WO1993015778A1 - Procede permettant l'inhibition de l'agregation des plaquettes sanguines - Google Patents

Procede permettant l'inhibition de l'agregation des plaquettes sanguines Download PDF

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Publication number
WO1993015778A1
WO1993015778A1 PCT/GB1993/000258 GB9300258W WO9315778A1 WO 1993015778 A1 WO1993015778 A1 WO 1993015778A1 GB 9300258 W GB9300258 W GB 9300258W WO 9315778 A1 WO9315778 A1 WO 9315778A1
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WO
WIPO (PCT)
Prior art keywords
blood
ozone
treatment
aggregation
ozone gas
Prior art date
Application number
PCT/GB1993/000258
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English (en)
Inventor
Anthony Ernest Bolton
Original Assignee
Anthony Ernest Bolton
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anthony Ernest Bolton filed Critical Anthony Ernest Bolton
Publication of WO1993015778A1 publication Critical patent/WO1993015778A1/fr

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Classifications

    • 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
    • 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
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0023—Agression treatment or altering
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3681—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/32—Oxygenators without membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0216—Ozone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/02—Gases
    • A61M2202/0266—Nitrogen (N)
    • A61M2202/0275—Nitric oxide [NO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/05—General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/051—General characteristics of the apparatus combined with other kinds of therapy with radiation therapy
    • A61M2205/053—General characteristics of the apparatus combined with other kinds of therapy with radiation therapy ultraviolet

Definitions

  • Platelets are the smallest of the formed elements ' of the blood. Every cubic millimeter of blood contains about 250 million platelets, as compared with only a few thousand white cells. There are about a trillion platelets in the blood of an average human adult. Platelets are not cells, but are fragments of- the giant bone-marrow cells called megakaryocytes. When a megakaryocyte matures, its cytoplasm breaks up, forming several thousand platelets. Platelets lack DNA and have little ability to synthesize proteins. When released into the blood, they circulate and die in about ten days. However, platelets do possess an active metabolism to supply their energy needs.
  • platelets contain a generous amount of contractile protein (actomyosin) , they are prone to contract much as muscles do. This phenomenon explains the shrinkage of a fresh blood clot after it stands for only a few minutes. The shrinkage plays a role in forming a hemostatic plug when a blood vessel is cut.
  • the primary function of platelets is that of forming blood clots. ' When a wound occurs, platelets are attracted to the site where they activate a substance (thrombin) which starts the clotting process. Thrombin, in addition to converting fibrinogen into fibrin, also makes the platelets sticky. Thus, when exposed to collagen and thrombin, the platelets aggregate to form a plug in the hole of an injured blood vessel.
  • Platelets not only tend to stick to one another, but to the walls of blood vessels as well. Because they promote clotting, platelets have a key role in the formation of thrombi. The dangerous consequences of thrombi are evident in many cardiovascular and cerebrovascular disorders.
  • a number of disease states in humans are believed to be associated with an aggregation of platelets in the blood.
  • These platelet aggregation associated conditions include: peripheral vascular disease; thrombotic diseases such as coronary thrombosis and pulmonary thrombosis; stroke; eclampsia and pre-ecla psia; and hypertension.
  • thrombotic diseases such as coronary thrombosis and pulmonary thrombosis
  • stroke eclampsia and pre-ecla psia
  • hypertension a study completed by the University of Oxford, England, and published in the British Medical Journal, Vol. 296, January 30 1988, pages 320-331, entitled "Secondary Prevention of Vascular Disease by Prolonged Antiplatelet Treatment"
  • therapies which inhibit platelet aggregation may be useful for treating occlusive vascular disease.
  • the study utilised aspirin, sulphinpyrazone, or aspirin and dipyridamole as the platelet aggregati
  • a method of treating blood which comprises contacting the blood with a blood platelet-aggregation inhibiting effective amount of ozone gas and ultraviolet radiation.
  • the ozone gas has a concentration of from about 0.5 to about 100 ⁇ g/ l.
  • the ozone gas has a concentration of from about 5 to about 50 ⁇ g/ml.
  • the ultraviolet radiation has a wavelength of from about 253.7 nm.
  • the blood is heated to a temperature of from about 0 to about 56°C while being contacted with the ozone gas and ultraviolet radiation.
  • the preferred temperature ranges from 37 to 43°C and the preferred temperature is 42.5°C.
  • the method is employed on a 10 ml aliquot of blood.
  • the blood is contacted with the ozone gas and ultraviolet radiation for a period of about 3 minutes.
  • the blood may be human blood.
  • the invention relates to blood treated by a method as described above and also relates to the use of blood treated by a method as described above and a method as described above in the preparation of a medicament.
  • the medicament may be for the treatment of peripheral vascular disease, a thrombotic disease, coronary thrombosis, pulmonary thrombosis, stroke, pre-eclampsia, and hypertension.
  • the term "aggregation of blood platelets” as used herein refers to the sticking together of platelets to other platelets and/or to the walls of a blood vessel.
  • the ozone gas used in connection with the inventive method has a concentration of ozone of from about 0.5 to about 100 ⁇ g/ml.
  • the ozone gas has a concentration of from about 5 to about 50 ⁇ g/ml.
  • Ultraviolet radiation having a wavelength of about 253.7 n has been found to provide the results of the invention, when utilized in conjunction with the ozone gas treatment. It is believed that ultraviolet radiation having emission wavelengths corresponding to standard UV-A and UV-B sources would also provide acceptable results.
  • the blood is preferably heated to a temperature of from about 0 to about 56 °C while being contacted with the ozone gas and ultraviolet radiation.
  • the blood is preferably heated to about 37-43 °C, most preferably about 42.5 °C, while being contacted with the ozone gas and ultraviolet radiation.
  • the aliquot of blood treated by the inventive technique is withdrawn from the human patient in any conventional manner known in the art.
  • the method preferably involves removing about 10 ml of blood, treating the same with ozone gas and ultraviolet radiation, then returning the treated blood to the patient by intramuscular injection.
  • Other conventional techniques or readministering the blood may be employed, such as intravenous injection, subcutaneous injection, and intraperitoneal injection.
  • the readministration of small volumes of host blood in this fashion is termed micro-auto-hemotherapy.
  • the invention also contemplates an embodiment wherein the blood is continuously removed from the patient's body and circulated through an apparatus which treats the blood with ozone gas and ultraviolet light before returning the blood to the patient. This procedure would have particular utility, for example, during the performance of operative procedures, such as coronary bypass surgery.
  • the blood is contacted with the ozone gas and ultraviolet radiation for a period of time sufficient to effectively inhibit the aggregation of blood platelets.
  • the method should be carried out under sterile conditions known to those of ordinary skill in the art.
  • the method of the invention may be carried out using conventional apparatus for ozonating blood and irradiating blood with ultraviolet light known to those skilled in the medical art.
  • an apparatus as disclosed in U.S. Patent No. 4,968,483 is employed to carry out the method of the invention.
  • the disclosure of U.S. Patent No. 4,968,483 is incorporated herein in its entirety by reference.
  • a method of inhibiting the aggregation of blood platelets in a human which comprises:
  • the invention also contemplates a method of treating a condition in a human associated with blood platelet aggregation, which comprises:
  • the method of inhibiting blood platelet aggregation provided by the invention will have therapeutic utility for treating a wide range of disease states associated with the aggregation of blood platelets in humans.
  • treating refers to the alleviation or prevention of a particular disorder. In the case of traumatic conditions such as stroke, preventative treatment is obviously preferred. Also, although the term
  • peripheral vascular disease peripheral vascular disease
  • arterial and venus disorders including thrombotic diseases such as coronary thrombosis, pulmonary thrombosis, arterial thrombosis, and venus thrombosis
  • stroke pre-eclampsia
  • hypertension hypertension
  • peripheral vascular disease the disease is thought to be associated with a reduction of endothelial- derived relaxing factor (EDGF) , low levels of which lead to a contraction of the smooth muscle of blood vessels, and hence a reduction in the diameter of the lumen of the vessel and a reduction in blood flow.
  • EDGF endothelial- derived relaxing factor
  • the major naturally occurring EDGF is nitric oxide.
  • nitric oxide stabilizes blood platelets, reducing their aggregation.
  • An increase in EDGF (nitric oxide) levels therefore, has a double beneficial effect on the circulatory system: it inhibits aggregation of platelets, making the blood more fluid, and it enlarges the diameter of the vessels, improving the flow.
  • the reverse, a reduction in nitri oxide levels is present in peripheral vascular disease.
  • the method of th invention is believed to increase nitric oxide levels in the blood, which may explain the mode of action in the inventive treatment of peripheral vascular disease and other conditions associated with blood platelet aggregation.
  • Pre-eclampsia may lead to eclampsia, an acute hypertensive crisis that may occur in the second or third trimester of pregnancy.
  • overactive platelet activity leading to the formation of thrombi in the placenta is believed to be a cause of the condition.
  • the inventive method which results in a stabilization of the patient's blood platelets and an inhibition of platelet aggregation, is therefore a potential treatment modality.
  • the method of the invention may be preferred over conventional antiplatelet therapies, where the administration of drugs to the mother is counterindicated.
  • the second 10 ml aliquot from each sample served as an untreated control.
  • Platelets were isolated from the control or treated samples by centrifugation, and their ability to aggregate in response to different concentrations of ADP (a natural platelet stimulator) was measured in an aggregometer.
  • a sample of both ozone-treated and untreated blood was used for quantitation of platelet numbers, using a Coulter counter.
  • aliquots of the blood were treated with different concentrations of ozone.
  • the blood was treated in the presence and absence of UV- light irradiation.
  • Platelet aggregation in the ozone-treated blood was expressed as a percentage of aggregation in the same-person untreated control blood.
  • the total platelet counts before and after ozone/UV treatment do not indicate a major loss of platelets from the blood as a result of ozonization.
  • ADP (0.01 M) in the presence or absence of ozone.
  • Example 1 the results of Example 1 indicate that the in vitro treatment of an"aliquot of blood with ozone gas and ultraviolet light inhibits the aggregation of blood 2D platelets.
  • This platelet inhibition has been found to be dose related to the ozone concentration. Further, platelet inhibition was found to critically depend on the combined treatment of ultraviolet light and ozone gas, as evidenced in Tables 4 and 5. Treatment with ozone gas alone resulted in minimal inhibition of platelet aggregation, while treatment with ultraviolet light alone produced no inhibition of platelet aggregation.
  • Nitric Oxide In order to elucidate the mechanism whereby ozonization/ UV light affects the aggregation of platelets in treated blood, the concentration of certain oxidized forms of nitrogen were measured.
  • nitric oxide is an intermediate in a metabolic pathway in which arginine is converted to citrulline.
  • Other stable end-products are nitrates and nitrites.
  • the nitric oxide content for several samples of blood treated with ultraviolet light and ozone gas according to Example 1 were indirectly determined by measuring the combined nitrate plus nitrite concentrations in the samples before and after treatment with ozone/UV light, after converting nitrite to nitrate.
  • nitrate plus nitrite concentrations after treatment according to the invention. This increase was consistently found in samples treated with ozone gas/UV light.
  • nitric oxide levels may be enhanced by the treatment with ozone gas/UV light, and this may be part of the mode of action by which an inhibition of blood platelet aggregation is achieved by the invention. This therapeutic effect would be consistent with the etiology of peripheral vascular disease described above.
  • the inhibitory effect is at least partiall dependent on the concentration of ADP, ozone being mor inhibitory at lower ADP concentrations. This may b interpreted as the higher agonist concentrations partiall overcoming the inhibitory effect of ozone b "hyperstimulating" the platelets. This suggests that th inhibition is at least partially reversible, and is probabl not acting by destroying the platelet's ability t aggregate.
  • the inhibitory effect appears to be dose related t ozone concentration, with higher concentrations of ozon resulting in a greater inhibition of platelet aggregation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
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  • Engineering & Computer Science (AREA)
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  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
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Abstract

Procédé de traitement du sang dans lequel on met le sang en contact avec une dose efficace d'ozone (sous forme de gaz) et de rayons ultraviolets inhibant l'agrégation plaquettaire. On peut administrer le sang à un patient tel que l'homme, pour inhiber l'agrégation des plaquettes sanguines.
PCT/GB1993/000258 1992-02-07 1993-02-08 Procede permettant l'inhibition de l'agregation des plaquettes sanguines WO1993015778A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83279892A 1992-02-07 1992-02-07
US07/832,798 1992-02-07

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WO1993015778A1 true WO1993015778A1 (fr) 1993-08-19

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034613A1 (fr) * 1995-05-05 1996-11-07 Vasogen Inc. Effets de revetement endothelial et traitement de troubles vasospastiques
US6086552A (en) * 1997-05-27 2000-07-11 Vasogen, Inc. Treatment of chronic post-traumatic pain syndromes
WO2000041705A1 (fr) * 1999-01-12 2000-07-20 Vasogen Ireland Limited Pretraitement contre la mort des cellules
WO2000029003A3 (fr) * 1998-11-13 2000-08-31 Vasogen Ireland Limited Technique de prevention et favorisant la regression de l'atherosclerose chez les mammiferes
US6264646B1 (en) 1998-11-13 2001-07-24 Vasogen Ireland Limited Method for preventing and reversing atherosclerosis in mammals
WO2001089538A2 (fr) * 2000-05-25 2001-11-29 Vasogen Ireland Limited Entites apoptotiques destinees a etre utilisees dans le traitement des troubles lies au dysfonctionnement de l'endothelium
US6432399B1 (en) 1997-09-12 2002-08-13 Vasogen Ireland Limited Treatment of stress and preconditioning against stress
AU760465B2 (en) * 1995-05-05 2003-05-15 Vasogen Ireland Limited Endothelial lining effects and treatment of vasospastic disorders
US6569467B1 (en) 1992-02-07 2003-05-27 Vasogen Ireland Limited Treatment of autoimmune diseases
US6669965B2 (en) 1992-02-07 2003-12-30 Vasogen Ireland Limited Method of treating atherosclerosis
US6696092B2 (en) 1992-02-07 2004-02-24 Vasogen Ireland Limited Endothelial lining effects and treatment of vasospastic disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3325641A (en) * 1964-02-17 1967-06-13 George W Jones Apparatus for treating a thin film of liquid by exposure to radiant energy
DE2926523A1 (de) * 1979-06-30 1981-01-22 Margit Stadtlaender Geraet zur therapeutischen behandlung von blut und anderen koerpereigenen wie auch koerperfremden fluessigkeiten, substanzen und gasen zum zweck der therapeutischen wie auch diagnostischen anwendung in der human- wie auch veterinaermedinzin usw.
US4968483A (en) * 1987-01-15 1990-11-06 Quarzlampenfabrik Dr.-Ing. Felix W. Muller Gmbh & Co. Kg Apparatus for the production of oxygenated blood

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3325641A (en) * 1964-02-17 1967-06-13 George W Jones Apparatus for treating a thin film of liquid by exposure to radiant energy
DE2926523A1 (de) * 1979-06-30 1981-01-22 Margit Stadtlaender Geraet zur therapeutischen behandlung von blut und anderen koerpereigenen wie auch koerperfremden fluessigkeiten, substanzen und gasen zum zweck der therapeutischen wie auch diagnostischen anwendung in der human- wie auch veterinaermedinzin usw.
US4968483A (en) * 1987-01-15 1990-11-06 Quarzlampenfabrik Dr.-Ing. Felix W. Muller Gmbh & Co. Kg Apparatus for the production of oxygenated blood

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPIL Week 9307, Derwent Publications Ltd., London, GB; AN 93-058408 *
PATENT ABSTRACTS OF JAPAN vol. 8, no. 34 (C-210)15 February 1984 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696092B2 (en) 1992-02-07 2004-02-24 Vasogen Ireland Limited Endothelial lining effects and treatment of vasospastic disorders
US6669965B2 (en) 1992-02-07 2003-12-30 Vasogen Ireland Limited Method of treating atherosclerosis
US6569467B1 (en) 1992-02-07 2003-05-27 Vasogen Ireland Limited Treatment of autoimmune diseases
AU721530B2 (en) * 1995-05-05 2000-07-06 Vasogen Ireland Limited Endothelial lining effects and treatment of vasospastic disorders
WO1996034613A1 (fr) * 1995-05-05 1996-11-07 Vasogen Inc. Effets de revetement endothelial et traitement de troubles vasospastiques
AU760465B2 (en) * 1995-05-05 2003-05-15 Vasogen Ireland Limited Endothelial lining effects and treatment of vasospastic disorders
US6086552A (en) * 1997-05-27 2000-07-11 Vasogen, Inc. Treatment of chronic post-traumatic pain syndromes
US6432399B1 (en) 1997-09-12 2002-08-13 Vasogen Ireland Limited Treatment of stress and preconditioning against stress
WO2000029003A3 (fr) * 1998-11-13 2000-08-31 Vasogen Ireland Limited Technique de prevention et favorisant la regression de l'atherosclerose chez les mammiferes
EA003421B1 (ru) * 1998-11-13 2003-04-24 Вейзоджен Айеленд Лимитед Способ предотвращения развития атеросклероза у млекопитающих
AU768300B2 (en) * 1998-11-13 2003-12-04 Vasogen Ireland Limited Method for preventing and reversing atherosclerosis in mammals
US6264646B1 (en) 1998-11-13 2001-07-24 Vasogen Ireland Limited Method for preventing and reversing atherosclerosis in mammals
WO2000041705A1 (fr) * 1999-01-12 2000-07-20 Vasogen Ireland Limited Pretraitement contre la mort des cellules
AU771162B2 (en) * 1999-01-12 2004-03-18 Centre De Recherche Du Centre Hospitalier De L'universite De Montreal Pre-conditioning against cell death
WO2001089538A3 (fr) * 2000-05-25 2002-08-01 Vasogen Ireland Ltd Entites apoptotiques destinees a etre utilisees dans le traitement des troubles lies au dysfonctionnement de l'endothelium
WO2001089538A2 (fr) * 2000-05-25 2001-11-29 Vasogen Ireland Limited Entites apoptotiques destinees a etre utilisees dans le traitement des troubles lies au dysfonctionnement de l'endothelium
US7279156B2 (en) 2000-05-25 2007-10-09 Vasogen Ireland Limited Apoptotic entities for use in treatment of endothelium dysfunction disorders

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