WO2021221636A1 - Appareil et procédé de traitement de sang pour détoxifier le lipopolysaccharide bactérien - Google Patents

Appareil et procédé de traitement de sang pour détoxifier le lipopolysaccharide bactérien Download PDF

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Publication number
WO2021221636A1
WO2021221636A1 PCT/US2020/030555 US2020030555W WO2021221636A1 WO 2021221636 A1 WO2021221636 A1 WO 2021221636A1 US 2020030555 W US2020030555 W US 2020030555W WO 2021221636 A1 WO2021221636 A1 WO 2021221636A1
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WO
WIPO (PCT)
Prior art keywords
blood
alkaline phosphatase
patient
disease
detoxification
Prior art date
Application number
PCT/US2020/030555
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English (en)
Inventor
Donald S. ORTH
Original Assignee
Orth Consulting, Llc
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 Orth Consulting, Llc filed Critical Orth Consulting, Llc
Priority to PCT/US2020/030555 priority Critical patent/WO2021221636A1/fr
Publication of WO2021221636A1 publication Critical patent/WO2021221636A1/fr

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Classifications

    • 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
    • A61M1/3687—Chemical treatment
    • 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
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3623—Means for actively controlling temperature of blood
    • 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
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption

Definitions

  • This invention relates to detoxifying Gram negative bacterial lipopolysaccharide (LPS) and other inflammatory compounds in a person’s blood. More particularly, an external biochemical reactor containing immobilized alkaline phosphatase enzymes for treating blood is described. BACKGROUND OF THE INVENTION [0002]
  • beneficial bacteria i.e., the commensal microbiome
  • potentially pathogenic bacteria i.e., the commensal microbiome
  • Gram negative bacteria have a cell wall surrounded by an outer membrane composed of lipopolysaccharides (LPS).
  • Harmful endotoxins can include lipoglycans and LPS, which are large molecules consisting of a lipid and a polysaccharide composed of O-antigen, an outer and inner protein core joined by a covalent bond, and a lipid A moiety joined to the inner core by phosphate groups.
  • the endotoxins produced by different Gram negative bacteria differ in their antigenicity due to differences in the O-antigen, but they all have the same biological effects which are mainly due to lipid A.
  • Lipid A contains two phosphate groups that are believed to be essential for its toxicity 1
  • LPS in the bloodstream may be neutralized to some extent by many blood components including plasma lipids and proteins and LPS-binding protein (LPB).
  • LPB LPS-binding protein
  • LPS binding to LPB elicits immune responses by presenting the LPS to cell surface pattern recognition receptors called CD14 and Toll-like receptors (e.g., TLR4) on macrophages, monocytes and endothelial cells.
  • CD14 cell surface pattern recognition receptors
  • TLR4 Toll-like receptors
  • Interaction of LPS with these cellular receptors on monocytes and macrophages results in 1) production and release of cytokines including tumor necrosis factor alpha (TNF ⁇ ), interleukins (e.g., IL-1, IL-6, IL-8) and platelet activating factor, resulting in activation of the arachidonic acid cascade to produce prostaglandins and leukotrienes, which are potent mediators of inflammation; 2) activation of the complement cascade C3 and C5a resulting in release of histamine which causes vasodilation, inflammation, and neutrophil chemotaxis; and 3) activation of the blood coagulation cascade that leads to acute disseminated intravascular coagulation, internal bleeding, hemorrhage and sepsis.
  • TNF ⁇ tumor necrosis factor alpha
  • interleukins e.g., IL-1, IL-6, IL-8
  • platelet activating factor e.g., IL-1, IL-6, IL-8
  • Sepsis is a life-threatening condition that develops when the body's response to infection causes injury to its own tissues and organs. Immediate, intensive treatment is crucial for surviving the condition and preventing septic shock because the risk of death from sepsis and septic shock increases with every passing hour.
  • Toxic shock occurs when the body has an overwhelming response to infection – sometimes referred to as a “cytokine storm” - that causes the blood pressure to drop to dangerously low levels and triggers damaging changes to the organs causing them to become dysfunctional and stop working.
  • Current treatment strategies include fluid replacement, antibiotics to control the infection, vasopressors to maintain adequate blood pressure, corticosteroids and anti-inflammatory drugs to lessen inflammation, and insulin to stabilize blood sugar 2
  • This disclosure describes a system, apparatus and method that can accomplish therapeutic removal of selected toxins within a biological system, including but not limited to those produced by Gram negative bacterial lipopolysaccharide (LPS) and other inflammatory compounds toxic to humans or animals.
  • LPS Gram negative bacterial lipopolysaccharide
  • a detoxification method includes the steps of inducing flow of patient blood through an extracorporeal device inlet and outlet in fluid connection to a circulatory system of a patient.
  • Biological agents contained within patient blood can be detoxified by passing patient blood over a biochemical reactor surface having attached or immobilized alkaline phosphatase enzyme, with the biochemical reactor being contained within the extracorporeal device.
  • the alkaline phosphatase further comprises Saccharomyces boulardii alkaline phosphatase.
  • the alkaline phosphatase detoxifies Gram negative bacterial lipopolysaccharide (LPS).
  • the alkaline phosphatase detoxifies at least one of Gram negative or Gram positive bacterial extracellular lipoteichoic acid, ATP, DNA, RNA or flagellin, yeast and fungal extracellular ATP, DNA and RNA, viral extracellular DNA and RNA, and host extracellular ATP, DNA, or RNA.
  • the alkaline phosphatase detoxifies biological agents contained within patient blood by dephosphorylation.
  • detoxifying biological agents using S In one embodiment, detoxifying biological agents using S.
  • boulardii alkaline phosphatase is used to therapeutically treat at least one of sepsis, septic shock, inflammation, bacteremia, yeast infections, fungal infections, viral infections, systemic inflammatory response syndrome (SIRS), Gram negative bacterial lipopolysaccharide (LPS)-exacerbated conditions, IBD, IBS, Crohn’s disease, ulcerative colitis, enterocolitis, NEC, meningitis, meningococcemia, trauma or hemorrhagic shock, burns, 4
  • SIRS systemic inflammatory response syndrome
  • LPS Gram negative bacterial lipopolysaccharide
  • alkaline phosphatase enzyme is immobilized by being covalently attached to the biochemical reactor surface.
  • the biochemical reactor surface further comprises at least one of capillary tubing and microbeads.
  • patient blood can be pumped through an extracorporeal device inlet and outlet in fluid connection to the circulatory system of a patient.
  • the biochemical reactor surface is provided with a continuous blood flow from the patient that continues until the biological agent(s) being detoxified have been reduced to predetermined levels.
  • a blood detoxification system includes an extracorporeal device having an inlet and outlet able to be placed in in fluid connection to the circulatory system of a patient.
  • a biochemical reactor surface having attached alkaline phosphatase enzyme can act to detoxify biological agents contained within patient blood.
  • the biochemical reactor can be contained within the extracorporeal device. 5
  • FIG. 1 illustrates a system including extracorporeal devices that can be attached to receive and detoxify blood or other fluids from a patient;
  • FIG.2 illustrates one embodiment of a method for detoxifying patient blood;
  • FIG. 1 illustrates a system including extracorporeal devices that can be attached to receive and detoxify blood or other fluids from a patient;
  • FIG.2 illustrates one embodiment of a method for detoxifying patient blood;
  • FIG. 1 illustrates a system including extracorporeal devices that can be attached to receive and detoxify blood or other fluids from a patient
  • FIG.2 illustrates one embodiment of a method for detoxifying patient blood
  • FIG. 1 illustrates a system including extracorporeal devices that can be attached to receive and detoxify blood or other fluids from a patient
  • FIG.2 illustrates one embodiment of a method for detoxifying patient blood
  • FIG. 1 illustrates a system including extracorporeal devices that can be attached to receive and detoxify blood or other fluids from a patient
  • FIG.2 illustrates one embodiment of
  • FIG. 3 illustrates one embodiment of an extracorporeal devices that can be attached to receive and detoxify blood that includes coiled tubing supporting immobilized enzymes
  • FIG.4 illustrates one embodiment of an extracorporeal device that can be attached to receive and detoxify blood that includes a flow chamber supporting beads with immobilized enzymes
  • FIG.5 illustrates one embodiment of an extracorporeal device that can be attached to receive and detoxify blood that is further connected to other diagnostic or therapeutic equipment. 6
  • the term “about”, when used in reference to numerical ranges, cutoffs, or specific values, is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times, will vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. The term “about” is used to encompass variations of this sort up to, or equaling, 10%.
  • attach refers to connecting or uniting by a chemical bond, link, or force in order to keep two or more chemical compounds, polymers, proteins, polysaccharides, lipids, nucleic acids, or other biological or manufactured compositions together.
  • “for example,” “for instance,” “such as,” or “including” are meant to introduce examples that further clarify a more general subject matter. Unless otherwise 7
  • an extracorporeal device, system or methods involving circulating, perfusing, or otherwise passing blood or other patient fluids through a system and device external to the body.
  • One or more internal surfaces of the external or extracorporeal system include immobilized enzymatic agents to interact with one or more patient fluid borne biologic agents.
  • FIG.1 illustrates a system 100 that can be attached to receive blood or other fluids from a human or animal patient.
  • the system 100 includes an extracorporeal device 110 having an inlet 112 and outlet 114.
  • a fluid pump 116 blood or other fluid is introduced and passed through a replaceable biochemical reactor 130.
  • the biochemical reactor 130 can form the entirety of the extracorporeal device 110.
  • a control and monitoring system 140 can be used to set fluid flow rates, maintain and monitor fluid temperature, and support sensors that can determine detoxification efficacy. 8
  • FIG.2 illustrates one embodiment of a method 200 for detoxifying human or animal patient blood.
  • a step 202 blood is drawn from a human or animal patient using a needle and suitable arterial or venous tap or puncture and transferred into an extracorporeal device.
  • the patient blood is detoxified in step 204, and the process intermittently or continuously repeated until a significant volume of patient blood has been processed and returned to the patient (step 206).
  • the patient can be disconnected, and the extracorporeal system cleaned. Cleaning can include sanitization or replacement of the biochemical reactor and readying the system for use by another patient.
  • withdrawal of fluids from a human or animal patient can include blood drawn by venipuncture or arterial taps.
  • Other bodily fluids such as cerebrospinal fluid, lymph fluid, urine, stomach and GI tract fluids can also be processed using the described systems and methods.
  • the pump can include continuous, intermittent, or variable speed pumps. These can include but are not limited to peristaltic pump systems.
  • the inlet and outlet can include luer locks or locking cannula systems.
  • biochemical reactor can include fluid flow structures such as tubing, capillary tubes, hollow fibers, porous structures, and chambers containing unattached polymer or magnetic beads.
  • Fluid flow structures can be formed in whole or in part from glass, metal, ceramic, or polymeric materials. Fluid flow structures can be continuous, split into multiple separate flow channels using a manifold, or contain circulating closed chamber structures.
  • immobilized enzymatic biologic agents can include alkaline phosphatase (AP), an enzyme with broad specificities that can catalyze dephosphorylation of DNA, RNA, ribo- and deoxyribonucleoside triphosphates in humans.
  • alkaline phosphatase can enzymatically react with adenosine triphosphate to yield adenosine diphosphate and a free phosphate.
  • alkaline phosphatase can remove phosphate from phosphate containing biologic agents such as nucleotides and proteins, inactivating or detoxifying the biologic agents.
  • alkaline phosphatase Various types or isozymes of alkaline phosphatase can be used, including but not limited to human or animal derived intestinal AP (IAP), tissue-nonspecific AP (ALPL), placental AP (ALPP), germ cell AP (GCAP), or yeast derived alkaline phosphatase. Because of wide availability, ease of culture, and long duration of enzymatic activity, alkaline phosphatase produced by strains of the yeast Saccharomyces cerevisiae var. boulardii (S. boulardii) can be used in one embodiment. Advantageously, S.
  • attachment of enzymatic biologic agents such as alkaline phosphatase (AP) can include linkage using conventional affinity tag binding, attachment or adsorption on glass, beads, alginate structures or other matrix, entrapment in insoluble beads or microspheres, enzymatic cross linkage to create an enzymatically reactive surface, or covalent bonding.
  • AP alkaline phosphatase
  • bonding can be random or site specific. Amino, thiol, carboxyl, or cyanogen bromide activation can be used. In some embodiments, discrete linking agents that are attached between the alkaline phosphatase and a surface can be used. In some embodiments, surfaces can be chemically modified to allow enzyme attachment, or functional groups exposed on the surface can be activated. Covalent or ionic coupling of a linking agent or enzyme to the surface can include linking of one or more functional groups on the surface or the enzyme. [0037] In one embodiment of the device, system, or method of FIGS.
  • biologic agents or compounds that interact with the immobilized enzymatic agents can include blood or fluid conveyed LPS, as well as adenosine triphosphate (ATP), DNA, RNA and flagellin. More specifically, in other embodiments, at least one of Gram negative or Gram positive bacterial extracellular lipoteichoic acid, ATP, DNA, RNA or flagellin, yeast and fungal extracellular ATP, DNA and RNA, viral extracellular DNA and RNA, and host extracellular ATP, DNA, or RNA can be detoxified after interaction with immobilized alkaline phosphatase.
  • ATP adenosine triphosphate
  • treatable diseases, conditions, or symptoms of humans or animals can include but are not limited to: 1) Stand-alone treatment or in conjunction with other treatment strategies for bacteremia, sepsis and septic shock including oral dosing and IV injection of IAP or other AP isozymes; 2) Treatment to lessen morbidity due to LPS translocating from the gastrointestinal tract into the bloodstream when the intestinal permeability barrier becomes compromised due 11
  • S. boulardii probiotics and/or oral IAP can additionally be used to accelerate return to normal homeostasis in the gastrointestinal tract; 5) Treatment to reduce the inflammatory response associated with necrotizing enterocolitis (NEC) and mitigate the septic response and end-organ injury; 6) Treatment of sepsis, septic shock, inflammation, bacteremia, yeast infections, fungal infections, viral infections, systemic inflammatory response syndrome (SIRS), Gram negative bacterial lipopolysaccharide (LPS)-exacerbated conditions, IBD, IBS, Crohn’s disease, ulcerative colitis, enterocolitis, NEC, meningitis, meningococcemia, trauma or hemorrhagic shock, burns, liver disease, pancreatitis, periodontal disease, pneumonia, cystic fibrosis, asthma, A1AT deficiency, COPD, pulmonary fibrosis, tuberculosis, coronary heart disease, congestive heart failure, renal disease, hemolytic ure
  • lupus erythematosus mast cell activation disorders, cancer, Alzheimer’s disease, diabetes, infections/abscess related diseases, and protein aggregation disorders including neurodegenerative diseases, Parkinson’s disease, amyloidosis, and patients undergoing surgery, cardiovascular surgery, and transplants; 7) Treatment of conditions associated with extracellular ATP, including hypoxia and ischemia that result in active release from cells and passive leakage from damaged/dying cells, and downregulation of ectonucleotidases.
  • Examples include but are not limited to SIRS, A1AT, COPD, IBD, IBS, diverticulosis, and diverticulitis; 8) Treatment of proinflammatory conditions derived from increased ATP, DNA and flagellin in patients with IBD, ulcerative colitis, or other disorder in which there is a decreased expression of IAP that results in excessive levels of proinflammatory compounds in the bloodstream; 9) Treatment to reduce levels of LPS, DNA, extracellular ATP and flagellin in the bloodstream that may be elevated following a course of systemic antibiotic treatment that altered the GI microbiome to favor non-commensal Gram negative bacteria including Escherichia coli, Citrobacter freundii, Enterobacter aerogenes, and other bacteria, resulting in increased translocation of LPS, DNA, external ATP and flagellin into the bloodstream.
  • FIG.3 illustrates one embodiment of an extracorporeal device that can be attached to receive and detoxify blood that includes coiled tubing supporting immobilized enzymes.
  • a system 300 can be attached to receive blood from vein connections to a patient’s arm.
  • the system 300 includes an extracorporeal device 310 having a luer lock inlet 312 and luer lock outlet 314.
  • a fluid pump 316 blood or other fluid is introduced and passed through a replaceable biochemical reactor 330 that includes coiled or otherwise compactified tubing.
  • FIG.4 illustrates one embodiment of an extracorporeal device that can be attached to receive and detoxify blood that includes a flow chamber supporting beads with immobilized enzymes.
  • a system 400 can be attached to receive blood or other fluids from arteries or vein connections to a patient’s arm.
  • the system 400 includes an extracorporeal device 410 having a luer lock inlet 412 and luer lock outlet 414.
  • a fluid pump 416 blood or other fluid is introduced and passed through a replaceable biochemical reactor 430 that includes a fluid chamber partially filled with 14
  • FIG.5 illustrates one embodiment of an extracorporeal device that can be attached to receive and detoxify blood that is further connected to other diagnostic or therapeutic equipment. As seen in FIG.
  • a system 500 can be attached to receive blood or other fluids from arteries or vein connections to a patient’s arm.
  • the system 500 includes an extracorporeal device 510 having a luer lock inlet 512 and luer lock outlet 514.
  • a fluid pump 516 blood or other fluid is introduced and passed through a replaceable biochemical reactor 530 that includes immobilized enzymatic agents such as alkaline phosphatase.
  • blood can be further processed by separate (as shown) or built-in diagnostic or therapeutic systems 540.
  • Diagnostic systems can include inline assays for free phosphate, real-time flow cytometry, or other blood health diagnostics.
  • Therapeutic systems can include additional hemoperfusion, hemofiltration, oxygenation, or other blood processing methods.
  • diagnostic or therapeutic systems 540 can include in-line sampling ports that permit periodic sample taking. 15
  • a sterile hypodermic needle set can be used for accessing a patient’s vein, (e.g., Blood Collection Set, Vaculet 21Gx3/4" Winged, w/Multi-Sample Adapter, 12" Tubing, or similar vein accessing device with a larger bore needle, if needed).
  • a patient’s vein e.g., Blood Collection Set, Vaculet 21Gx3/4" Winged, w/Multi-Sample Adapter, 12" Tubing, or similar vein accessing device with a larger bore needle, if needed).
  • a 36” length of sterile plastic tubing can be used to pass through a peristaltic pump and connect the Vaculet with the biochemical reactor with a luer lock.
  • the peristaltic pump or similar pumping device can be used for pumping blood from the patients arm to the biochemical reactor.
  • An external continuous-flow biochemical reactor is prepared by immobilizing S. boulardii alkaline phosphatase (SBAP) on the inner surface of polystyrene, polymethacrylate, or other plastic capillary tubing as described by Habja and Guttman “Continuous-flow biochemical reactors: Biocatalysis, bioconversion, and bioanalytical applications using immobilized microfluidic enzyme reactors”. J. Flow.
  • the plastic tubing When ready for use, the plastic tubing is placed into a 12”x 12” x12” chamber that has a lid that opens for placement of the tubing inside, a side opening with a luer lock for connection to the plastic tubing from the patient’s arm (by way of the peristaltic pump), and a second side opening with a luer lock for connecting to the line that returns blood to the patient.
  • the plastic tubing can be used without insertion into a chamber, with the pump and tubing together forming a portion of the extracorporeal device by themselves.
  • the continuous-flow biochemical reactor can dephosphorylate approximately 50% of the LPS, external ATP, DNA and flagellin in blood per passage through it as the blood is pumped slowly (e.g., flow rate of 0.5 – 50 mL/min, and typically up to 10 mL/min) through the capillary tubing before returning it to the patient.
  • EXAMPLE 2 A sterile hypodermic needle set can be used for accessing a patient’s vein and a peristaltic pump can be used for pumping blood from the patients arm to a biochemical reactor.
  • An external continuous-flow biochemical reactor is prepared by use of a sterile 250 mL closed container with a magnetic stirring bar that contains 10 – 150 g, and preferably 50 g of microbeads with immobilized SBAP, prepared by covalent bonding to have 50 – 1,500 IU SBAP, and preferably 200 – 500 IU SBAP prepared aseptically in the biochemical reactor.
  • the external continuous-flow biochemical reactor has inlet and 17
  • the container with SBAP covalently immobilized on the plastic beads is sterilized and may be stored in the refrigerator at 4°C for several months prior to use.
  • the container When ready for use, the container is placed onto a magnetic stirrer and stirring is started when blood begins to fill the container.
  • a length of sterile plastic tubing is used to connect the biochemical reactor to the patient’s arm vein for returning treated blood to the patient’s arm or leg vein.
  • the peristaltic pump may be turned on after checking to ensure that all connections are tight so that they will not leak or allow the blood to become contaminated, and the pump is run continuously.
  • the biochemical reactor chamber is maintained at approximately body temperature (37°C) by use of a thermostatically-controlled heating device.

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Un procédé de détoxication comprend les étapes consistant à induire un écoulement de sang de patient à travers une entrée et une sortie de dispositif extracorporel en raccord fluidique avec le système circulatoire d'un patient. Des agents biologiques comprenant un lipopolysaccharide (LPS) contenus dans le sang du patient peuvent être détoxifiés en faisant passer le sang du patient sur une surface de réacteur biochimique ayant une enzyme phosphatase alcaline de Saccharomyces boulardii fixée ou immobilisée, le réacteur biochimique étant contenu à l'intérieur du dispositif extracorporel.
PCT/US2020/030555 2020-04-29 2020-04-29 Appareil et procédé de traitement de sang pour détoxifier le lipopolysaccharide bactérien WO2021221636A1 (fr)

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PCT/US2020/030555 WO2021221636A1 (fr) 2020-04-29 2020-04-29 Appareil et procédé de traitement de sang pour détoxifier le lipopolysaccharide bactérien

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PCT/US2020/030555 WO2021221636A1 (fr) 2020-04-29 2020-04-29 Appareil et procédé de traitement de sang pour détoxifier le lipopolysaccharide bactérien

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140166578A1 (en) * 2006-03-09 2014-06-19 Aethlon Medical, Inc. Extracorporeal removal of microvesicular particles
US20170002481A1 (en) * 2008-02-21 2017-01-05 Technion Research & Development Foundation Ltd. Methods of attaching a molecule-of-interest to a microtube

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140166578A1 (en) * 2006-03-09 2014-06-19 Aethlon Medical, Inc. Extracorporeal removal of microvesicular particles
US20170002481A1 (en) * 2008-02-21 2017-01-05 Technion Research & Development Foundation Ltd. Methods of attaching a molecule-of-interest to a microtube

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORÉ MARGRET I, VANDENPLAS YVAN: "Saccharomyces boulardii CNCM I-745 Improves Intestinal Enzyme Function: A Trophic Effects Review", CLINICAL MEDICINE INSIGHTS: GASTROENTEROLOGY, LIBERTAS ACADEMICA, vol. 11, 1 January 2018 (2018-01-01), pages 117955221775267, XP055870087, ISSN: 1179-5522, DOI: 10.1177/1179552217752679 *

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