WO2000072851A1 - Method of sterilizing - Google Patents
Method of sterilizing Download PDFInfo
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- WO2000072851A1 WO2000072851A1 PCT/US2000/014353 US0014353W WO0072851A1 WO 2000072851 A1 WO2000072851 A1 WO 2000072851A1 US 0014353 W US0014353 W US 0014353W WO 0072851 A1 WO0072851 A1 WO 0072851A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/002—Dendritic macromolecules
- C08G83/003—Dendrimers
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/02—Amines; Quaternary ammonium compounds
- A01N33/04—Nitrogen directly attached to aliphatic or cycloaliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/3463—Organic compounds; Microorganisms; Enzymes
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
- A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
- A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
- A23L3/358—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0088—Liquid substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L101/00—Compositions of unspecified macromolecular compounds
- C08L101/005—Dendritic macromolecules
Definitions
- the present invention relates generally to methods of sterilizing materials and particularly to a method of inactivating infectious prions .
- sterilizing materials There are large numbers of known methods of sterilizing materials. Many methods involve heating a material to a temperature at which pathogens are killed or inactivated. Other methods involve exposing the material to compounds which kill or inactivate pathogens which are contacted by the compounds. Still other methods involve irradiating a material with a sufficient amount of a particular type of radiation for a period of time sufficient to inactivate, disrupt or kill pathogens in the material. These methods are generally directed toward killing bacteria and inactivating viruses present in or on the material. Although sterilization methods may be quite affective in killing bacteria or inactivating viruses, they do not generally inactivate pathogenic proteins such as prions which can be responsible for a number of fatal diseases.
- P ⁇ on diseases are a group of fatal neurodegenerative disorders that can occur in hereditary, sporadic, and infectious forms (Prusiner, S B Scrapie p ⁇ ons Annu Rev Microbwl 43, 345-374 (1989)) These illnesses occur m humans and a variety of other animals (Prusiner, S B P ⁇ ons Proc Natl Acad Sci USA 95, 13363-13383 (1998)) P ⁇ ons are infectious protems
- PrP The normal, cellular form of the p ⁇ on protein (PrP) designated PrP c contains three ⁇ - helices and has little ⁇ - sheet, m contrast, the protein of the p ⁇ ons denoted PrP Sc is rich m ⁇ -sheet structure
- PrP Sc the central nervous system (CNS) precedes neurologic dysfunction accompanied by neuronal vacuolation and astrocytic ghosis
- Taghavim, ⁇ et al Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276, 1119-1122 (1997); Masullo, C, Macchi, G., Xi, Y.G. & Pocchiari, M. Failure to ameliorate Creutzfeldt-Jakob disease with amphotericin B therapy. J. Infect. Dis. 165, 784-785 (1992); Ladogana, A., et al. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J. Gen. Virol. 73, 661-665 (1992)), all have demonstrated only modest potential to impede prion propagation, and none have been shown to effect the removal of pre-existing prions from an infected host.
- PrP gene of mammals expresses a protein which can be the soluble, non-disease form PrP c or be converted to the insoluble, disease form PrP Sc .
- PrP c is encoded by a single-copy host gene [Basler, Oesch et al. (1986) Cell 46:417-428] and when PrP c is expressed it is generally found on the outer surface of neurons.
- Many lines of evidence indicate that prion diseases result from the transformation of the normal form of prion protein (PrP c ) into the abnormal form (PrP Sc ). There is no detectable difference in the amino acid sequence of the two forms.
- PrP Sc when compared with PrP c has a conformation with higher ⁇ -sheet and lower ⁇ -helix content (Pan, Baldwin et al. (1993) Proc Natl Acad Sci USA 90: 10962-10966; Safar, Roller et al. (1993) JBiol Chem
- the presence of the abnormal PrP Sc form in the brains of infected humans or animals is the only disease-specific diagnostic marker of prion diseases.
- PrP Sc plays a key role in both transmission and pathogenesis of prion diseases (spongiform encephalopathies) and it is a critical factor in neuronal degeneration (Prusiner (1997) The Molecular and Genetic Basis of Neurological Disease, 2nd Edition : 103-143).
- the most common prion diseases in animals are scrapie of sheep and goats and bovine spongiform encephalopathy (BSE) of cattle (Wilesmith and Wells (1991) Curr Top Microbiol Immunol 172:21-38).
- insoluble protein examples include: A ⁇ peptide in amyloid plaques of Alzheimer's disease and cerebral amyloid angiopathy (CAA); ⁇ -synuclein deposits in Lewy bodies of Parkinson's disease, tau in neurofibrillary tangles in frontal temporal dementia and Pick's disease; superoxide dismutase in amyotrophic lateral sclerosis; huntingtin in Huntington's disease; and prions m Creutzfeldt-Jakob disease (CJD) (for reviews, see Glenner et al. (1989) J Neurol. Sci. 94 1- 28; Haan et al (1990) dm. Neurol. Neurosurg 92(4) 305-310).
- CAA Alzheimer's disease and cerebral amyloid angiopathy
- CJD Creutzfeldt-Jakob disease
- amyloid can be present in cerebral and memngeal blood vessels (cerebrovascular deposits) and m brain parenchyma (plaques)
- the mam amyloid component is the amyloid ⁇ protein (A ⁇ ).
- a ⁇ amyloid ⁇ protein
- the A ⁇ peptide which is generated from the amyloid ⁇ precursor protein (APP) by two putative secretases, is present at low levels in the normal CNS and blood.
- Two major variants, A ⁇ l ⁇ 0 and A ⁇ i. 42 are produced by alternative carboxy-terminal truncation of APP (Selkoe et al.(1988) Proc. Natl. Acad. Sci. USA 85:7341-7345; Selkoe, (1993) Trends Neurosci 16:403-409).
- a ⁇ W2 is the more fibrillogenic and more abundant of the two peptides in amyloid deposits of both AD and CAA.
- AD cases are also associated with amyloid deposition in the vascular walls (Hardy (1997), supra; Haan et al. (1990), supra; Terry et al., supra; Vinters (1987), supra; Itoh et al. (1993), supra; Yamada et al. (1993), supra; Greenberg et al. (1993), supra; Levy et al. (1990), supra).
- These vascular lesions are the hallmark of CAA, which can exist in the absence of AD.
- TTR Human transthyretin
- SSA semle systemic amyloidosis
- FAP familial amyloid polyneuropathy
- the cause of amyloid formation in FAP are pomt mutations m the TTR gene, the cause of SSA is unknown
- the clinical diagnosis is established histologically by detecting deposits of amyloid m situ m bioptic matenal
- amyloid fibrils in the brains of Alzheimer's and prion disease patients are known to result in the inflammatory activation of certain cells.
- primary microglial cultures and the THP-1 monocytic cell line are stimulated by fibrillar ⁇ -amyloid and prion peptides to activate identical tyrosine kinase-dependent inflammatory signal transduction cascades.
- the signaling response elicited by ⁇ -amyloid and prion fibrils leads to the production of neurotoxic products, which are in part responsible for the neurodegenerative .
- the present invention offers a means of sterilizing materials which contain conformationaUy altered proteins such as prions.
- Figure 1 is a schematic drawing of a dendrimer molecule showing the defined "generations" of homodisperse structure created using a repetitive divergent growth technique.
- the specific diagram is of PAMAM, generation 2.0 (ethylene diamine core).
- a method whereby any type of object can be sterilized by combining normal sterilization procedures with the use of a polycationic dendrimer which is capable of rendering a conformationaUy altered protein such as a prion non-infectious.
- the method is particularly useful in sterilizing medical devices such as surgical instruments and catheters which have been used and brought into contact with blood or brain tissue.
- Objects sterilized via the method are also part of the invention and include capsules which are made from geletin extracted from cattle which cattle may be infected with prions, i.e.
- polycationic dendrimers can be combined with conventional antibacterial and antiviral agents in aqueous or alcohol solutions to produce disinfecting agents or surgical scrubs.
- Branched polycations for use in the invention include, but are not limited to, polypropylene imine, polyethyleneimine (PEI) poly(4'-aza-4'-methylheptamethylene D-glucaramide), polyamidoamines and suitable fragments and/or variants of these compounds.
- PEI polyethyleneimine
- An aspect of the invention is a method of treating objects with a composition characterized by its ability to render proteins associated with diseases non-infectious.
- An advantage of the invention is that proteins such as prions can be rendered non-infectious without the need for extreme conditions such as exposure to heat over long periods of time, e.g. 1-10 hours at 100°-200°C.
- compositions can be useful while containing only very low concentrations of polycationic dendrimers, e.g. 1% to 0.001%.
- the method is thus useful for subjects suffering from disorders such as bovine spongiform encephalopathy, Creutzfeldt- Jacob Disease, fatal familial msomma, GSS for Gerstmann-Straussler-Schemker Disease, kuru, scrapie, Alzheimer's Disease, Frontal temporal dementia, Huntington's disease, ALS, Pick's disease, Parkinson's disease, Diabetes Type II, multiple myeloma, familial amyloidotic polyneuropathy, medullary carcinoma of thyroid, chrome renal failure, congestive heart failure, semle cardiac and systemic amyloidosis, chrome inflammation, atherosclerosis, and familial amyloidosis
- the branched polycation can be administered to a subject in an amount non-toxic to the subject, for example a dosage of 0 001 mg to 1 mg/kg body weight per day
- the polycation may be administered m a smgle dosage form, or it may be repeatedly administered to the subject
- the branched polycation may
- the present mvention also provides a method of enhancing clearance of a disease related conformation of a protem from a meat food product by contacting the meat with a compound which enhances clearance of a conformationaUy altered protem at a pH of 5 or less for a time sufficient to allow for destruction of conformationaUy altered protem
- An advantage of the mvention is that conformationaUy altered protem such as pnons can be rendered non-infectious with a method which need only consist of applying a polycationic dendrimer preferably held at a pH of 5 0 or less
- detergent is used to mean any substance that reduces the surface tension of water
- the detergent may be a surface active agent which concentrates at oil-water mterfaces, exerts emulsifying action and thereby aids m removing soils e g common sodium soaps of fatty acids
- a detergent may be anionic, catiomc, or momomc depending on their mode of chemical action
- Detergents include linear alkyl sulfonates (LAS) often aided by "builders "
- a LAS is preferably an alkyl benzene sulfonate ABS which is readily decomposed by microorganisms (biodegradable).
- the LAS is generally a straight chain alkyl comprising 10 to 30 carbon atoms.
- the detergent may be in a liquid or a solid form.
- conformationaUy altered protein is used here to describe any protein which has a three dimensional conformation associated with a disease.
- the conformationaUy altered protein may cause the disease, be a factor in a symptom of the disease or appear as a result of other factors.
- the conformationaUy altered protein appears in another conformation which has the same amino acid sequence.
- the conformationaUy altered protein formed is "constricted” in conformation as compared to the other "relaxed" conformation which is not associated with disease.
- diseases with associated proteins which assemble two or more different conformations wherein at least one conformation is an example of a conformationaUy altered protein.
- Alzheimer's Disease APP A ⁇ peptide, ⁇ 1 -antichymotrypsin, tau, non-A ⁇ component, presenillin 1, presenillin 2 apoE
- acid is used to describe any compound or group of compounds which has one or more characteristics of (a) sour taste; (b) turns litmus dye red; (c) reacts with certain metals to form a salt; (d) reacts with certain bases or alkalines to form a salt.
- An acid comprises hydrogen and in water undergoes ionization so that H 3 0 + ions are formed - also written as HT and refe ⁇ ed to as hydronium ions or simply hydrogen ions.
- Weak acids such as acetic acid or carbonic acid may be used as may strong acids such as hydrochloric acid, nitric acid and sulfuric acid.
- the acid is preferably present in a concentration so as to obtain a pH of 5 or less, more preferably 4 or less and still more preferably 3.5 ⁇ 1.
- an effective dose or “amount effective” is meant an amount of a compound sufficient to provide the desired sterilizing result. This will vary depending on factors such as the type of object or material being sterilized and the amount or concentration of infectious proteins which might be present. Polycations of the invention or more specifically polycationic dendrimer compounds of the invention could be mixed with a material in an amount in a range 1 to 500 ⁇ g of dendrimer per ml or mg of material being sterilized. The concentration is sufficient if the resulting composition is effective in decreasing the infectivity of conformationaUy altered proteins such that the treated material over time would not result in infection.
- the effective dose or concentration range needed to sterilize can vary considerably. It is also pointed out that the dose needed to treat an amount of material may vary somewhat based on the pH the treatment is carried out at and the amount of time the compound is maintained in contact with the material at the desired low pH (e.g., 5.0 or less) level.
- LD 50 is the dose of an active substance that will result in 50 percent lethality in all treated experimental animals. Although this usually refers to invasive administration, such as oral, parenteral, and the like, it may also apply to toxicity using less invasive methods of administration, such as topical applications of the active substance.
- amine-terminated includes primary, secondary and tertiary amines.
- PrP protein PrP
- PrP PrP protein and like are used interchangeably herein and shall mean both the infectious particle form PrP Sc known to cause diseases (spongiform encephalopathies) in humans and animals and the noninfectious form PrP c which, under appropriate conditions is converted to the infectious PrP Sc form.
- Particles are comprised largely, if not exclusively, of PrP Sc molecules encoded by a PrP gene. Prions are distinct from bacteria, viruses and viroids. Known prions infect animals to cause scrapie, a transmissible, degenerative disease of the nervous system of sheep and goats, as well as bovine spongiform encephalopathy (BSE), or "mad cow disease", and feline spongiform encephalopathy of cats.
- BSE bovine spongiform encephalopathy
- prion diseases known to affect humans are (1) kuru, (2) Creutzfeldt-Jakob Disease (CJD), (3) Gerstmann-Straussler-Scheinker Disease (GSS), and (4) fatal familial insomnia (FFI).
- CJD Creutzfeldt-Jakob Disease
- GSS Gerstmann-Straussler-Scheinker Disease
- FFI fatal familial insomnia
- PrP gene is used herein to describe genetic material which expresses proteins including known polymorphisms and pathogenic mutations.
- the term “PrP gene” refers generally to any gene of any species which encodes any form of a prion protein. Some commonly known PrP sequences are described in Gabriel et al., Proc. Natl. Acad. Sci. USA 89:9097-9101 (1992) and U.S.
- PrP gene can be from any animal, including the "host” and “test” animals described herein and any and all polymorphisms and mutations thereof, it being recognized that the terms include other such PrP genes that are yet to be discovered.
- the protein expressed by such a gene can assume either a PrP c (non-disease) or PrP Sc (disease) form.
- standardized prion preparation e.g., brain homogenate
- the mammal may (1) include a transgene as described herein; (2) have and ablated endogenous prion protein gene; (3) have a high number of prion protein gene from a genetically diverse species; and/or (4) be a hybrid with an ablated endogenous prion protein gene and a prion protein gene from a genetically diverse species.
- Different combinations of 1-4 are possible, e.g., 1 and 2.
- AD Alzheimer's disease
- AD-type pathology refers to a combination of CNS alterations including, but not limited to, formation of neuritic plaques containing amyloid ⁇ protein in the hippocampus and cerebral cortex.
- AD-type pathologies can include, but are not necessarily limited to, disorders associated with aberrant expression and/or deposition of APP, overexpression of APP, expression of aberrant APP gene products, and other phenomena associated with AD.
- Exemplary AD-type pathologies include, but are not necessarily limited to, AD-type pathologies associated with Down's syndrome that is associated with overexpression of APP.
- phenomenon associated with Alzheimer's disease refers to a structural, molecular, or functional event associated with AD, particularly such an event that is readily assessable in an animal model. Such events include, but are not limited to, amyloid deposition, neuropathological developments, learning and memory deficits, and other AD- associated characteristics.
- Cerebral amyloid angiopathy refers to a condition associated with formation of amyloid deposition within cerebral vessels which can be complicated by cerebral parenchymal hemorrhage. CAA is also associated with increased risk of stroke as well as development of cerebellar and subarachnoid hemorrhages (Vinters (1987) Stroke 18:311-324; Haan et al. (1994) Dementia 5:210-213; Itoh et al. (1993) /.
- CAA can also be associated with dementia prior to onset of hemorrhages.
- the vascular amyloid deposits associated with CAA can exist in the absence of AD, but are more ftequendy associated with AD.
- phenomenon associated with cerebral amyloid angiopathy refers to a molecular, structural, or functional event associated with CAA, particularly such an event that is readily assessable in an animal model. Such events include, but are not limited to, amyloid deposition, cerebral parenchymal hemorrhage, and other CAA-associated characteristics.
- ⁇ -amyloid deposit refers to a deposit in the brain composed of A ⁇ as well as other substances. Abbreviations used herein include:
- AD Alzheimer's disease
- CAA cerebral amyloid angiopathy
- Hu for human HuPrP for human prion protein
- SHaPrP for a Syrian hamster prion protein
- PAMAM polyamidoamide dendrimers
- PrP Sc for the scrapie isoform of the prion protein
- PrP c for the cellular contained common, normal isoform of the prion protein; PrP 27-30 or PrP Sc 27-30 for the treatment or protease resistant form of PrP Sc ;
- ALS for amyotrophic lateral sclerosis
- HD for Huntington's disease
- the invention comprises compositions of compounds found to be effective in rendering conformationaUy altered proteins non-infective.
- the compositions are preferably low pH solutions comprised of a non-toxic weak acid such as acetic acid having dissolved therein a branched polycation.
- Prefened compositions of the invention are in the form of aqueous or alcohol solutions which are comprised of a branched polycation, an antibacterial, an antifungal and an antiviral compound.
- the compositions are coated on, mixed with, injected into or otherwise brought into contact with a material to be sterilized.
- the composition is applied in a manner so that the branched polycation is maintained at a low pH (e.g.
- compositions of the invention are useful in cleaning and sterilizing and may be comprised of a polycationic dendrimers, a detergent, and an acid proving a pH of about 3.5 ⁇ 1.
- Dendrimers are branched compounds also known as "starburst” or “star” polymers due to a characteristic star-like structure (see Figure 1).
- sterilizing compositions of the invention comprise a cationic dendrimer preferably dissolved in a low pH solvent such as acetic acid.
- a cationic dendrimer preferably dissolved in a low pH solvent such as acetic acid.
- suitable dendrimers are disclosed in U.S. Pat. Nos. 4,507,466, 4,558, 120, 4,568,737, 4,587,329, 4,631,337, 4,694,064, 4,713,975, 4,737,550, 4,871,779, and 4,857,599 to D.
- A. Tomalia, et al. which are hereby incorporated by reference to disclose and describe such compounds.
- Dendrimers typicaUy have tertiary amines which have a pKa of 5.7.
- the dendrimers can optionally be chemically or heat treated to remove some of the tertiary amines.
- Other suitable cations include polypropylene imine, polyethyleneimine (PEI), which has tertiary amines with a pKa of 5.9, and poly(4'-aza-4'-methylheptamethylene D-glucaramide), which has tertiary amines with a pKa of 6.0.
- the cationic dendrimer is preferably dissolved in the low pH solvent such as vinegar in a concentration of 0.0001 % or more, preferably 0.01 % or more and more preferably about 1 %.
- the dendrimers for use in the invention are polyamidoamines (hereinafter "PAMAM").
- PAMAM dendrimers are particularly biocompatible, since polyamidoamine groups resemble peptide bonds of proteins.
- PAMAM dendrimers are prepared in tiers called generations (see generations 0, 1 and 2 in Figure 1) and therefore have specific molecular weights.
- the full generation PAMAM dendrimers have amine terminal groups, and are cationic, whereas the half generation dendrimers are carboxyl terminated. Full generation PAMAM dendrimers are thus preferred for use in the present invention.
- PAMAM dendrimers may be prepared having different molecular weights and have specific values as described in Table 1 below for generations 0 through 10.
- the number of terminal amine groups for PAMAM dendrimers generations 0 through 10 range from 4 to 4,096, with molecular weights of from 517 to 934,720.
- PAMAM dendrimers are available commercially from Aldrich or Dendritech.
- Polyethyleneimine or polypropylene dendrimers or quaternized forms of amine-terminated dendrimers may be prepared as described by Tomalia et. al, Angew, Chem. Int. Ed. Engl., 29: 138-175 (1990) incorporated by reference to describe and disclose methods of making dendrimers.
- compositions for reducing, inhibiting, or otherwise mitigating the degree of infectivity of a protein are comprised of any compound capable of destroying conformationaUy altered proteins when in a low pH environment, (e.g. a polycationic dendrimer) in solution, suspension or mixture.
- compositions of the invention preferably contain highly branched polycations, e.g. polycationic dendrimer, in a concentration from 0.0001 to 10% of the formulation.
- highly branched polycations e.g. polycationic dendrimer
- the percentage amount of each ingredient can vary.
- a solvent ingredient e.g. water or alcohol
- the last listed ingredient is present in a range of 0.5% to 5%.
- the other ingredients are present in an amount in a range of 1 % to 60% and more generally 5% to 20% .
- the polycationic compounds of the invention are added in amounts of about 0.01 % to 5% and preferably 0J % to 2% and more preferably about 1 % . The amount added is an amount needed to obtain the desired effect.
- Formulations of the invention used with a cell culture have the advantage that they are non-toxic.
- parenteral administration of a solution of the formulations of the invention is preferably nontoxic at a dosage of 0.1 mg/mouse, which is an LD 50 of less than one at 40 mg/Kg.
- Various nutrient formulations and/or injectable formulations of the type known to those skilled in the art can be used to prepare formulations for treating cell cultures.
- SuperFect is a mixture of branched polyamines de ⁇ ved from heat-mduced degradation of a PAMAM dendnmer (Tang, M X , Redemann, C T & Szoka, F C J In vitro gene delivery by degraded polyamidoamine dendrimers Bwconjug Chem 7, 703-714 (1996)) Knowing this structure the ability of several other branched and unbranched polymers to eliminate PrP Sc from ScN2a cells (Table 1) The branched polymers investigated mclude vanous preparations of PEI, as weU as intact PAMAM and PPI dendrimers Dendrimers are manufactured by a repetitive divergent growth technique, allowing the synthesis of successive, well-defined "generations" of homodisperse structures ( Figure 1) The potency of both PAMAM and PPI dendrimers in eliminating PrP Sc from ScN2a cells mcreased as the generation level mcreased The most potent compounds with respect to eliminating PrP Sc were PAMAM generation 4
- PrP c is converted into PrP Sc in caveolae-like domains (CLDs) or rafts (Gorodinsky, A. & Harris, D.A. Glycolipid-anchored proteins in neuroblastoma cells form detergent-resistant complexes without caveolin. J. Cell Biol. 129, 619-627 (1995); Taraboulos, A., et al. Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibits formation of the scrapie isoform. J. Cell Biol. 129, 121-132 (1995); Vey, M., et l.
- Branched polyamines may bind directly to PrP Sc a ⁇ anged as an amyloid with exposed negatively-charged moieties and induce a conformational change under acidic conditions.
- Treatment of PrP 27-30 with acid decreases turbidity and increases a-helical content, suggesting that such conditions might dissociate PrP Sc into monomers (Safar, J., Roller, P.P., Gajdusek, D.C. & Gibbs, C.J., Jr.
- Scrapie amyloid (prion) protein has the conformational characteristics of an aggregated molten globule folding intermediate). It is therefore possible that polyamines bind to an equilibrium unfolding intermediate of PrP Sc present under acidic conditions.
- polyamines might sequester a cryptic, negatively charged component bound to PrP Sc that is essential for protease resistance, but which is only released when PrP Sc undergoes an acid-induced conformational change. Such a component might act as a chaperone for PrP Sc inside endosomes or lysosomes.
- polyamines activate an endosomal or lysosomal factor which can induce a conformational change in PrP Sc .
- more work will be required to determine the precise mechanism by which branched polyamines destroy PrP Sc .
- the in vitro assay described here is generally applicable in the search for compounds that effectively clear conformationaUy altered proteins present in food thereby preventing a number of degenerative diseases, where the accumulation of proteins seems to mediate the pathogenesis of these illnesses.
- simulating lysosomes, where proteases hydrolyze proteins under acidic conditions the in vitro brain homogenate assay is able to rapidly evaluate the efficacy of a variety of polyamines to induce degradation of PrP Sc .
- the in vitro assay which used scrapie infected brain homogenate to test for compounds which clear PrP Sc could be modified to assay for compounds which would clear any conformationaUy altered protein.
- the assay is ca ⁇ ied out by homogenizing the organ or tissue where the conformationaUy altered protein is present in the highest concentration.
- the pH of the homogenate is then reduced to less than 5.0 and preferably 4.0 or less.
- pancreatic tissue can be homogemzed to produce an assay to test for compounds which clear amylin which is associated with type II Diabetes.
- Homogemzed kidney could be used to test for compounds which clear ⁇ 2 - microglobulin and homogemzed heart or vascular tissue used to test for compounds which clear atrial natriuretic factor.
- organs and tissue types which can be homogemzed to test for other compounds which clear other conformationaUy altered proteins.
- the compounds found via the assay provide a new tool for exploring the conversion of a protein to conformationaUy altered protein, e.g. PrP c into PrP Sc .
- the mechanism by which branched polyamines render PrP Sc susceptible to proteolysis remains to be established. Whether the interaction of branched polyamines with PrP Sc is reversible is unknown. In addition, we do not know whether branched polyamines are able to solubilize PrP Sc without ineversibly denaturing the protein. Whatever the mechanism by which branched polyamines interact with PrP So , it is likely to be different from that found with chaotropes as well as denaturing detergents and solvents (Prusiner,
- Such an approach may find merit in developing an effective therapeutics for one or more of the common, degenerative illnesses including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, fro ⁇ totemporal dementia, adult onset diabetes mellitus and the amyloidoses (Beyreuther, K. & Masters, C.L. Serpents on the road to dementia and death.
- the common, degenerative illnesses including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, fro ⁇ totemporal dementia, adult onset diabetes mellitus and the amyloidoses (Beyreuther, K. & Masters, C.L. Serpents on the road to dementia and death.
- the mvention is based on the discovery that several dendntic polycations, mcludmg the starburst dendrimers SuperfectTM (QIAGEN®, Valencia, CA), polyamidoamide (PAMAM), and the hyperbranched polycation polyethyleneimine (PEI), were surpnsingly found to eliminate PrP Sc from cultured scrapie-infected neuroblastoma cells
- PAMAM polyamidoamide
- PEI hyperbranched polycation polyethyleneimine
- EXAMPLE IB The blot described above was stripped of antibody, exposed to labeled R073 and redeveloped.
- the antibody 3F4 used in Example 1 binds to PrP c but not to PrP Sc .
- R073 binds to PrP Sc and PrP c .
- Lanes 1, 2 and 3 show decreasing amounts of PrP Sc and lanes 4 and 5 show no detectable PrP Sc .
- EXAMPLE 2B To determine the time-dependent effect of SuperFect three different panels with four lanes each were prepared and run as follows ScN2a cells were exposed to 7 5 ⁇ g/ml SuperFect (lanes 1-4), PEI (average molecular weight ⁇ 60,000)(lanes 5-8), or PAMAM, generation 4 0 (lanes 9-12) Time of exposure times for each polyamine 0 hours (lanes 1, 5, and 9), 4 hours (lanes 2, 6, and 10), 8 hours (lanes 3, 7, and 11), 16 hours (lanes 4, 8, and 12) AU samples were subjected to limited proteolysis to measure PrP Sc Apparent molecular weights based on migration of protem standards are 38, 26, and 15 kDa Lanes of each of the three panels show decreasmg amounts of PrP Sc
- EXAMPLE 3 In this example four panels A,B, C and D were created with panels having three double (control and test) lanes each ScN2a cells were exposed to 1 5 ⁇ g/ml (A) SuperFect, (B) PEI
- PrP Sc levels The lanes 1 control and 3 where chloroqume was added show clear bands for PrP Sc whereas lanes 2 and 4 with no chloroqume show barely detectable amounts of PrP Sc
- the four lanes were prepared as follows ScN2a cells were treated Lane 1 Control media Lane 2 7 5 ⁇ g/ml PEI (average molecular weight ⁇ 60,000) Lane 3 PEI plus 100 ⁇ M chloroqume Lane 4 PEI plus 30 ⁇ M NH 4 C1 Chloroqume and NH 4 C1 were added 1 h p ⁇ or to addition of PEI Cells were harvested 16 hours after addition of PEI AU samples shown were subjected to limited proteolysis to measure PrP Sc Apparent molecular weights based on migration of protem standards are 38, 26, and 15 kDa EXAMPLE 4B Eight lanes with SuperFect (+SF) and eight lanes without SuperFect (-SF) were prepared.
- Lanes 1-8 of each group had an adjusted pH of 3.6 consult 4, 5, 6, 7, 8, 9 and 9.6.
- In vitro mixture of crude mouse brain homogenates with SuperFect under a range of pH conditions was performed as described in methods (measured final pH of each sample denoted above the lanes).
- All samples shown were subjected to limited proteolysis to measure PrP Sc . Apparent molecular weights based on migration of protein standards are 30 and 27 kDa.
- AU lanes of the -SF group showed PrP Sc present.
- Lanes 3-8 of the +SF group showed PrP Sc .
- lanes 1 and 2 with respective pH levels of 3.6 and 4.0 showed very slight detectable PrP Sc .
- the results show that the ability of a blanched polycation such as SuperFect to clear PrP Sc is pH dependent.
- EXAMPLE 5 Sixteen different lanes were prepared as described. Lanes 1 and 2 were control lanes and each of lanes 3-16 contained a different compound as tested in Table 1. The test compounds were all polyamines. Thus, the results show removal of PrP Sc from brain homogenate in vitro by various polyamines. Samples were incubated with polyamines at pH 3.6 and processed as described in Methods. Each polyamine was tested at 60 ⁇ g/ml concentration. Lanes 1 and 2: control. Lane 3: poly-(L)lysine. Lane 4: PAMAM, generation 0.0. Lane 5: PAMAM, generation 1.0. Lane 6: PAMAM, generation 2.0. Lane 7: PAMAM, generation 3.0. Lane 8: PAMAM, generation 4.0.
- Lane 9 PAMAM-OH, generation 4.0.
- Lane 10 PPI, generation 2.0.
- Lane 11 PPI, generation 4.0.
- Lane 12 linear PEI.
- Lane 13 high MW PEI.
- Lane 14 low MW PEI.
- Lane 15 average MW PEI.
- Lane 16 SuperFect.
- AU samples shown were subjected to limited proteolysis to measure PrP Sc . Apparent molecular weights based on migration of protein standards are 30 and 27 kDa.Table 1. Removal of PrP Sc by polymer compounds.
- IC50 approximate concentration of polymer required to reduce PrP Sc to 50% of control levels in ScN2a cells after exposure for 16 hours. AU compounds were tested at 5 different concentrations. PrP Sc levels were measured by densitometry of Western blot signals.
- DOTAP DOTAP -mediated transfection
- 15 ⁇ g pSPOX MHM2 was resuspended in 150 ⁇ l ste ⁇ le Hepes Buffered Salme (HBS) on the day of transfection
- HBS Hepes Buffered Salme
- the DNA solution was then mixed with an equal volume of 333 ⁇ g/ml DOTAP (Boehringer Mannheim) m HBS m Falcon 2059 tubes and mcubated at room temperature for 10 minutes to allow formation of DNA/lipid complexes Supplemented DME (2 5 ml) was added to the mixture, and this was then pipetted onto drained cell monolayers The following day, the medium containing DNA/lipid was removed and replaced with fresh supplemented DME Cells were harvested three days later
- the dendrimer SuperfectTM was used to determine if it could exert a similar inhibitory effect on PrP Sc in either crude brain homogenates or purified PrP 27-30 rods.
- Homogenates were adjusted to 10 mg/ml protein with PBS and 50 ⁇ l was added to 450 ⁇ l of lysis buffer containing 100 mM NaCl, 1 mM EDTA, 0.55% sodium deoxycholate, 0.55% Triton X-100, and 50 mM Tris-HCl pH 7.5.
- the SuperfectTM compound is a high molecular weight component of heat-degraded PAMAM Starburst dendrimers, which is a catiomc, highly-branched, monodisperse polymers (Tang et al , (1996) Bioconjugate Chem 1 703-714)
- PAMAM Starburst dendrimers which is a catiomc, highly-branched, monodisperse polymers
- To identify other potentially usefid anti-pnon therapeutic agents we screened three other dendntic polycations and two lmear catiomc polymers for their ability to clear PrP Sc from ScN2a cells Among the dendntic macromolecules tested, polyetheleneimine (PEI) was the most potent, removing the majonty of PrP Sc from ScN2a cells after 3 hrs when used at a concentration of 10 ⁇ g/ml Intact PAMAM displayed a potency comparable to SuperfectTM, removing approximately half of the detectable
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BR0011055-8A BR0011055A (en) | 1999-06-01 | 2000-05-24 | Sterilization method |
NZ515607A NZ515607A (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing |
EP00932766A EP1187622A4 (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing |
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MXPA01012357A MXPA01012357A (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing. |
IL14676900A IL146769A0 (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing |
JP2000620963A JP2003500169A (en) | 1999-06-01 | 2000-05-24 | Sterilization method |
KR1020017015483A KR20020006050A (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing |
AU50441/00A AU771547B2 (en) | 1999-06-01 | 2000-05-24 | Method of sterilizing |
AU2004202594A AU2004202594A1 (en) | 1999-06-01 | 2004-06-11 | Method of sterilizing |
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US09/322,903 US6214366B1 (en) | 1999-06-01 | 1999-06-01 | Clearance and inhibition of conformationally altered proteins |
US09/322,903 | 1999-06-15 | ||
US09/406,972 | 1999-09-28 | ||
US09/406,972 US6419916B1 (en) | 1999-06-01 | 1999-09-28 | Assay for compounds which affect conformationally altered proteins |
US09/447,456 | 1999-11-22 | ||
US09/447,456 US6331296B1 (en) | 1999-06-01 | 1999-11-22 | Food additives which affect conformationally altered proteins |
US09/494,814 | 2000-01-31 | ||
US09/494,814 US6322802B1 (en) | 1999-06-01 | 2000-01-31 | Method of sterilizing |
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Cited By (12)
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WO2001054736A2 (en) * | 2000-01-31 | 2001-08-02 | The Regents Of The University Of California | Compositions treated to inactivate infectious proteins |
US6517855B2 (en) | 1999-06-01 | 2003-02-11 | The Regents Of The University Of California | Method of sterilizing |
US6720355B2 (en) | 1997-02-21 | 2004-04-13 | The Regents Of The University Of California | Sodium dodecyl sulfate compositions for inactivating prions |
US6719988B2 (en) | 1997-02-21 | 2004-04-13 | The Regents Of The University Of California | Antiseptic compositions for inactivating prions |
WO2004047869A1 (en) * | 2002-11-26 | 2004-06-10 | Danmarks Fødevareforskning | Dendrimer conjugates for selective of protein aggregates |
JP2005519088A (en) * | 2002-02-28 | 2005-06-30 | マイクロセンズ バイオファージ リミテッド | Abnormal prion protein binding |
DE102004040119A1 (en) * | 2004-08-18 | 2006-04-27 | Heinrich-Heine-Universität Düsseldorf | Agent, useful for e.g. inactivating infectious prion and decontaminating device, instrument or appliance infected with prion, comprises a nano-particle |
AU2002348517B2 (en) * | 2001-10-05 | 2007-04-26 | American Sterilizer Company | In vitro model for priocidal activity |
WO2008137195A1 (en) * | 2007-05-01 | 2008-11-13 | General Electric Company | Method for removing microbes from surfaces |
US7981444B2 (en) | 2004-04-20 | 2011-07-19 | Dendritic Nanotechnologies, Inc. | Dendritic polymers with enhanced amplification and interior functionality |
US7985424B2 (en) | 2004-04-20 | 2011-07-26 | Dendritic Nanotechnologies Inc. | Dendritic polymers with enhanced amplification and interior functionality |
WO2015145100A1 (en) * | 2014-03-28 | 2015-10-01 | Gama Healthcare Ltd | A liquid antimicrobial composition |
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US8324372B2 (en) * | 2007-07-13 | 2012-12-04 | Handylab, Inc. | Polynucleotide capture materials, and methods of using same |
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- 2000-05-24 AU AU50441/00A patent/AU771547B2/en not_active Ceased
- 2000-05-24 BR BR0011055-8A patent/BR0011055A/en not_active IP Right Cessation
- 2000-05-24 MX MXPA01012357A patent/MXPA01012357A/en not_active Application Discontinuation
- 2000-05-24 KR KR1020017015483A patent/KR20020006050A/en not_active Application Discontinuation
- 2000-05-24 EP EP00932766A patent/EP1187622A4/en not_active Withdrawn
- 2000-05-24 WO PCT/US2000/014353 patent/WO2000072851A1/en not_active Application Discontinuation
- 2000-05-24 CA CA002375237A patent/CA2375237A1/en not_active Abandoned
- 2000-05-24 IL IL14676900A patent/IL146769A0/en unknown
- 2000-05-24 JP JP2000620963A patent/JP2003500169A/en not_active Withdrawn
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Cited By (26)
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US7226609B2 (en) | 1997-02-21 | 2007-06-05 | The Regents Of The University Of California | Sodium dodecyl sulfate compositions for inactivating prions |
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WO2001054736A3 (en) * | 2000-01-31 | 2002-05-16 | Univ California | Compositions treated to inactivate infectious proteins |
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EP1187622A1 (en) | 2002-03-20 |
KR20020006050A (en) | 2002-01-18 |
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JP2003500169A (en) | 2003-01-07 |
IL146769A0 (en) | 2002-07-25 |
BR0011055A (en) | 2002-05-21 |
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