US20150335576A1 - Methods of using polymers - Google Patents

Methods of using polymers Download PDF

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US20150335576A1
US20150335576A1 US14/410,901 US201314410901A US2015335576A1 US 20150335576 A1 US20150335576 A1 US 20150335576A1 US 201314410901 A US201314410901 A US 201314410901A US 2015335576 A1 US2015335576 A1 US 2015335576A1
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toxin
sorbent
acute over
pore volume
pore
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Phillip P. Chan
Vincent J. Capponi
Thomas D. Golobish
Humayra Begum Ali
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Cytosorbents Corp
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Cytosorbents Corp
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Definitions

  • the present invention relates generally to materials, methods, kits and devices for the reduction of toxin contamination.
  • Toxins are exogenous or endogenous substances that cause a disruption in normal physiologic functions and may cause disease. They cause disease by coming in contact with or being absorbed by body tissues that include the intestines, skin or mucosal membranes. There are thousands, if not millions of substances that can act as toxins. Even some substances that are normally not toxins can become toxins under the proper conditions. Toxins vary significantly in their strength and the rapidity in which they act. Treatments have been developed for exposure to toxins and include removal from contact with the toxin, and the use of antidotes.
  • Antidotes are substances that can counter act the effects of toxins. However, most antidotes are specific to only one type of toxin or family of toxins. Therefore, it is impossible for hospitals, clinics, field hospitals, doctor's offices, ambulances, and other first responders to carry an antidote for every toxin. In addition, antidotes have not been developed for many toxins and quantities of some antidotes may be too distant to effectively be used in the treatment of some exposures to toxins.
  • suitable materials and methods of reducing contamination by one or more toxins in a biological substance comprising contacting the biological substance with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and sorbing the toxin.
  • Suitable methods of treating contamination by one or more toxins in a subject in need thereof comprising contacting a biological substance of the subject with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and sorbing the toxin.
  • kits to reduce contamination by one or more toxins in a biological substance comprising a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and a vessel to store said sorbent when not in use together with packaging for same.
  • suitable devices to reduce contamination by one or more toxins in a biological substance comprising a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and a vessel wherein the sorbent is located inside the vessel such that the biological substance can be directly introduced into the vessel.
  • compositions comprising a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and a food product or a potable liquid.
  • a sorbent capable of sorbing one or more non-toxic subunits, wherein when two or more of those subunits are combined forms a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm, and sorbing the one or more non-toxic subunits.
  • Also provided herein are methods of treating contamination by one or more toxins in a subject in need thereof comprising contacting a biological substance of the subject with an effective amount of a sorbent capable of sorbing one or more non-toxic subunits, wherein when two or more of those subunits are combined forms a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm, and sorbing the one or more non-toxic subunits.
  • FIG. 1 illustrates pore volume of the sorbent plotted as a function of the pore diameter of the sorbent on a log scale.
  • FIG. 2 illustrates the Clostridium difficile Toxin A removal as a function of time.
  • FIG. 3 illustrates the Clostridium difficile Toxin B removal as a function of time.
  • anti-microbial agent includes antibacterial agents, anti-viral agents, antifungal agents, antiseptics and the like. Suitable antimicrobial agents include, but are not limited to isoniazid, rifampin, pyrazinamide, ethambutol, erythromycin, vancomycin, tetracycline, chloramphenicol, sulfonamides, gentamicin, amoxicillin, penicillin, streptomycin, p-aminosalicyclic acid, clarithromycin, clofazimine, minocycline, sulfonamides, ethionamide, cycloserine, kanamycin, amikacin, capreomycin, viomycin, thiacetazone, rifabutin and the quinolones, such as ciprofloxacin, ofloxacin and sparfloxicin, rifampin, oseltamivir, acyclovir, lamivudi
  • Antibacterial agents includes but are not limited to ⁇ -lactam antibacterial agents including, e.g. carbenicillin; ampicillin, cloxacillin, oxacillin and pieracillin, cephalosporins and other cephems including, e.g. cefaclor, cefamandole, cefazolin, cefoperazone, ceftaxime, cefoxitin, ceftazidime, ceftriazone and carbapenems including, e.g., imipenem and meropenem; and glycopeptides, macrolides, quinolones (e.g. nalidixic acid), tetracyclines, and aminoglycosides (e.g. Gentamicin and Paromomycin).
  • ⁇ -lactam antibacterial agents including, e.g. carbenicillin; ampicillin, cloxacillin, oxacillin and pieracillin, cephalosporins and other cephems
  • biocompatible is defined to mean the sorbent is capable of coming in contact with physiologic fluids, living tissues, or organisms without producing unacceptable clinical changes during the time that the sorbent is in contact with the physiologic fluids, living tissues, or organisms. In some embodiments, it is intended that the sorbent is tolerated by the gut and alimentary canal of the organism.
  • the sorbents of the present invention are preferably non-toxic.
  • a biocompatible sorbent may be a biodegradable polymer, a resorbable polymer, or both.
  • microbe includes a bacteria, viruses, fungi and parasites.
  • toxin is used to mean a substance identified as an etiological agent linked to a negative clinical outcome.
  • Toxins include toxin subunits, toxin precursors, and virulence factors.
  • the toxin can be from a biological source such as bacteria, viruses, fungi, parasites, plants or animals.
  • a toxin may be pre-formed or may only become toxic once in the presence of a biological substance.
  • botulinum toxin (one of 7 subtypes) is made by the bacterium, Clostridium botulinum , often under anaerobic conditions, such as in canned goods.
  • this pre-formed botulinum toxin is one of the most potent toxins known, blocking neuromuscular transmission by inhibiting acetylcholine release in the synapse, causing paralysis and respiratory failure.
  • Ricin toxin made from castor beans, is another example of a pre-formed toxin that when inhaled, injected, or ingested can be fatal.
  • Amatoxins, from mushrooms, and aflatoxin, which are mycotoxins produced by strains of the fungus species, Aspergillus are examples of other pre-formed toxins.
  • a toxin may also be made within the body, often by microbes, but can be made by the patient's own cells, as occurs in viral infection.
  • Examples include toxins TcdA and TcdB, made by Clostridium difficile bacterium and released into the intestinal lumen that kills cells in the gastrointestinal tract, leading to severe, potentially life-threatening diarrhea.
  • Another example is Shiga-like toxin or verotoxin that is produced by certain strains of Escherichia coli that are frequently transmitted by contaminated undercooked meat, vegetables, or fruit and cause food-borne illness.
  • Verotoxin is produced by the bacterium in the intestinal lumen, but then is absorbed into the bloodstream, where it is taken up by vascular endothelial cells, killing them. Verotoxin preferentially targets the glomerulus, causing renal failure and can lead to fatal hemolytic uremic syndrome.
  • NSP4 toxin produced by a patient's own cells following gastrointestinal infection with the virus, rotavirus.
  • Rotavirus is the most common cause of severe diarrhea in infants, killing more than 600,000 patients a year.
  • NSP4 acts as an enterotoxin, activating ion channels in the colonic epithelium, causing a profuse secretory diarrhea, without causing any structural damage.
  • An excess of a normally non-toxic substance can also become a toxin when present at high concentrations.
  • An example includes cytokines, which are normally produced proteins of the immune system that at low levels are important for immune system function, but at high levels become inflammatory toxins that cause cell death, severe inflammation, and organ dysfunction.
  • Toxins can also be formed by the metabolism of a non-toxic precursor or protoxin.
  • a non-toxic precursor or protoxin is amyloid precursor protein, a non-toxic protein produced in the body that when cleaved by enzymes called secretases, can form the fragment beta-amyloid protein, a toxin that can lead to the formation of amyloid plaques, the pathogenic root cause of Alzheimer's disease.
  • Non-toxic subunits or precursors can also become toxins when combined with each other.
  • An example of this is the production of lethal factor, edema factor, and protective antigen by Bacillus anthracis , which is responsible for the disease anthrax.
  • Staphylococcus aureus alpha toxin which is not toxic as a monomer, but becomes a potent hemolytic toxin when seven monomers assemble into a pore forming complex.
  • a substance may also have no toxic effects when in one location in the body, but may become a toxin when placed in another part of the body.
  • An example of this is the gram negative bacterial endotoxin, lipopolysaccharide, which has little toxicity in the intestinal lumen, but causes septic shock if it escapes into the bloodstream.
  • Toxins can also be common enzymes, such as lipases, amylases, trypsin, hyaluronidase, collagenase and others that cause cell or tissue damage when not appropriately regulated, or when active in a region of the body that is not protected against their enzymatic action. When these substances help the spread or virulence of pathogens in the body, they are classified as “virulence factors”. These are examples and not meant to be limiting.
  • gastrointestinal lumen refers to the space or cavity within a gastrointestinal tract.
  • gastrointestinal disorder includes gastritis, Ménétrier disease, gastrointestinal ulceration, gastroenteritis, gastrointestinal inflammatory disease, enteric infection, gut-mucosal injury, inflammatory bowel disease, celiac disease, and the like.
  • sorbent includes adsorbents and absorbents.
  • physiologic fluids are liquids that originate from the body and can include, but are not limited to, nasopharyngeal, oral, esophageal, gastric, pancreatic, hepatic, pleural, pericardial, peritoneal, intestinal, prostatic, seminal, vaginal secretions, as well as tears, saliva, lung or bronchial secretions, mucus, bile, blood, lymph, plasma, serum, synovial fluid, cerebrospinal fluid, urine, and interstitial, intracellular, and extracellular fluid, such as fluid that exudes from burns or wounds.
  • carrier fluids are exogenously administered liquids that include, but are not limited to, liquids administered orally, via a feeding tube, peritoneally, or rectally such as an enema or colonic wash.
  • biocompatible sorbents compositions can be manufactured that sorb toxins, toxin precursors, toxin subunits, or virulence factors, collectively termed “toxins” of a broad range of sizes irrespective of other physical characteristics.
  • the biocompatible sorbents can be used to inhibit or reduce contamination by one or more toxins when introduced into a biological substance, generally mammalian, and particularly human.
  • the biological substance can also be a manufactured substance that supports proliferation or maintenance of a micro-organism.
  • the sorbent compositions will be useful in reducing toxins while working in conjunction with anti-microbial agents that kill or halt the growth of microbes that are either directly producing the toxin or causing the toxin to be produced.
  • the sorbent compositions will be also useful in situations where other treatments may not be unavailable for a variety of reasons.
  • the sorbents can be used in cases where the toxin has not been definitively identified.
  • Another instance where the present biocompatible sorbent and methods may be useful is when a toxin is identifiable, but not yet sufficiently typed or cultured for targeted treatments.
  • anti-microbials cannot be used, for fear of greater toxin release when the microbe dies that will worsen the patient's condition.
  • the present biocompatible sorbent compositions are comprised of a plurality of pores.
  • the biocompatible sorbents are designed to adsorb a broad range of toxins from less than 1 kDa to 1,000 kDa. While not intending to be bound by theory, it is believed the sorbent acts by sequestering molecules of a predetermined molecular weight within the pores. The size of a molecule that can be adsorbed by the polymer will increase as the pore size of the polymer increases. Conversely, as the pore size is increased beyond the optimum pore size for adsorption of a given molecule, adsorption of said protein may or will decrease.
  • a porous polymer that absorbs small to midsize protein molecules equal to or less than 50,000 Daltons (50 kDa) and excludes absorption of large blood proteins comprises the pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ are in the range of 0.5 cc/g to 5.0 cc/g dry sorbent.
  • the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) to pore volume between 100 ⁇ acute over ( ⁇ ) ⁇ to 1,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) of the sorbent is smaller than 3:1.
  • a porous polymer that optimally absorbs midsize to large size protein molecules of approximately 300,000 Daltons and excludes or minimizes absorption of very large blood proteins comprises the pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ are in the range of 0.5 cc/g to 5.0 cc/g dry sorbent.
  • the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) to pore volume between 1,000 ⁇ acute over ( ⁇ ) ⁇ to 10,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) of the sorbent is smaller than 2:1.
  • a porous polymer that optimally absorbs very large size protein molecules equal to or less than 1,000,000 Daltons and excludes or minimizes absorption of very large blood proteins comprises the pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ are in the range of 0.5 cc/g to 5.0 cc/g dry sorbent.
  • the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) to pore volume between 10,000 ⁇ acute over ( ⁇ ) ⁇ to 40,000 ⁇ acute over ( ⁇ ) ⁇ (pore diameter) of the sorbent is smaller than 3:1.
  • the biocompatible sorbent is introduced into a biological substance.
  • the term biological substance includes substances found in vivo, generally from a mammal such as dogs, cats, rabbits, cows, sheep, horses, pigs and goats, preferably a human.
  • the biological substances are, for example, cells, or physiologic fluids such as saliva, nasopharyngeal, blood, plasma, serum, gastrointestinal fluid, bile, cerebrospinal fluid, pericardial, vaginal fluid, seminal fluid, prostatic fluid, peritoneal fluid, pleural fluid, urine, synovial fluid, interstitial fluid, intracellular fluid or cytoplasm, lymph, bronchial secretions, mucus, or vitreous or aqueous humor.
  • physiologic fluids such as saliva, nasopharyngeal, blood, plasma, serum, gastrointestinal fluid, bile, cerebrospinal fluid, pericardial, vaginal fluid, seminal fluid, prostatic fluid, peri
  • the term also includes substances that support proliferation or maintenance of eukaryotic or prokaryotic cells, viruses, fungi, or protozoa ex vivo, such as culture media, biological matrices, eggs and the like.
  • the biocompatible sorbent and biological substance can be introduced and admixed either in vivo or ex vivo.
  • Toxins are most commonly organic substances such as proteins, peptides, carbohydrates, lipids, nucleic acids, and combinations thereof (e.g. multimeric or multi-subunit proteins, glycoproteins, glycolipids, lipoproteins, etc.). Toxins can also include organic chemicals (e.g. alkaloids), as well as certain inorganic molecules (e.g. cyanide).
  • organic chemicals e.g. alkaloids
  • inorganic molecules e.g. cyanide
  • Toxins can be produced by a wide range of organisms.
  • toxins can be produced by micro-organisms such as bacteria, viruses, fungi and parasites.
  • Toxins can also be formed by macro-organisms such as insects, fish, crustaceans, shellfish, amphibians, reptiles, birds, and mammals.
  • Toxins can also be produced by vegetative matter such as plants, algae, and phytoplankton.
  • Viruses typically contain the genetic code, via DNA or RNA, or other nucleic acid sequences, to direct the cells they infect to manufacture viral proteins, including toxins. Many toxins can also be found environmentally, the product of natural processes.
  • Toxins can be formed by the assembly and/or modification of subunits that may or may not be toxic by themselves. Toxins may be non-toxic substances at low concentrations, but becomes toxic at higher concentrations. Some toxins may be location specific. Toxins can also be byproducts of metabolism of non-toxic precursors. Toxins can also be artificially synthesized and manufactured (e.g. biowarfare applications, etc).
  • Exogenous toxins can be ingested, injected, inhaled, absorbed by the skin or mucosal surfaces, such as the buccal or oral mucosa, the sublingual mucosa, the nasal mucosa, the sinuses, the nasopharynx, the oropharynx, the respiratory tract, the gastrointestinal tract, the urogenital tract, and the eye mucosa.
  • Endogenous toxins can be produced anywhere in the body, such as in the blood, the gastrointestinal tract, the respiratory tract, the urogenital tract, within tissues, and within body cavities.
  • Non-toxic precursors can also be absorbed from the environment or produced in the body, and are then converted in the body into toxins via metabolism or other modification.
  • Toxins can cause pathology via a number of different mechanisms. Some cause the direct killing of cells.
  • brown recluse spider venom contains a number of toxins that make it both cytolytic and hemolytic. These toxins are enzymes such as hyaluronidase, deoxyribonuclease, ribonuclease, alkaline phosphatase, and lipase. Sphingomyelinase D is thought to be the protein component responsible for most of the tissue destruction and hemolysis caused by brown recluse spider envenomation.
  • toxins are from enteric pathogens such as Clostridium difficile , Enterohemorrhagic E. coli (EHEC)) such as E. coli OE 157:H7 or E. coli O 104:H4, Vibrio cholera, Shigella dysenteriae , and rotovirus.
  • EHEC Enterohemorrhagic E. coli
  • E. coli OE 157:H7 or E. coli O 104:H4 Vibrio cholera, Shigella dysenteriae , and rotovirus.
  • These toxins can damage or kill cells of the gastrointestinal mucosa, and can alter gastrointestinal homeostasis, often resulting in diarrhea and vomiting that can lead to dehydration, malabsorption, and potentially even death, particularly in the young, the elderly, and immunocompromised subjects.
  • toxins can result in more serious complications such as colitis, bloody diarrhea, gastrointestinal bleeding, a decrease in immune system function, toxic megacolon, intestinal perforation, shock, sepsis and death.
  • a compromise of the gastrointestinal mucosa caused by infection and toxins, can further lead to the translocation of bacteria and toxins, such as endotoxin, from the intestinal tract, into the blood or body, which can trigger or exacerbate sepsis.
  • bacteria and toxins such as endotoxin
  • Enteric pathogens are commonly found in the environment and include bacteria, viruses, parasites and plants.
  • Pathogenesis may be directly related to the organism (e.g. Yersinia enterocolitica , Norwalk virus), related to a toxin produced by organism (e.g. Clostridium difficile , Enterotoxigenic E. coli (ETEC)), caused by changes in cellular function resulting in release of pro-inflammatory cytokines (e.g., Enteropathogenic E. coli (EPEC), Camplylobacter jejuni ), or a combination of these of mechanisms (e.g. Vibrio cholera, Shigella dysenteriae ).
  • ETEC Enterotoxigenic E. coli
  • Embodiments of the present invention can be used to inhibit or reduce contamination by toxins across a broad range of molecular weights and a pre-formed toxin or a toxin formed in the presence of the biological substance.
  • An example of a toxin formed in the presence of a biological substance is a bacterial endotoxin, such as lipopolysaccharide (LPS).
  • LPS lipopolysaccharide
  • the appearance of LPS in the host bloodstream is believed to lead to the endogenous production of a variety of host factors that directly and indirectly mediate the toxicity of LPS.
  • These host-derived mediators include many now well-recognized inflammatory cytokines, endocrine hormones, and a number of other endogenous factors such as leukotrienes and platelet activating factor.
  • Cytokines such as TNF- ⁇ , IL-1, and IFN- ⁇ are released from stimulated macrophages and T lymphocytes as a result of infection by a variety of microorganisms, including bacteria, viruses, fungi, and parasites.
  • the interacting factors comprise the cytokine cascade.
  • TNF-alpha has been observed to stimulate production of other types of cytokines.
  • IL-1 induces responses observed in inflammation in general, such as fever, increase of leukocytes, activation of lymphocytes, and induction of biosynthesis of acute phase protein in liver.
  • these cytokines and others can be inflammatory toxins and cause undesirable effects such as capillary leak, cell death via apoptosis, hemodynamic instability, organ dysfunction, and cachexia.
  • cytokines such as IL-8 act as a signal that attracts white blood cells such as neutrophils to the region of cytokine expression.
  • white blood cells such as neutrophils
  • the release of enzymes and superoxide anions by neutrophils is essential for destroying the infecting bacteria.
  • ARDS adult respiratory distress syndrome
  • the toxin is from one or more diverse biological sources.
  • Biological sources can comprise one or more bacteria, viruses, fungi, or parasites as shown in Table 1, a non-exclusive list of toxins, toxin subunits, and their representative pathogens.
  • perfringens Clostridium C. perfringens 43 kDa Alpha toxin Aerolysin Aeromonas A. hydrophila 52 KDa Pseudomonas Pseudomonas P. aeruginosa 66 kDa Exotoxin A Shiga-like toxin Escherichia Enterohemorrhagic E. coli 69 kDa (STX-1, STX-2; (EHEC) verotoxin) Shiga toxin Shigella dysenteria 70 kDa Cholera Toxin Vibrio Vibrio cholerae 84 kDa Enterotoxigenic LT Escherichia Enterotoxigenic E.
  • ETEC 86 kDa (heat labile enterotoxin) Lipopolysaccharide Gram negative bacteria 10 kDa, up Endotoxin to 1000 kDa aggregated Lipoteichoic acid Gram positive bacteria 10 kDa Endotoxin Cyanotoxins Cyanobacteria Varied sizes Pertussis toxin Bordetella B. pertussis 105 kDa Tetanus Toxin Clostridium C. tetani 150 kDa Botulinum toxin Clostridium C. botulium 150 kDa C. diff toxin B Clostridium C. difficile 250-270 kDa (TcdB) C. diff toxin A Clostridium C. difficile 308 kDa (TcdA)
  • Table 2 is a non-exclusive list of viral toxins where the present sorbent can be used to reduce or inhibit contamination of a biological substance.
  • Table 3 is a non-exclusive list of fungal toxins where use of the present sorbent can reduce or inhibit contamination of a biological substance.
  • Table 4 is a non-exclusive list of plant-derived toxins where use of the present sorbent can reduce or inhibit contamination of a biological substance.
  • Table 5 is a non-exclusive list of animal-derived toxins where use of the present sorbent can reduce or inhibit contamination of a biological substance.
  • compositions of biocompatible sorbents can comprise a mixture of sorbents with different pore structures. Such a mixture will be advantageous, for example, when the pathogen has not been definitively identified or there is reason to suspect there are multiple pathogens associated with the gastroenteritis, such as with the ingestion of contaminated water.
  • the present methods and sorbents can be used in treating infections with Clostridium difficile via oral or rectal administration.
  • C. difficile is commonly acquired in hospitals worldwide and other long-term healthcare settings. It is a leading cause of severe diarrhea in these institutions. In the hospital setting the consequences include, longer stays, more readmissions and higher costs. (Glouliouris et al., Clin. Med., 11:75-79, 2011).
  • C. difficile spores are excreted in large numbers by patients and contamination can survive for months or years.
  • the bacteria are generally inhibited by the normal flora of the gastrointestinal system, but an imbalance or disruption in the colonic flora, allows for C. difficile to proliferate and produce toxins resulting in diarrhea, and possibly fever and colitis.
  • the present methods and sorbents can be used in treating bacterial toxins in the blood using a hemocompatible sorbent in an extracorporeal hemoperfusion system.
  • Standard hemodialysis, hemofiltration and charcoal hemoperfusion are not capable of removing toxins larger than approximately 10 kDa.
  • High molecular weight cutoff filters, and mid-molecular weight sorbent cartridges are not ideally suited for broad, particularly large (>60 kDa) toxin removal.
  • This sorbent system in conjunction with antibiotics, could be used to remove pathogen derived toxins from blood, plasma or serum in a range of less than 1 kDa to more than 400 kDa.
  • infections that also produce blood-borne toxins include Staphylococcus aureus and methicillin-resistant Staphlococus aureus (MRSA) that produce alpha toxin or toxic shock syndrome toxin-1; enterohemorrhagic E. coli enteral infection associated with systemic shiga-like toxin toxemia; Clostridium perfringens infection with alpha toxin production causing necrotizing fasciitis; Aeromonas wound infection with aerolysin toxin production, and others.
  • MRSA methicillin-resistant Staphlococus aureus
  • the sorbent comprises a coated polymer comprising at least one crosslinking agent and at least one dispersing agent.
  • Some preferred coated polymers comprise at least one crosslinking agent and at least one dispersing agent.
  • Suitable dispersing agents include hydroxyethyl cellulose, hydroxypopyl cellulose, poly(hydroxyethyl methacrylate), poly(hydroxyethyl acrylate), poly(hydroxypropyl methacrylate), poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethyl acrylate), poly(diethylamimoethyl methacrylate), poly(diethylaminoethyl acrylate), poly(vinyl alcohol), poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and salts of poly(acrylic acid) and mixtures thereof.
  • Suitable crosslinking agents include divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythrital dimethacrylates, pentaerythrital trimethacrylates, pentaerythrital, tetramethacrylates, pentaerythritol diacrylates, pentaerythritol triiacrylates, pentaerythritol tetraacrylates, dipentaerythritol dimethacrylates, dipentaerythritol trimethacrylates, dipentaerythritol tetramethacrylates, dipentaerythritol diacrylates, dipentaerythritol
  • porogens are Benzyl alcohol, Cyclohexane, Cyclohexanol, Cyclohexanol/toluene mixtures, Cyclohexanone, Decane, Decane/toluene mixtures, Di-2-ethylhexylphosphoric acid, Di-2-ethylhexyl phthalate, 2-Ethyl-1-hexanoic acid, 2-Ethyl-1-hexanol, 2-Ethyl-1-hexanol/n-heptane mixtures, 2-Ethyl-1-hexanol/toluene mixtures, Isoamyl alcohol, n-Heptane, n-Heptane/ethylacetate, n-Heptane/isoamyl acetate, n-Heptan
  • Preferred sorbents comprise polymers derived from one or more monomers selected from divinylbenzene and ethylvinylbezene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pen
  • Some preferred polymers comprise ion exchange polymers.
  • Some preferred polymers comprise cellulosic polymers.
  • Suitable polymers include cross-linked dextran gels such as SephadexTM.
  • Certain preferred polymers comprise porous highly crosslinked styrene or divinylbenzene copolymers. Some of these copolymers comprise a macroporous or mesoporous styrene-divinylbenzene-ethylstyrene copolymer subjected to a partial chloromethylation to a chlorine content of up to 7% molecular weight. Other of these polymers are a hypercrosslinked polystyrene produced from crosslinked styrene copolymers by an extensive chloromethylation and a subsequent post-crosslinking by treating with a Friedel-Crafts catalyst in a swollen state.
  • polystyrene produced from crosslinked styrene copolymers by an extensive additional post-crosslinking in a swollen state with bifunctional crosslinking agents selected from the group comprising of monochlorodimethyl ether and p-xylilene dichloride
  • hydrophilic self-wetting polymers that can be administered as dry powder containing hydrophilic functional groups such as, amines, hydroxyl, sulfonate, and carboxyl groups.
  • Certain polymers useful in the invention are macroporous polymers prepared from the polymerizable monomers of styrene, divinylbenzene, ethylvinylbenzene, and the acrylate and methacrylate monomers such as those listed below by manufacturer.
  • DiaionTM HP 10 DiaionTM HP 20, DiaionTM HP 21, DiaionTM HP 30, DiaionTM HP 40, DiaionTM HP 50, DiaionTM SP70, DiaionTM SP 205, DiaionTM SP 206, DiaionTM SP 207, DiaionTM SP 700, DiaionTM SP 800, DiaionTM SP 825, DiaionTM SP 850, DiaionTM SP 875, DiaionTM HP 1MG, DiaionTM HP 2MG, DiaionTM CHP 55A, DiaionTM CHP 55Y, DiaionTM CHP 20A, DiaionTM CHP 20Y, DiaionTM CHP 2MGY, DiaionTM CHP 20P, DiaionTM HP 20SS, DiaionTM SP 20SS, and DiaionTM SP 207SS.
  • Purolite Company PurosorbTM AP 250 and PurosorbTM AP 400.
  • the present invention does not rely on charge or a ligand-receptor complex binding reaction to inhibit or reduce pathogen toxicity.
  • a polymer using acid functional group(s) attached to the polymer backbone to bind Clostridium difficile Toxin A and Toxin B is described by Bacon Kurtz et al. (U.S. Pat. No. 6,890,523). The interaction in Kurtz is ionic where a hydrophobic or hydrophilic group attached to the polymer binds the toxin.
  • Chamot et al. (US Patent Application 2006/009169) describe using inorganic polymer particles linked to a toxin binding moiety comprised of oligosaccharide sequences that bind C. difficile Toxin A and Toxin B. Also described is a toxin binding surface pore size 2 ⁇ larger than toxin diameter. Chamot described oligosaccharide moieties that bind toxins to form a ligand/receptor-like complex.
  • the polymer materials used as the sorbent are generally not metabolizable by human and animal, but may be synthesized from materials characterized as being a biodegradable polymer, a resorbable polymer, or both. Certain polymers may be irregular or regular shaped particulates such as powders, beads, or other forms with a diameter in the range of 0.1 micron meters to 2 centimeters.
  • the polymers used in the instant invention preferably have a biocompatible and hemocompatible exterior surface coatings but are not absolutely necessary, especially in certain circumstances, such as oral or rectal administration. Certain of these coatings are covalently bound to the polymer particle (beads, for example) by free-radical grafting.
  • the free-radical grafting may occur, for example, during the transformation of the monomer droplets into polymer beads.
  • the dispersant coating and stabilizing the monomer droplets becomes covalently bound to the droplet surface as the monomers within the droplets polymerize and are converted into polymer.
  • Biocompatible and hemocompatible exterior surface coatings can be covalently grafted onto the preformed polymer beads if the dispersant used in the suspension polymerization is not one that imparts biocompatibility or hemocompatibility. Grafting of biocompatible and hemocompatible coatings onto preformed polymer beads is carried out by activating free-radical initiators in the presence of either the monomers or low molecular weight oligomers of the polymers that impart biocompatibility or hemocompatibility to the surface coating.
  • the route of administration can be systemic or localized.
  • the compositions may be given orally, rectally or via a feeding tube.
  • the sorbent can be supplied as a dry powder or other dry particulate capable of being wetted externally or internally in the alimentary canal, including in the gastric or enteric environment, with or without the addition of wetting agents such as ethyl or isopropyl alcohol, potable liquids such as water, or other carrier fluid.
  • wetting agents such as ethyl or isopropyl alcohol, potable liquids such as water, or other carrier fluid.
  • Other possible routes of administration include subcutaneous or transdermal delivery. In some embodiments, administration is topical.
  • Such methods include ophthalmic administration, administration to skin or wounds, direct administration into a body cavity or joint, and delivery to mucous membranes such as nasal, oral, vaginal and rectal delivery or other delivery to the alimentary canal.
  • the treatment is extracorporeal.
  • Extracorporeal administration would include removal of inflammatory mediators from blood or physiologic fluids by circulating the fluids through a device containing sorbent and returning it back to the body.
  • such methods include local or systemic administration through a parenteral route. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (including intrathecal or intraventricular, administration).
  • the sorbent may be formulated as for example, a powder, a tablet, a capsule, a solution, a slurry, an emulsion, a suppository, or in a food substance.
  • the sorbent may be packaged in portable bottles, vials, blister packs, bags, pouches, or other container that allows for either single or multiple dosages.
  • the sorbent may be sterile or non-sterile.
  • the polymer may be sterilized by standard methods. Such methods are well known to those skilled in the art.
  • the therapeutically effective amount can be administered in a series of doses separated by appropriate time intervals, such as hours.
  • the compositions of the instant invention may be administered by methods well known to those skilled in the art.
  • the synthesis process consists of (1) preparing the aqueous phase, (2) preparing the organic phase, (3) carrying out the suspension polymerization, (4) purifying the resulting porous polymeric adsorbent product (work-up), and (5) addition of a hemo-compatible coating.
  • a 5 L or 0.5 L kettle reactor was fitted with an over-head stirrer, a water cooled condenser, a multi-level stirrer blade, a thermocouple, and a bubbler.
  • a gasket was installed between the top lid and bottom kettle.
  • the 5 L set-ups had a baffle plate assembly and two flat rubber gaskets installed between the top lid and bottom kettle. All unused ports were capped with the appropriate plug.
  • Temperature was controlled with a heating mantle which was regulated by a temperature controller fitted with the above-mentioned thermocouple.
  • Polyvinyl alcohol (“PVA”) was dispersed in one half of the water charge at room temperature (RT) and then heated to 70° C.
  • the remaining salts: MSP, DSP, TSP, & Sodium Nitrite were then dissolved in the remainder of the water charge.
  • the PVA solution and salts solution were each added to the reactor and heated to the desired reaction temperature with stirring.
  • the pre-mixed organic phase, including the initiator, was poured into the reactor onto the aqueous phase with the stirring speed set at the revolutions per minute (“rpm”) for formation of appropriate droplet size. Once the temperature reached the set-point, the reaction timer was set for 16 hours and started and the reaction was allowed to proceed.
  • a kettle reactor was fitted with an over-head stirrer, a multi-level stirrer blade, and a thermocouple. All unused ports were capped with the appropriate plug and one open hose adapter as a vent. A gasket was installed between the top lid and bottom kettle. Temperature was controlled with a heating mantle regulated by a temperature controlled fitted with the above-mentioned thermocouple.
  • Vinylpyrrolidinone (VP) and water were added between 39° C. and 40° C.
  • the two hour reaction timer was started when the temperature reached 40° C.; the reaction was allowed to proceed.
  • the solvent was siphoned out to the bead level.
  • the beads were then washed 3 times with RT water at a rate of 1 bed volume per half hour.
  • the beads were steam stripped for 6 hours.
  • the beads were rewet in isopropyl alcohol and washed ten times in purified H 2 O.
  • the polymer was then dried in an oven at 100° C.
  • FIG. 1 is the log differential pore structures for Examples 1-18.
  • the pore volume is divided up into categories within pore size ranges for each of the sorbent polymers and these values are provided in Tables 7 and 8.
  • the capacity pore volume is that pore volume that is accessible to protein sorption and consists of the pore volume in pores larger than 100 ⁇ in diameter.
  • the effective pore volume is that pore volume that is selectively accessible to proteins smaller than approximately 50,000 Daltons and consists of pore diameters within the range of 100 to 1000 ⁇ in diameter.
  • the oversized pore volume is the pore volume accessible to proteins larger than approximately 50,000 Daltons and consists of the pore volume in pores larger than 1000 ⁇ in diameter.
  • the undersize pore volume is the pore volume in pores smaller than 100 ⁇ acute over ( ⁇ ) ⁇ diameter and is not accessible to proteins larger than about 10,000 Daltons.
  • the capacity pore volume is that pore volume that is accessible to protein sorption and consists of the pore volume in pores larger than 1,000 ⁇ in diameter.
  • the effective pore volume is that pore volume that is selectively accessible to proteins smaller than about 300,000 Daltons and consists of pore diameters within the range of 1000 to 10000 ⁇ in diameter.
  • the oversized pore volume is the pore volume accessible to proteins larger than 300,000 Daltons and consists of the pore volume in pores larger than 1000 ⁇ in diameter.
  • the undersize pore volume is the pore volume in pores smaller than 1,000 ⁇ acute over ( ⁇ ) ⁇ diameter and is not accessible to proteins larger than about 10,000 Daltons.
  • the capacity pore volume is that pore volume that is accessible to protein sorption and consists of the pore volume in pores larger than 500 ⁇ in diameter.
  • the effective pore volume is that pore volume that is selectively accessible to proteins smaller than 1,000,000 Daltons and consists of pore diameters within the range of 10,000 to 40,000 ⁇ in diameter.
  • the oversized pore volume is the pore volume accessible to proteins larger than 1,000,000 Daltons and consists of the pore volume in pores larger than 40,000 ⁇ in diameter.
  • the undersize pore volume is the pore volume in pores smaller than 10,000 ⁇ acute over ( ⁇ ) ⁇ diameter and is not accessible to proteins larger than about 40,000 Daltons.
  • Table 7 provides the pore volumes and pore volume ratios for Examples 1-18.
  • Table 8 provides the pore volume ratios for Examples 1-18.
  • the main objective of this study was to evaluate the ability of polymer beads (Porous beads ID's: TDG-057-118, RJR-090-136, RJR-090-091, RJR-090-137, RJR-090-023 and RJR-090-178, and non-porous bead ID: RT-075-1-14) to bind Clostridium difficile rTcdA. Eight types of beads, those with and without pores, were utilized. rTcdA was evaluated at a concentration of 100 ⁇ g/ml.
  • Table 9 provides the weight of polymers used for Example 21.
  • FIG. 2 shows C. difficile Toxin A removal over time.
  • the main objective of this study was to evaluate the ability of polymer beads (Porous bead ID: RJR-090-016, and non-porous bead ID: RJR-090-014) to bind and remove Clostridium difficile rTcdB toxin in vitro at toxin concentrations of 25 and 100 ⁇ g/mL, as compared to a no-bead control.
  • polymer beads Porous bead ID: RJR-090-016, and non-porous bead ID: RJR-090-014
  • the weight of the porous beads reflects their high degree of porosity compared to the non-porous beads Immediately after addition of toxin, one tube in each group containing either no beads, non-porous bead or porous beads was allowed to sit without agitation for 45 minutes to allow the beads to settle by gravity. A 225 ⁇ l sample was taken from these tubes and stored at ⁇ 20° C. These were designated as the 0.75 h samples. Sample tubes, designated 1.75 h and 2.75 h respectively, were mixed continuously on a tube roller. At time-points of 1.0 and 2.0 hours after the start of the experiment, respectively, tubes were removed from the roller and set in a rack for 45 min for the beads to settle. A 225 ⁇ l sample was removed from these tubes.
  • the main objective of this study was to evaluate the ability of Cytosorbents' Beads (Porous beads ID's: TDG-057-118, RJR-090-136, RJR-090-091, RJR-090-137, RJR-090-023 and RJR-090-087, and non-porous bead ID: RT-075-1-14) to bind Clostridium difficile rTcdB. Seven types of beads, those with and without pores, and a no bead control were utilized. rTcdB was evaluated at a concentration of 100 ⁇ g/ml.
  • FIG. 3 shows C. difficile Toxin B removal over time.
  • BoNT/A1 was evaluated at concentrations of 10, 50 and 100 ng/ml in phosphate buffered saline. No beads, or a fixed volume of 40 ⁇ L each of either non-porous ( ⁇ 32.1 ng dry bead weight) or porous beads ( ⁇ 5.5 ng dry bead weight) were incubated with either 10, 50 or 100 ⁇ g/ml of BoNT/A1 at a 0.3 ml final working volume in a 2-mL screw cap microfuge tube.
  • the experiment was performed to keep the interstitial volume (outside of the beads) constant at 0.3 mL.
  • the weight of the porous beads reflects their high degree of porosity compared to the non-porous beads
  • a 225 ⁇ l sample was taken from one tube in each group containing no beads, non-porous beads, or porous beads and stored at ⁇ 20° C. These were designated as the 0 h samples. Tubes correlating to the 1 and 2 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1 or 2 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use.
  • the main objective of this study was to evaluate the ability of CytoSorbents polymer beads (Porous bead ID: TDG-071-167, Large Pore Bead ID: RJR-090-013 and non-porous bead ID: RT-075-14-1) to bind Shiga Like Toxin 1.
  • the main objective of this study was to evaluate the ability of CytoSorbents polymer beads (Porous bead ID: TDG-071-167, Large Pore Bead ID: RJR-090-013 and non-porous bead ID: RT-075-14-1) to bind Shiga Like Toxin 2.
  • Tubes correlating to the 1.25 and 2.25 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1.25 or 2.25 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay. As can be seen, the both standard and large porous beads have a better kinetics of removal in contrast to the non-porous beads.
  • the main objective of this study was to evaluate the ability of CytoSorbents polymer beads (Small Porous bead ID: TDG-057-145, Modified, Batch 1, ⁇ 106/+45, Large porous bead ID: RJR-090-016 and non-porous bead ID: RJR-090-014) to bind ricin toxin.
  • Ricin toxin was evaluated at concentrations of 100 and 1000 ⁇ g/ml in phosphate buffered saline.
  • Tubes correlating to the 1.75 and 2.75 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1.75 or 2.75 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay (Thermo Scientific, Cat. NO. 23225). As can be seen, the small porous beads have a better kinetics of removal in contrast to the large porous beads initially. No-bead control or the non-porous beads removed no toxins and no more than 9%, respectively.
  • the main objective of this study was to evaluate the ability of CytoSorbentsTM polymer beads (Small Porous bead ID: TDG-057-145, Modified, Batch 1, ⁇ 106/+45, Large porous beads bead ID: RJR-090-016 and non-porous bead ID: RJR-090-014) to bind cholera toxin.
  • Tubes correlating to the 1.75 and 2.75 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1.75 or 2.75 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay (Thermo Scientific, Cat. NO. 23225). As can be seen, the small porous beads have a better kinetics of removal in contrast to the large porous beads. No-bead control or the non-porous beads removed no toxins and less than 25%, respectively.
  • the main objective of this study was to evaluate the ability of CytoSorbents polymer beads (Porous bead ID: TDG-071-167, Large Pore Bead ID: TDG-057-118 and non-porous bead ID: RT-075-14-1) to bind C. perfringens enterotoxin.
  • C. perfringens enterotoxin was evaluated at concentrations of 50 and 100 (ideally 11.46 and 31.42) ⁇ g/ml in phosphate buffered saline.
  • Tubes correlating to the 1.5 and 2.5 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1.5 or 2.5 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay (Thermo Scientific, Cat. NO. 23225). As can be seen, the large porous beads have a better kinetics of removal from 31.42 mg/mL of toxin in contrast to the standard and non-porous beads. No-bead control or the non-porous beads did not remove any toxin.
  • the main objective of this study was to evaluate the ability of CytoSorbents polymer beads (Small Porous bead ID: TDG-057-145, and non-porous bead ID: RJR-090-014) to bind Staphylococcus enterotoxin B. Two types of beads, those with and without pores, were utilized. Staphylococcus enterotoxin B was evaluated at concentrations of 50 and 100 (ideally 43.02 and 97.85) ⁇ g/ml in phosphate buffered saline.
  • Tubes correlating to the 1.75 and 2.75 h samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 1.75 or 2.75 hours, a 225 ⁇ L sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay. As can be seen, the small porous beads have a better kinetics of removal (greater than or equal to 98% by 0.75 h) in contrast to the non-porous beads. No-bead control or the non-porous beads did not remove toxins as efficiently.
  • Staphylococcus Enterotoxin B adsorption results are shown in Table 20.
  • the main objective of this study was to evaluate the ability of two different CytoSorbents porous bead types (Small Pore: RJR-100-144; Large Pore: RJR-100-168) and non-porous beads (RJR-090-158) to bind Staphylococcus aureus ⁇ -Hemolysin.
  • S. aureus ⁇ -Hemolysin was evaluated at concentrations of 50 and 100 ug/ml in phosphate buffered saline.
  • Tubes correlating to the 0.5 h, 1.5 h, and 2.5 hours samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 0.5 h, 1.5 h, or 2.5 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay (Thermo Scientific, Cat. NO. 23225). The BCA assay indicates that both porous polymers have better kinetics of removal than the no bead control and the non-porous beads.
  • the main objective of this study was to evaluate the ability of various CytoSorbents porous bead types (bead #1: SFA-102-106, bead #2: CytoSorb Lot 08311, bead #3: TDG-057-118) and non-porous beads (RT-075-14-1) to bind Escherichia coli STa toxin.
  • Escherichia coli STa toxin was evaluated at concentrations of 50 and 100 ⁇ g/mL in phosphate buffered saline.
  • a 225 ⁇ l sample was taken from one tube in each groups containing no beads, non-porous beads, or porous beads and immediately stored at ⁇ 20° C. Tubes correlating to the 0.5 h, 1.5 h, and 2.5 hours samples were placed on a tube roller and mixed continuously. After incubation at room temperature of either 0.5 h, 1.5 h, or 2.5 hours, a 225 ⁇ l sample was removed from the appropriate tubes. All samples were stored at ⁇ 20° C. until use. Following collection of all samples, the protein concentration remaining in each sample was evaluated using the BCA (bicinchoninic acid) protein assay (Thermo Scientific, Cat. NO. 23225) The BCA assay indicates that all three porous polymers have better kinetics of removal than the no bead control and the non-porous beads.

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WO2017176796A1 (en) * 2016-04-04 2017-10-12 University Of Virginia Patent Foundation Compositions and methods for preventing and treating disease
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WO2017155677A1 (en) * 2016-03-08 2017-09-14 Cytosorbents Corporation The use of a hemocompatible porous polymer bead sorbent for removal of pamps and damps
EP3426229A4 (en) * 2016-03-08 2019-11-06 Cytosorbents Corporation USE OF A HEMOCOMPATIBLE POROUS POLYMER PEARL SORBENT FOR THE REMOVAL OF MOLECULAR MOLECULAR MOLECULES ASSOCIATED WITH PATHOGENIC AGENTS (PAMP) AND MOLECULAR MOLECULAR MOLECULES ASSOCIATED WITH INJURIES (DAMP)
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US10973890B2 (en) 2016-09-13 2021-04-13 Allergan, Inc. Non-protein clostridial toxin compositions
WO2018217629A1 (en) * 2017-05-23 2018-11-29 Cytosorbents Corporation Method of treating traumatic brain injury
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WO2019046506A1 (en) * 2017-08-31 2019-03-07 Cytosorbents Corporation REDUCTION OF FINAL PRODUCTS OF ADVANCED GLYCATION FROM BODILY FLUIDS
WO2021211772A1 (en) * 2020-04-14 2021-10-21 Cytosorbents Corporation Improved immune response and decreased immunoparalysis with immunomodulating treatment

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