- a chemotherapeutic effector agent 44 induces the production of LDL receptors 46 which enhance the cytotoxic effect of p-LDL.
- the malignant cell 36 will die in preference to normal cells.
- FIG. 1A shows the olefinic region of a spectrum from a normal plasma sample.
- the ratio of the peak at 128-129 to the peak at 130-131 is near one.
- FIG. IB shows the same region of a spectrum of a blood sample from a patient having untreated cancer.
- the ratio of the peak at 128-129 ppm of resonance frequency to the peak at 130-131 ppm is substantially less than 0.9. This decreased ratio indicates a cancerous condition, as described in patent No. 4,912,050.
- the decreased ratio is caused by the oxidation of linoleic acid, the fatty acid which produces the signal at 128 ppm.
- 2A & B show the olefinic region of 125.8 MHz proton decoupled C-13 spectra from normal human plasma and the same plasma following the addition of peroxidase (2mg/ml) and 3 aliquots of 3% hydrogen peroxide (100 1/ml) at hourly- intervals.
- the 128/130 ratio was substantially decreased following treatment.
- in vitro oxidation produces a shift in the olefinic region of the spectrum similar to that caused by the host's own response to cancer.
- FIGS. 3A and B show the olefinic region of - mouse plasma sample control and two hours af *,r treatment with tumor necrosis factor (TNF) , respectively. It shows the same reduced ratio (128/130) as seen in the untreated cancer and peroxidized samples.
- TNF tumor necrosis factor
- Linoleic acid is oxidized to a much greater extent than oleic acid, both by the host as a response to cancer and by peroxidase in vitro.
- Oleate 11, as shown in FIG. 4, contains only a single cis double bond 12.
- the double bond 12 serves an important role in preserving the fluidity of cell membranes, however, it is capable of only minimal stabilization of a free radical intermediate 13. Since the method of oxidation both naturally and in vitro is through hydroxyl free-radical (“OH) induction, oleate 11 is only minimally oxidized. Linoleate 14, however, contains two unconjugated double bonds 15, 16, as shown in FIG. 4.
- a radical 17 is formed by removal of a proton; the easiest protons 18, 19 to remove are from the methylene group 21 between the two double bonds 15,16.
- the free radical intermediate 17 is very stable, i.e. has a low free energy compared to an oleic acid-derived radical, because the lone electron is delocalized across the now conjugated double bond system. Accordingly, the reaction to produce the free radical intermediate 17 of linoleate 14 is much more thermodynamically favored and therefore much (about twenty times) faster than for oleate 11, and linoleate 14 is oxidized to a much greater degree.
- the cytotoxic activity of peroxidized low density lipoproteins was investigated.
- P-LDL were prepared by treating lipoproteins with peroxide in the presence of horseradish peroxidase. Lipid peroxidation was monitored using C-13 NMR. In all experiments, one control was a solution of media containing peroxidase to which peroxide had been added, but which contained no LDL. In all instances, this control produced no effect.
- FIGS. 2A & B show the C-13 spectra of LDL before and after peroxide treatment, respectively.
- the p-LDL used had a 128/130 ratio of less than 0.8. Cytotoxicity increases with a decreasing ratio.
- the p-LDL were tested for cytotoxicity on a variety of malignant and non-malignant cells in culture. P-LDL kill all cells when a high enough dose is used, but malignant cells require much lower levels of p-LDL than non-malignant cells.
- FIG. 5A shows an electron micrograph of a control prostate adenocarcinoma cell 20.
- the cytoplasm 22 looks normal and the mitochondria 24 are intact.
- FIGS. 5B & C show electron micrographs of prostate adenocarcinoma cells 20 at 1.5 and at 4 hours after treatment with a 1:40 dilution of p-LDL, respectively.
- FIGS. 5B & C show the formation of cytoplasmic blebs 26 and the disruption of mitochondria 24 which were virtually converted to vacuoles 28.
- P-LDL was also used to kill Colo205, a colon adenocarcinoma; HepG2, a hepatoblastoma; and "Alexander cells, " a hepatocarcinoma line.
- U937 cells In comparing two pairs of malignant:"normal" cells for relative sensitivity to p-LDL toxicity, U937 cells, a transformed monocyte-like line was compared to a monocyte fraction, and mesothelioma cells were compared to mesothelial cells.
- the U937 cells were completely dead in 24 hours with a dose of p-LDL at 1:60 dilution, but the normal monocytes were more than 80% viable even at a dose of 1:10 dilution of p-LDL. A similar difference was observed for the second pair.
- sensitivity which makes it possible to bolster the systemic level of p-LDL in a cancerous patient to fight cancer while not substantially injuring the. patient.
- Adriamycin (Ad) and other molecules of its class have long been used as chemotherapeutic agents effective against certain types of cancer. They also have been suspected of generating free-radicals. The mechanism for such action is unknown, but two possible mechanisms are shown,below:.
- Low density lipoprotein is obtained from Sigma Chemical, catalog no. L2139, or prepared from fresh human or animal plasma by standard methods.
- Lindren FT Silvers A, Jutagir R, Layshot L, Bradley DD. Lipids 1977; 12:278-282 and Lindren FT, Adamson GL, Jensen L.C, Wood PD. Lipids 1975; 10:750-756.
- Oxidized low density lipoprotein is prepared using either soluble horseradish peroxidase (Ehzyme Commission Classification No. 1.11.1.7) or immobilized . horseradish peroxidase as a catalyst.
- the immobilized enzyme has the advantage that it can be removed from the solution of oxidized low density lipoprotein before use.
- Each ml of low density lipoprotein.solution (5 ⁇ .mg. protein - per ml) is diluted with an equal volume of Dulbeccc s phosphate buffered saline, and peroxidase of either form is added to a level of 800-1000 units per ml of solution.
- 0.1 ml of 3% hydrogen peroxide, H 2 0 2 is added per ml of low density lipoprotein solution.
- the solution is maintained at room temperature and 0.1 ml of peroxide solution per ml low density lipoprotein solution is added each hour for two hours.
- a C-13 spectrum is obtained on the oxidized low density lipoprotein solution to determine the extent of lipid peroxidation as measured by the 128/130 ppm ratio.
- the preparation is stored at 2-6° C.
- Peroxidized low density lipoprotein is prepared by treating 5 mg of protein/ml human low density lipoprotein (as described in Example 1) with 2 mg/ml of horseradish peroxidase Type II. This is followed by the addition of 70 to 200 liters of 3% hydrogen peroxide in one or two equal aliquots, the second addition being made several hours after the first addition.
- the peroxidation level is measured by the ratio of the intensity of the resonances at 128 and 130 ppm in the solution's carbon—13 NMR spectrum. A lower ratio indicates a reduction of the amount of polyunsaturated fatty acid side chains in the lipoprotein lipids.
- the 128/130 ppm ratio is typically greater than 0.9 before peroxidation and between 0.7 and 0.85 after peroxidation.
- This technique can be employed wit -any lipoprotein. It. is particularly desirable to peroxidize low density lipoproteins. Peroxidized low density lipoprotein, prepared by the aforementioned technique, was added to cultured cells at a variety of dilutions. The cultured cancerous cells were readily killed by the peroxidized low density lipoproteins.
- Oxidized lipoproteins were prepared by reacting 8-methoxypsoralen with lipoprotein-containing plasma and ultraviolet light.
- 8-methoxypsoralen was added to two aliquots of plasma and those aliquots as well as two control aliquots were irradiated with the same type of light as that used by Edelson et al.
- the control plasma showed no change in the 128/130 ppm C-13 ratio following 30 minutes of ultraviolet A irradiation (the ratio was 0.98 before and 0.97 afterwards).
- the 8-methoxypsoralen containing plasma showed a reduction of the ratio from a pre-irradiation value of 0.98 to 0.77 following 30 minutes of light treatment.
- free-radical induced oxidation appears to occur and may be responsible for the therapeutic effect observed by Edelson et al
- Oxidized lipoproteins were prepared by the addition of adriamycin to six aliquots of normal plasma and bubbling intermittently with 95% 0 2 :5% C0 2 . An equal amount of adriamycin was also added to six additional aliquots of plasma and bubbled similarly with 95% N 2 :5% C0 2> The ratio of the 128/130 ppm resonances changed as shown in the Table below. The lower ratio, as compared with the control sample indicates that peroxidation has occurred. Adriamycin mediated lipid peroxidation occurred in the presence of oxygen but not in its absence.
- a cholesterol lowering drug such as lovastatin
- lovastatin is administered orally or intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Selectivity is.based on. the fact that malignant cells,grow, divide and synthesize new membranes at a much greater rate than noncancerous cells and thus have a much greater intake of the cytotoxic low density lipoproteins.
- Lipoproteins are one source of fuel for a cell's metabolism. Tauri ⁇ e ..
- a cholesterol lowering drug such as lovastatin
- lovastatin is administered orally or intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Selectivity is based on the fact that malignant cells grow, divide and synthesize new membranes at a much greater rate than noncancerous cells and thus have a much greater intake of the cytotoxic low density lipoproteins.
- Lipoproteins are one source of fuel for a cell's metabolism. Taurine (NH 2 CH 2 CH 2 S0 3 H/ethanolamine- sulfonic acid) may also be used to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- peroxidized low density lipoprotein is injected intravenously.
- the growth of the tumor is monitored by conventional methods and the peroxidized low density lipoprotein dose is adjusted accordingly.
- peroxidized low density lipoprotein is injected intravenously.
- the growth of the tumor 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 growth of the tumor is monitored by conventional methods and the ditertiary butyl peroxide dose adjusted accordingly.
- a cholesterol lowering drug such as lovastatin, may also be injected intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Taurine NH 2 CH 2 CH 2 S0 3 H/ethanolaminesulfonic acid
- Taurine NH 2 CH 2 CH 2 S0 3 H/ethanolaminesulfonic acid
- the patient's blood oxygen supply may also be augmented by inhalation of elemental oxygen or by i.v. injection of perflurocarbon 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.
- 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 peroxidizes the plasma lipoproteins. in the presence of the hydrogen peroxide.
- a cholesterol lowering drug such as lovastatin
- lovastatin is administered orally or intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Selectivity is based on the fact that malaria-infected cells have a higher metabolism rate than healthy cells and thus have a much greater intake of the cytotoxic low density lipoproteins.
- Lipoproteins are one source of fuel for a cell's metabolism.
- Taurine (NH 2 CH 2 CH 2 S0 3 H/ethanolamine-sulfonic acid) may also be used to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Table I below shows results of an experiment where over a 12 hour period malaria-infected red blood cells were treated with several different agents, in accordance with the present invention. Table I shows the cell count of treated cells as compared to the cell count of untreated cells.
- a cholesterol lowering drug such as lovastatin
- lovastatin is administered orally or intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- Selectivity is based on the fact that malaria-infected cells have a higher metabolism rate than healthy cells and thus have a much greater intake of the cytotoxic low density lipoproteins.
- Lipoproteins are one source of fuel for a cell's metabolism.
- Taurine (NH 2 CH 2 CH 2 S0 3 H/ethanolamine-sulfonic acid) may also be used to increase the number of low density lipoprotein receptors on the diseased cell membranes ⁇
- peroxidized low density lipoprotein is injected intravenously.
- the progress of the malaria 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 malaria 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 malaria infection is monitored by conventional methods and the ditertiarybutyl peroxide dose adjusted accordingly.
- a cholesterol lowering drug such as lovastatin, may also be administered orally or intravenously to increase the number of low density lipoprotein receptors on the diseased cell membranes.
- the patient's blood oxygen supply may also be augmented by inhalation of elemental oxygen or by i.v. injection of perflurocarbon 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 peroxidizes the plasma lipoproteins in the presence of the hydrogen peroxide.
- 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.
- oxidized LDL The effect of oxidized LDL on HIV-infected cells was tested in an independent laboratory with the following results.
- CR10 cells chronically infected with HIV-1/NIT virus and Phytohemagglutinin stimulated cultured peripheral blood mononuclear cells from individuals negative for HIV-1 antibody were incubated with an oxidized form of LDL. After 48 hours of incubation, exclusion assays were performed to determine cell survival following treatment with LDL.
- the Trypan Blue Exclusion assay results show that oxidized LDL has a selectively toxic effect on HIV-1 infected cells. See Table I below for specific test results.
- 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.
- 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 perflurocarbon 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 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 a theoretically healthy individual.
- the lipoproteins of the blood supply are then oxidized by adding an oxidant to the blood, thus producing of 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 oxidized lipoproteins are added to the same blood supply.
- the oxidized lipoprotein-containing blood may be stored until used.
- 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 perflurocarbon fluosal to the blood.
- the lipoprotein content of the blood could also be augmented by adding lipoproteins enriched with triglycerides, phospholipids, or cholesterol esters.
- a chemotherapeutic effector agent may be added to the blood to further increase the number of lipoprotein receptors on the diseased cells or to further enhance the diseased cells' ability to take-up lipoproteins.
- Taurine and lovastatin are examples of such agents.
- 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. 10, 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 exits from the top of the container.
- the oxidized lipoprotein-containing blood 74 is 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 (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR909007721A BR9007721A (en) | 1989-10-06 | 1990-10-04 | PROCESS AND APPARATUS FOR TREATING A DISEASE STATUS AND PROCESS FOR THE PREPARATION OF LOW DENSITY OXIDATED LIPOPROTELNA |
FI921431A FI921431A (en) | 1989-10-06 | 1992-04-01 | FOERFARANDE FOER ANVAENDNING AV OXIDERADE LIPOPROTEINER. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41838289A | 1989-10-06 | 1989-10-06 | |
US418,382 | 1989-10-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991004744A1 true WO1991004744A1 (en) | 1991-04-18 |
Family
ID=23657894
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1990/005680 WO1991004744A1 (en) | 1989-10-06 | 1990-10-04 | Methods and apparatus for treating disease states using oxidized lipoproteins |
PCT/US1990/005679 WO1991005536A2 (en) | 1989-10-06 | 1990-10-04 | Novel oxidized lipoproteins and methods for their preparation |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1990/005679 WO1991005536A2 (en) | 1989-10-06 | 1990-10-04 | Novel oxidized lipoproteins and methods for their preparation |
Country Status (7)
Country | Link |
---|---|
EP (2) | EP0494992A4 (en) |
JP (2) | JPH05500963A (en) |
AU (2) | AU7040091A (en) |
BR (2) | BR9007725A (en) |
CA (2) | CA2067364A1 (en) |
FI (2) | FI921431A (en) |
WO (2) | WO1991004744A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992017173A2 (en) * | 1991-04-02 | 1992-10-15 | Jean Berque | Use of riboflavin for treating hiv-related diseases, herpes, retinitis pigmentosa and malaria |
WO2004096368A1 (en) * | 2003-04-25 | 2004-11-11 | Hamburger Stiftung Zur Förderung Von Wissenschaft Und Kultur | Treatment of hi-virus infections with oxidised blood proteins |
WO2006059082A1 (en) * | 2004-11-30 | 2006-06-08 | Trigen Limited | Oxidised lipids as reversal agents for boronic acid drugs |
EP1994941A3 (en) * | 2000-10-20 | 2012-07-25 | Hamburger Stiftung zur Förderung von Wissenschaft und Kultur | Medicine containing at least one oxidised protein |
US9551768B2 (en) | 2013-03-15 | 2017-01-24 | East Carolina University | NMR method for monitoring changes in the core of lipoprotein particles in metabolism and disease |
US10775458B2 (en) | 2018-03-05 | 2020-09-15 | Texas Tech University System | Method and system for non-invasive measurement of metabolic health |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994023302A1 (en) * | 1993-04-07 | 1994-10-13 | The Australian National University | Immunological assay of oxidatively modified human low density lipoproteins in plasma |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2095338A (en) * | 1927-08-20 | 1937-10-12 | Ig Farbenindustrie Ag | Process for oxidizing organic substances in the liquid phase and apparatus therefor |
US2095388A (en) * | 1935-08-03 | 1937-10-12 | Bendix Radio Corp | Electrical regulator apparatus |
US3655700A (en) * | 1970-02-02 | 1972-04-11 | Zoecon Corp | Oxygenated unsaturated aliphatic carboxylic acids and esters |
US4226713A (en) * | 1978-04-24 | 1980-10-07 | Goldberg Jack M | Diagnostic agents |
JPS5810056A (en) * | 1981-07-10 | 1983-01-20 | 株式会社クラレ | Blood purifying apparatus |
DD243714A1 (en) * | 1985-10-08 | 1987-03-11 | Akad Wissenschaften Ddr | PROCESS FOR STABILIZING IMMOBILIZED GLUCOSE OXIDASE |
-
1990
- 1990-10-04 CA CA002067364A patent/CA2067364A1/en not_active Abandoned
- 1990-10-04 BR BR909007725A patent/BR9007725A/en not_active Application Discontinuation
- 1990-10-04 WO PCT/US1990/005680 patent/WO1991004744A1/en not_active Application Discontinuation
- 1990-10-04 JP JP3502153A patent/JPH05500963A/en active Pending
- 1990-10-04 BR BR909007721A patent/BR9007721A/en not_active Application Discontinuation
- 1990-10-04 CA CA002067356A patent/CA2067356A1/en not_active Abandoned
- 1990-10-04 AU AU70400/91A patent/AU7040091A/en not_active Abandoned
- 1990-10-04 JP JP2515223A patent/JPH05501258A/en active Pending
- 1990-10-04 EP EP19900916422 patent/EP0494992A4/en not_active Withdrawn
- 1990-10-04 EP EP19910901910 patent/EP0495014A4/en not_active Withdrawn
- 1990-10-04 AU AU70452/91A patent/AU7045291A/en not_active Abandoned
- 1990-10-04 WO PCT/US1990/005679 patent/WO1991005536A2/en not_active Application Discontinuation
-
1992
- 1992-04-01 FI FI921431A patent/FI921431A/en not_active Application Discontinuation
- 1992-04-01 FI FI921430A patent/FI921430A0/en not_active Application Discontinuation
Non-Patent Citations (5)
Title |
---|
CHRISTOPHERSON, Biochim, Biophys Acta 1968 164(1) 35-46 CHEMICAL ABSTRACTS, Volume 69, 1968 Abstract 84736e. * |
GARNER, et al Lipids, 1984 19(11) 863-8 CHEMICAL ABSTRACTS, Volume 102, 1985 Abstract 42042v. * |
HATZELMANN, et al Eur J. Biochem 1989 180(3) 527-33 CHEMICAL ABSTRACTS, Volume 110, 1989, Abstract 171599w. * |
POKORNY, et al Tluszcze Srodki Piorace Kosmet 1971 15(5) 35 CHEMICAL ABSTRACTS, Volume 78, 1973 Abstract 39713v. * |
See also references of EP0494992A4 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992017173A2 (en) * | 1991-04-02 | 1992-10-15 | Jean Berque | Use of riboflavin for treating hiv-related diseases, herpes, retinitis pigmentosa and malaria |
WO1992017173A3 (en) * | 1991-04-02 | 1993-01-07 | Jean Berque | Use of riboflavin for treating hiv-related diseases, herpes, retinitis pigmentosa and malaria |
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 |
WO2004096368A1 (en) * | 2003-04-25 | 2004-11-11 | Hamburger Stiftung Zur Förderung Von Wissenschaft Und Kultur | Treatment of hi-virus infections with oxidised blood proteins |
AP2248A (en) * | 2003-04-25 | 2011-07-12 | Hamburger Stiftung Zur Forderung Von Wissenschaft Und Kultur | Treatment of HI-virus infections with oxidised blood proteins. |
US20130142779A1 (en) * | 2003-04-25 | 2013-06-06 | Hamburger Stiftung Zur Foerderung Von Wissenschaft Und Kultur | Treatment of Hi-Virus infections with oxidised blood proteins |
WO2006059082A1 (en) * | 2004-11-30 | 2006-06-08 | Trigen Limited | Oxidised lipids as reversal agents for boronic acid drugs |
US9551768B2 (en) | 2013-03-15 | 2017-01-24 | East Carolina University | NMR method for monitoring changes in the core of lipoprotein particles in metabolism and disease |
US10613169B2 (en) | 2013-03-15 | 2020-04-07 | East Carolina University | Methods for monitoring changes in the core of lipoprotein particles in metabolism and disease |
US10775458B2 (en) | 2018-03-05 | 2020-09-15 | Texas Tech University System | Method and system for non-invasive measurement of metabolic health |
Also Published As
Publication number | Publication date |
---|---|
EP0495014A4 (en) | 1993-07-28 |
CA2067356A1 (en) | 1991-04-07 |
CA2067364A1 (en) | 1991-04-07 |
BR9007725A (en) | 1992-08-18 |
EP0494992A4 (en) | 1993-03-31 |
JPH05501258A (en) | 1993-03-11 |
WO1991005536A3 (en) | 1991-08-08 |
FI921431A0 (en) | 1992-04-01 |
FI921430A (en) | 1992-04-01 |
FI921430A0 (en) | 1992-04-01 |
AU7040091A (en) | 1991-04-28 |
BR9007721A (en) | 1992-08-18 |
AU7045291A (en) | 1991-05-16 |
JPH05500963A (en) | 1993-02-25 |
WO1991005536A2 (en) | 1991-05-02 |
EP0495014A1 (en) | 1992-07-22 |
EP0494992A1 (en) | 1992-07-22 |
FI921431A (en) | 1992-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5192264A (en) | Methods and apparatus for treating disease states using oxidized lipoproteins | |
Fuhrman et al. | Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties | |
US5366440A (en) | Methods for treating disease states using oxidized lipoproteins in conjunction with chemotherapeutic effector agents | |
Ross et al. | Increased levels of ethane, a non-invasive marker of n-3 fatty acid oxidation, in breath of children with attention deficit hyperactivity disorder | |
US20050238623A1 (en) | Method for treating mammals with modified mammalian blood | |
JPH0671482B2 (en) | Device for externally treating blood | |
JPH08501278A (en) | Selective cell inactivation in blood | |
WO1991004744A1 (en) | Methods and apparatus for treating disease states using oxidized lipoproteins | |
WO2015164780A1 (en) | Nanoparticle therapy in cancer | |
Deng et al. | Inhibition of caveolae contributes to propofol preconditioning-suppressed microvesicles release and cell injury by hypoxia-reoxygenation | |
CA2217551C (en) | Photoactivated hypericin and the use thereof | |
US5571082A (en) | Method of producing therapeutic effect upon an organism to reduce the pathologic lymphocyte population | |
JPS63192718A (en) | Drug for suppressing hepatopathy | |
US5217716A (en) | Method for treating viral infections using oxidized lipoproteins | |
Hagerty et al. | The processing and presentation of the self-antigen hemoglobin. Self-reactivity can be limited by antigen availability and costimulator expression. | |
WO1992001467A1 (en) | Method for treating viral infections using oxidized lipoproteins | |
JP2005508829A (en) | Apoptotic bodies for use in the treatment of endothelial dysfunction | |
CA2269364A1 (en) | Treatment of inflammatory and allergic disorders | |
Lankin et al. | Modification of lipoprotein (a) by natural dicarbonyls induced their following free radical peroxidation | |
CN116421741A (en) | Engineering platelet and preparation method and application thereof | |
CN112915104A (en) | Application of copper sulfide, copper sulfide nanocomposite and preparation method and application thereof | |
CN116407545A (en) | Novel aggregation-induced emission substance targeted delivery triple therapy for tumor chemotherapy and radiotherapy immunotherapy | |
CN117337974A (en) | Lycopene preparation and preparation method thereof | |
Bugaj et al. | Photostability of lipid components of human blood plasma lipoproteins during exposure to long wave ultraviolet radiation (UV-A) alone and in the presence of 8-methoxypsoralen | |
Andreu et al. | The role of UV irradiation in the prevention of HLA alloimmunization and in therapeutic apheresis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA FI JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 921431 Country of ref document: FI |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2067356 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1990916422 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1990916422 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1990916422 Country of ref document: EP |