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WO2011088474A2 - Sulindac et dérivés de sulindac et leurs applications aux infections - Google Patents

Sulindac et dérivés de sulindac et leurs applications aux infections Download PDF

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Publication number
WO2011088474A2
WO2011088474A2 PCT/US2011/021587 US2011021587W WO2011088474A2 WO 2011088474 A2 WO2011088474 A2 WO 2011088474A2 US 2011021587 W US2011021587 W US 2011021587W WO 2011088474 A2 WO2011088474 A2 WO 2011088474A2
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WIPO (PCT)
Prior art keywords
subject
virus
infection
sulindac
compound
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PCT/US2011/021587
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WO2011088474A3 (fr
Inventor
Natalie Mcdonald
James Murray
Thomas Hodge
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PERRYMAN DAVID
Zirus Inc
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PERRYMAN DAVID
Zirus Inc
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • compositions and methods relate to the use of compounds for decreasing infection by a pathogen. More particularly, the compositions and methods relate to the use of sulindac, sulindac sulfide, sulindac sulfone and their derivatives, for decreasing infection in a subject by a virus.
  • Figure 1 shows an antiviral dose response curve for sulindac.
  • Figure 2 shows an antiviral dose response curve for sulindac.
  • Figure 3 shows relative cell densities of MRC-5 cells infected with HRV1 A (4 days post-infection, inoculum not washed away).
  • Figure 4 shows relative cell densities of MRC-5 cells infected with HRV1 A (4 days post-infection, inoculum not washed away).
  • Figure 5 shows relative CPE inhibition in the presence of drugs / antagonists
  • Figure 8 discloses sulindac and sulindac-related compounds. There are 136 compounds disclosed in this figure. Any of the 1 6 compounds disclosed herein can be used with any of the methods disclosed herein. Each of the 136 compounds is listed with its formula and IUPAC name.
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • subject is meant an individual.
  • the subject is a mammal such as a primate, and, more preferably, a human.
  • Non-human primates include marmosets, monkeys, chimpanzees, gorillas, orangutans, and gibbons, to name a few.
  • subject includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (for example, ferret, chinchilla, mouse, rabbit, rat, gerbil, guinea pig, etc.) and avian species (for example, chickens, turkeys, ducks, pheasants, pigeons, doves, parrots, cockatoos, geese, etc.).
  • livestock for example, cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals for example, ferret, chinchilla, mouse, rabbit, rat, gerbil, guinea pig, etc.
  • avian species for example, chickens, turkeys, ducks, pheasants, pigeons, doves, parrots, cockatoos, geese, etc.
  • the subjects can also include, but are not limited to fish (for
  • a "moiety” is part of a molecule (or compound, or analog, etc.).
  • a “functional group” is a specific group of atoms in a molecule.
  • a moiety can be a functional group or can include one or functional groups.
  • aryl as used herein is a ring radical containing 6 to 18 carbons, or preferably 6 to 12 carbons, comprising at least one aromatic residue therein.
  • aryl radicals examples include phenyl, naphthyl, and isochroman radicals.
  • aryl as used throughout the specification and claims is intended to include both "unsubstituted aryls" and “substituted aryls", the later denotes an aryl ring radical as defined above that is substituted with one or more, preferably 1, 2, or 3 organic or inorganic substituent groups, which include but are not limited to a halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido acyloxy, nitro, cyano, carboxy, carboalkoxy, al
  • the organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "aryl” can themselves be substituted, as described above, if appropriate.
  • heteroaryl refers to an aryl ring radical as defined above, wherein at least one of the aryl ring carbons has been replaced with a heteroatom, which include but are not limited to nitrogen, oxygen, and sulfur atoms.
  • heteroaryl residues include pyridyl, bipyridyl, furanyl, and thiofuranyl residues.
  • Substituted "heteroaryl” residues can have one or more organic or inorganic substituent groups, as referred to hereabove for aryl groups, bound to the carbon atoms of the heteroaromatic rings.
  • the organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon moiety.
  • "Unbranched” or “Branched” alkyls comprise a non-cyclic, saturated, straight or branched chain hydrocarbon moiety having from 1 to 24 carbons, 1 to 12 carbons, 1 to 6 carbons, or 1 to 4 carbon atoms.
  • alkyl radicals examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, n-propyl, wo-propyl, butyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.
  • alkyl as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter denotes an alkyl radical analogous to the above definition that is further substituted with one, two, or more additional organic or inorganic substituent groups.
  • Suitable substituent groups include but are not limited to H, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkoxy, heteroaryl, substituted heteroaryl, aryl
  • an "alkoxy” can be a substitutent of a carbonyl substituted "alkyl” forming an ester. When more than one substituent group is present then they can be the same or different.
  • the organic substituent moieties can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "alkyl" chain can themselves be substituted, as described above, if appropriate.
  • lower alkyl refers to a C 1-4 alkyl group, and includes both substituted and substituted lower alkyls.
  • cycloalkyl refers to a hydrocarbon structure wherein the structure is closed to form at least one ring.
  • Cycloalkyls typically comprise a cyclic radical containing 3 to 8 ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.
  • Cycloalkyl radicals can be multicyclic and can contain a total of 3 to 18 carbons, or preferably 4 to 12 carbons, or 5 to 8 carbons. Examples of multicyclic cycloalkyls include decahydronapthyl, adamantyl, and like radicals.
  • cycloalkyl as used throughout the specification and claims is intended to include both “unsubstituted cycloalkyls” and “substituted cycloalkyls", the later denotes an cycloalkyl radical analogous to the above definition that is further substituted with one, two, or more additional organic or inorganic substituent groups that can include but are not limited to hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamid
  • cycloalkenyl refers to a cycloalkyl radical as defined above that comprises at least one carbon-carbon double bond. Examples include but are not limited to cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2- cyclopeiitenyl, 3-cyclopentenyl, 1-cyclohexyl, 2-cyclohexyl, 3-cyclohexyl and the like.
  • alkenyl refers to an alkyl residue as defined above that also comprises at least one carbon-carbon double bond. Examples include but are not limited to vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl and the like.
  • alkenyl includes dienes and trienes of straight and branch chains.
  • alkynyl refers to an alkyl residue as defined above that further comprises at least one carbon-carbon triple bond. Examples include but are not limited ethynyl, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 - pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and the like.
  • alkynyl includes di- and tri-ynes.
  • alkoxy refers to an alkyl residue, as defined above, bonded directly to an oxygen atom, which is then bonded to another moiety. Examples include methoxy, ethoxy, n-propoxy, wo-propoxy, n-butoxy, -butoxy, « ⁇ -butoxy and the like.
  • substituted refers to an -OR group, in which R is an alkyl group that bears at least one substituent.
  • cycloalkoxy refers to an alkoxy group in which the alkyl portion is cycloalkyl.
  • haloalkoxy refers to a haloalkyl residue as defined above that is directly attached to an oxygen to form trifluoromethoxy
  • halo- As used herein, the terms "halo-,” “halogen,” “halogenated” and similar terms refer to a fluoro, chloro, bromo or iodo group.
  • haloalkyl refers to an alkyl residue as defined above, that is substituted with one or more halogens, such as a trifluoromethyl, pentafluoroethyl, chloromethyl and the like.
  • acyl refers to a R-C(O)- residue having an organic R group containing 1 to 8 carbons. Examples include but are not limited to formyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, and natural or un-natural amino acids.
  • acyloxy refers to an acyl radical as defined above, directly attached to an oxygen to form an organic R-C(O)0- residue. Examples include but are not limited to acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.
  • azide As used herein, the term “azide”, “azido” and their variants refer to any moiety or compound comprising the monovalent group -N3 or the monovalent ion ⁇ 3 " ⁇ .
  • hydroxy and "hydroxyl” as used herein refer to an -OH group.
  • hydroxyalkyl refers to an alkyl substituent that is substituted with a hydroxyl group.
  • cyano refers to a -C ⁇ N group.
  • amino as used herein without modification refers to a -NH 2 group.
  • alkylamine and “alkylamino” as used herein refer to a moiety comprising an NH radical substituted with one organic substituent group, which includes but is not limited to alkyls, substituted alkyls, cycloalkyls, aryls, or arylalkyls.
  • alkylamino groups include methylamino (-NH-CH 3 );
  • ethylamino (-NHCH 2 CH 3 ), hydroxyethylamino (-NH-CH 2 CH 2 OH), and the like.
  • aminoalkylamino refers to an alkylamino group in which the alkyl portion is substituted with an additional amino group.
  • hydroxyalkylamino refers to an alkylamino group in which the alkyl portion is further substituted with a hydroxyl group.
  • polyhydroxyalkylamino refers to an alkylamino group in which the alkyl portion is further substituted with two or more hydroxyl groups.
  • dialkylamine and “dialkylamino” as used herein refer to a moiety comprising a nitrogen atom substituted with two organic radicals that can be the same or different, which can be selected from but are not limited to aryl, substituted aryl, alkyl, substituted alkyl or arylalkyl, wherein the terms have the same definitions found throughout. Some examples include dimethylamino, methylethylamino, diethylamino and the like.
  • dialkylaminoalkyl refers to a dialkylamino group in which the amino portion is substituted upon an additional alkyl group.
  • dialkylaminoalkylamino refers to a dialkylamino group in which the amine portion is substituted upon an additional alkyl group, and that additional alkyl group is further substituted upon a second amino group.
  • N-morpholino refers to a substituent in which the nitrogen atom of morpholine [6-member ring -N-(CH 2 )-(CH 2 )-0-(CH 2 )-(CH 2 )-] is bonded to an organic moiety.
  • alkylthio refers to a -S-R substituent in which R is an alkyl group.
  • alkylsulfide refers to a -R-S-R' substituent in which R and R' are independently alkyl groups.
  • mercapto refers to a -S-H substituent.
  • carboxy refers to (Nl ⁇ CO in which at least one of the hydrogen atoms is replaced by a bond to an organic moiety.
  • cation refers to a species bearing a positive charge of 1 + or higher. Such cations include but are not limited to the alkali metal cations, alkaline earth metal cations, transition metal cations, ammonium salts, sulfonium salts, phosphonium salts, cycloheptatrienyl cations, hydroazulenium, and other positively charged species.
  • esters as used herein is represented by the formula— C(O)OR, where R can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • carbonate group as used herein is represented by the formula -OC(O)O , where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • keto group as used herein is represented by the formula -C(O)R, where R is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • aldehyde as used herein is represented by the formula -C(O)H or -R- C(O)H, wherein R can be alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • carboxyl and “carboxylic acid” as used herein refer to a moiety having the formula -C(O)OH.
  • ether as used herein is represented by the formula AOA 1 , where A and A 1 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • urethane as used herein is represented by the formula -OC(O)NRR ⁇ where R and R' can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • silica group as used herein is represented by the formula -SiRR'R", where R, R', and R" can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy, or heterocycloalkyl group described above.
  • sulfo-oxo group as used herein is represented by the formulas -S(O) 2 R, -OS(O) 2 R, or , -OS(O) 2 0R, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • Disclosed are methods of decreasing infection, in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula I
  • the indene nucleus may be substituted in the 1 -position by an aryl ring system such as benzene, naphthalene or biphenyl or a heteroaryl ring system such as a pyrrole, furan, thiophene, pyridine, imidazole, pyrazine, thiazole, etc.
  • an aryl ring system such as benzene, naphthalene or biphenyl or a heteroaryl ring system such as a pyrrole, furan, thiophene, pyridine, imidazole, pyrazine, thiazole, etc.
  • alkylsulfinyl or alkylsulfonyl substituent which contains an alkylsulfinyl or alkylsulfonyl substituent and may be further substituted with a halogen (chloro, fluoro or bromo), hydroxy, alkoxy (methoxy, ethoxy, propoxy, etc.) or halo alkyl (fluoromethyl, ehloromethyl, trifluoromethyl, etc.) group.
  • halogen chloro, fluoro or bromo
  • hydroxy alkoxy
  • alkoxy methoxy, ethoxy, propoxy, etc.
  • halo alkyl fluoromethyl, ehloromethyl, trifluoromethyl, etc.
  • R 3 , R 4 , R 5 and R 6 each may be halogen (fluoro, chloro or bromo), lower alkoxy (methoxy, ethoxy .i-propoxy, etc.), lower alklower alkyl (methyl, ethyl, propyl, isopropyl, etc.), nitro, amino or substituted amino such as dialkylamino, acylamino, alkylamine, etc.
  • R 3 , R 4 , R 5 and R 6 are not however limited to this class and may, if desired, represent substituents such as hydrogen, aryl, aryloxy, hydroxy, mercapto, haloalkyl, sulfamyl, carboxy, carboalkoxy, carbamide and many other groups.
  • the compounds disclosed herein may be isomerized into their cis and trans isomers by procedures well known in the art. It should be further noted that the cis isomer of the compounds is substantially more active than the trans isomer. Accordingly, it is to be understood that reference throughout the specification and appended claims to these compounds is intended to encompass not merely the compounds per se but includes their geometric isomers (cis, trans).
  • alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl derivatives can be racemic mixtures of optically active enantiomorphs which may be resolved into their (+) and (-) forms by techniques well known in the art.
  • Rl is lower alkyl an additional asymmetric atom results which gives rise to two additional enantiomorphs, which are also considered to be within the scope.
  • Also provided herein is a method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of sulindac wherein the pathogen is not LdMNPV or influenza. Further provided are methods of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of a compound having the structure of formula I
  • Ar may be aryl or heteroaryl;
  • R 1 may be hydrogen, lower alkyl or halogenated lower alkyl;
  • R 2 may be hydrogen or alkyl;
  • R 3 , R 4 , R 5 and R 6 each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy;
  • R7 may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl, for example methylsulfinyl, methylsulfide, methylthio,
  • Ar is a phenyl ring, and R7 is bonded at the ring's para- position.
  • methods of decreasing infection in a subject by a pathogen by said method comprising administering to the subject an effective amount of sulindac having the structure of formula II
  • kits for decreasing in a subject infection by a respiratory virus comprising administering to the subject an effective amount of sulindac having the structure of formula II wherein the compound decreases infection in the subject.
  • Disclosed herein is a method of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of sulindac having the structure of formula II wherein the respiratory virus is a rhinovirus, and wherein the compound decreases infection in the subject.
  • kits for decreasing in a subject infection by a respiratory virus comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula I I I wherein the compound decreases infection in the subject.
  • kits for decreasing infection in a subject by a respiratory virus comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula I II wherein the respiratory virus is a rhinovims, and wherein the compound decreases infection in the subject.
  • kits for decreasing infection in a subject by a respiratory virus comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV wherein the compound decreases infection in the subject.
  • a method of decreasing infection in a subject by a respiratory virus comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV wherein the respiratory virus is a rhinovirus, and wherein the compound decreases infection in the subject.
  • the subject can be found to be in need of a decrease in infection.
  • the subject can be diagnosed with an infection, such as a viral infection.
  • the viral infection can be a respiratory virus, such as rhinovirus.
  • Methods of detecting a viral infection are known to those of skill in the art.
  • viral infections can be diagnosed via growth of the virus in a cell culture from a specimen taken from the subject, or by detection of virus-specific antibodies in the blood, or by detection of virus antigens, or by detection of virus nucleic acids, or by observation of virus particles by electron microscopy, or by hemagglutination assay. Examples of detecting viruses ca be found, for example, in U.S. Patent Applications
  • Also disclosed herein is a method of decreasing infection in a subject by a pathogen comprising: a) determining that a subject has an infection; and b) administering to the subject an effective amount of a compound having the structure of formula I
  • the subject is diagnosed with an infection prior to treatment.
  • the infection can be a viral infection, and can be diagnosed by the methods previously disclosed.
  • a method of preventing infection by a pathogen in a subject comprising administering to the subject an effective amount of a compound to prevent infection having the structure of any one of formulas I-I V.
  • the subject can be found to be in need of prevention of infection. Examples include, but are not limited to, a COPD or asthma patient and/or an immune suppressed patient.
  • Also disclosed is a method of inhibiting or reducing virus replication comprising administering to the subject an effective amount of a compound to inhibit or reduce the virus replication having the structure of any one of formulas I-IV.
  • Inhibiting or reducing viral replication includes the spread to additional host cells or tissues.
  • any of the compounds disclosed herein can be administered in combination with an additional therapeutic agent, including more than one additional therapeutic agents.
  • the therapeutic agent can be an antiviral compound, antibacterial agent, antifungal agent, antiparasitic agent, anti-inflammatory agent, or anti-cancer agent.
  • the therapeutic agent can be used to treat rhinovirus or influenza, for example.
  • the additional therapeutic agent can be in the same or in a different formulation as the compound having the structure of any one of formulas I-IV.
  • the subject can be diagnosed with asthma prior to treatment.
  • the asthma or associated conditions can be treated or prevented by treating or preventing rhinovirus.
  • exacerbations is meant a worsening of the disease or symptoms compared to what it would have been if the subject were not infected with a virus, such as rhinovirus.
  • the subject can be 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times worse compared to the subject's symptoms without rhinovirus present.
  • COPD chronic obstructive pulmonary disease
  • exacerbations comprising administering to the subject a compound having the structure of any one of formulas I-IV, thereby treating or preventing COPD or associated conditions.
  • the COPD or associated conditions can be treated or prevented by treating or preventing rhinovirus.
  • the compounds disclosed herein can be administered intranasally, orally, or intramuscularly.
  • the compound can also be administered via inhalation.
  • a compound having the structure of formula I (sulindac) and an additional therapeutic agent.
  • the therapeutic agent can be an anti-infective agent, such as an antiviral agent.
  • antiviral agents are disclosed herein.
  • compositions comprising sulindac formulated for antiviral administration in a dose that decreases at least one adverse clinical side effect of the clinically approved sulindac (150mg or 200mg twice daily dose).
  • the dosage can be, for example, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 160, 170, 180, 190 mg, or any amount below, or in between that decreases at least one adverse clinical side effect.
  • the dosage is typically administered twice daily for a total daily dose.
  • the methods provided herein could utilize a total daily dose of less than 400mg or 300mg per day, for example 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 1 0, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 310, 320, 330, 340, 350, 360, 370, 380, 390 mg per day, or any amount below or in between that decreases at least one adverse clinical side effect compared to the currently approved 300mg and 400mg daily sulindac dose.
  • composition comprising sulindac in packaging having a label with a decreased adverse clinical side effect profile compared to sulindac approved in the United States for arthritis (Osteoarthritis, Rheumatoid arthritis), Ankylosing spondylitis, Acute painful shoulder (Acute subacromial
  • the composition can be modified for example by changing the dose, or formulation.
  • a label having decreased adverse clinical side effect profile can be obtained by changing the dosage, formulation, administration frequency, or administration course of sulindac.
  • sulindac could be administered for shorter duration than it is currently utilized, for example for a single dose, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 day administration course.
  • the dose of sulindac could be greater than the currently approved 150 and 200mg twice a day dose (for example 250, 300mg etc.).
  • it could be administered other than twice a day (for example once a day, three times a day, four times a day etc.).
  • Sulindac potential side effects include ulcer with gastrointestinal bleeding and stomach perforation, and severe hypersensitivity with liver failure.
  • the current sulindac label can be found in Example 4.
  • Congestive heart failure especially in patients with marginal cardiac function; palpitation; hypertension, thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants.
  • Vertigo insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease.
  • Blurred vision visual disturbances; decreased hearing; metallic or bitter taste.
  • a potentially fatal apparent hypersensitivity syndrome has been reported.
  • This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions— see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).
  • a rare occurrence of fulminant necrotizing fasciitis particularly in association with Group A ⁇ -hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, sometimes with fatal outcome.
  • “Pharmaceutically acceptable salts” are those salts derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali metal (e.g.
  • salts include hydrochlorides, hydrobromides, sulfates, mesylates, maleates, and fumarates.
  • references to a compound include the compounds as well as its pharmaceutically acceptable salts.
  • An infection can be a viral infection, bacterial infection, fungal infection or a parasitic infection, to name a few. All strains and types of pathogenic infection are contemplated herein. A decrease or inhibition of infection can occur in a cell, in vitro, ex vivo or in vivo.
  • infection encompasses all phases of pathogenic life cycles including, but not limited to, attachment to cellular receptors, entry, internalization, disassembly, replication, genomic integration of pathogenic sequences, transcription of viral RNA, translation of viral RNA, transcription of host cell mRNA, translation of host cell mRNA, proteolytic cleavage of pathogenic proteins or cellular proteins, assembly of particles, endocytosis, cell lysis, budding, and egress of the pathogen from the cells, alone or combination.
  • a decrease in infection can be a decrease in attachment to cellular receptors, a decrease in entry, a decrease in internalization, a decrease in disassembly, a decrease in replication, a decrease in genomic integration of pathogenic sequences, a decrease in translation of mRNA, a decrease in proteolytic cleavage of pathogenic proteins or cellular proteins, a decrease in assembly of particles, a pathogen from the cells.
  • This decrease does not have to be complete as this can range from decrease in endocytosis, a decrease in cell lysis, a decrease in budding, or a decrease in egress of the a slight decrease to complete ablation of the infection.
  • a decrease in infection can be at least about 10%, 20%, 30%, 40%, 50%, 60, 70%, 80%, 90%, 95%, 100% or any other percentage decrease in between these percentages as compared to the level of infection in a cell that has not been contacted with a compound set forth herein.
  • treatment is meant a method of reducing the effects of an existing infection.
  • Treatment can also refer to a method of reducing the disease or condition itself rather than just the symptoms.
  • the treatment can be any reduction from native levels and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease.
  • Treatment can range from a positive change in a symptom or symptoms of viral infection to complete amelioration of the viral infection as detected by art-known techniques.
  • a disclosed method is considered to be a treatment if there is about a 10% reduction in one or more symptoms of the disease in a subject with the disease when compared to native levels in the same subject or control subjects.
  • a decrease in infection can be a decrease of hours, a day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days or any time in between that it takes to see improvement in the symptoms, viral load or any other parameter utilized to measure improvement in a subject. For example, if it normally takes 7 days to see improvement in a subject not taking the composition, and after administration of the composition, improvement is seen at 6 days, the composition is effective in decreasing infection. This example is not meant to be limiting as one of skill in the art would know that the time for improvement can vary depending on the infection.
  • prevent is meant a method of precluding, delaying, averting, obviating, forestalling, stopping, or hindering the onset, incidence, severity, or recurrence of infection.
  • the disclosed method is considered to be a prevention if there is about a 10% reduction in onset, incidence, severity, or recurrence of infection, or symptoms of infection (e.g., inflammation, fever, lesions, weight loss, etc.) in a subject exposed to an infection when compared to control subjects exposed to an infection that did not receive a composition for decreasing infection.
  • the reduction in onset, incidence, severity, or recurrence of infection can be about a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to control subjects. For example, and not to be limiting, if about 10% of the subjects in a population do not become infected as compared to subjects that did not receive preventive treatment, this is considered prevention.
  • viral infections include but are not limited to, infections caused by RNA viruses (including negative stranded RNA viruses, positive stranded RNA viruses, double stranded RNA viruses and retroviruses) and DNA viruses. All strains, types, subtypes of DNA and RNA viruses are contemplated herein.
  • RNA viruses include, but are not limited to picornaviruses, which include aphthoviruses (for example, foot and mouth disease virus O, A, C, Asia 1, SAT1, SAT2 and SAT3), cardioviruses (for example, encephalomycarditis virus and Theiller's murine encephalomyelitis virus), enteroviruses (for example polioviruses 1 , 2 and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses 1-7, 9, 1 1-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10 and simian enteroviruses 1-18), erboviruses (for example, equine rhinitis virus), hepatovirus (for example human hepatitis A virus and a
  • parechoviruses for example, human parechovirus 1 and human parechovirus 2
  • rhinovirus for example, rhinovirus A, rhinovirus B, rhinovirus C, HRV16, HRVit (VR-1 1757), HRV14 (VR-284), or HRV 1A (VR-1559), human rhinovirus 1-100 and bovine rhinoviruses 1-3) and teschoviruses (for example, porcine teschovirus).
  • RNA viruses include caliciviruses, which include noroviruses (for example, Norwalk virus), sapoviruses (for example, Sapporo virus), lagoviruses (for example, rabbit hemorrhagic disease virus and European brown hare syndrome) and vesiviruses (for example vesicular exanthema of swine virus and feline calicivirus).
  • noroviruses for example, Norwalk virus
  • sapoviruses for example, Sapporo virus
  • lagoviruses for example, rabbit hemorrhagic disease virus and European brown hare syndrome
  • vesiviruses for example vesicular exanthema of swine virus and feline calicivirus.
  • RNA viruses include astroviruses, which include mastorviruses and avastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis, Getah virus, Everglades virus, Venezuelan equine encephalitis virus and Aura virus) and rubella viruses.
  • alphaviruses for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis, Getah virus, Everglades virus, Venezuelan equine encephalitis virus and Aura virus
  • rubella viruses for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis, Getah virus, Everglades virus, Venezuelan equine encephalitis virus and Aura virus
  • RNA viruses include the flaviviruses (for example, tick-borne encephalitis virus, Tyuleniy virus, Aroa virus, Dengue virus (types 1 to 4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Kokobera virus, Ntaya virus, Spondweni virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, Cell fusing agent virus, pestivirus, GB virus A, GBV-A like viruses, GB virus C, Hepatitis G virus, hepacivirus (hepatitis C virus (HCV)) all six genotypes), bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).
  • flaviviruses for example, tick-borne encephalitis virus, Tyuleniy virus, Aroa virus, Dengue virus (types 1 to 4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Koko
  • RNA viruses are the coronaviruses, which include, human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63 and HCoV- OC43. Coronaviruses also include bat SARS-like CoV, turkey coronavirus, chicken coronavirus, feline coronavirus and canine coronavirus. Additional RNA viruses include arteriviruses (for example, equine arterivirus, porcine reproductive and respiratory syndrome virus, lactate dehyrogenase elevating virus of mice and simian hemorraghic fever virus).
  • human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63 and HCoV- OC43. Coronaviruses also include bat SARS-like CoV, turkey coronavirus, chicken coronavirus, feline coronavirus and canine coronavirus.
  • Additional RNA viruses include arteriviruses (for
  • RNA viruses include the rhabdoviruses, which include Iyssaviruses (for example, rabies, Lagos bat virus, Mokola virus, Duvenhage virus and European bat lyssavirus), vesiculoviruses (for example, VSV-Indiana, VSV- New Jersey, VSV-Alagoas, Piry virus, Cocal virus, Maraba virus, Isfahan virus and Chandipura virus), and ephemeroviruses (for example, bovine ephemeral fever virus, Sydney River virus and Berrimah virus).
  • RNA viruses include the filoviruses. These include the Marburg and Ebola viruses (for example, EBOV-Z, EBOV-S, EBOV-IC and EBOV-R.
  • the paramyxoviruses are also RNA viruses.
  • these viruses are the rubulaviruses (for example, mumps, parainfluenza virus 5, human parainfluenza virus type 2, Mapuera virus and porcine rubulavirus), avulaviruses (for example, Newcastle disease virus), respoviruses (for example, Sendai virus, human parainfluenza virus type 1 and type 3, bovine parainfluenza virus type 3), henipaviruses (for example, Hendra virus and Nipah virus), morbilloviruses (for example, measles, Cetacean morvilliirus, Canine distemper virus, Peste-des-petits-ruminants virus, Phocine distemper virus and Rinderpest virus), pneumoviruses (for example, human respiratory syncytial virus A2, Bl and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (for example, human respiratory syncy
  • Additional paramyxoviruses include Fer-de-Lance virus, Tupaia paramyxovirus, Menangle virus, Tioman virus, Beilong virus, J virus, Mossman virus, Salem virus and Nariva virus.
  • Additional RNA viruses include the orthomyxoviruses.
  • influenza viruses and strains e.g., influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza A H1N1 (including but not limited to A/WS/33, A/NWS/33 and A California/04/2009 strains) influenza B, influenza B strain Lee, and influenza C viruses
  • influenza viruses and strains e.g., influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza A H1N1 (including but not limited to A/WS/33, A/NWS/33 and A California/04/2009 strains) influenza B, influenza B strain Lee, and influenza C viruses
  • H 2 N2, H3N2, H5N1, H7N7, H 1N2, H9N2, H7N2, H7N3 and H 10N7 H 2 N2, H3N2, H5N1, H7N7, H 1N2, H9N2, H7N2, H7N3 and H 10N7
  • Orthobunyaviruses for example, Akabane virus, California encephalitis, Cache Valley virus, Snowshoe hare virus,
  • nairoviruses for example, Washington sheep virus, Crimean-Congo hemorrhagic fever virus Group and Hughes virus
  • phlebo viruses for example, Candiru, Punta Toro, Rift Valley Fever, Sandfly Fever, Naples, Toscana, Sicilian and Chagres
  • hantaviruses for example, Hantaan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andes and Thottapalayam
  • RNA viruses for example, Akabane virus, California encephalitis, Cache Valley virus, Snowshoe hare virus,
  • nairoviruses for example, Washington sheep virus, Crimean-Congo hemorrhagic fever virus Group and Hughes virus
  • phlebo viruses for example, Candiru, Punta Toro, Rift Valley
  • Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV and WWAV are also RNA viruses.
  • Borna disease virus is also an RNA virus.
  • Hepatitis D (Delta) virus and hepatitis E are also RNA viruses.
  • RNA viruses include reoviruses, rotaviruses, birnaviruses, chrysoviruses, cystoviruses, hypoviruses partitiviruses and totoviruses.
  • Orbiviruses such as African horse sickness virus, Blue tongue virus, Changuinola virus, Chenuda virus, Chobar Gorge Corriparta virus, epizootic hemorraghic disease virus, equine encephalosis virus, Eubenangee virus, Ieri virus, Great Island virus, Lebombo virus, Orungo virus, Palyam virus, Peruvian Horse Sickness virus, St. Croix River virus, Umatilla virus, Wad Medani virus, Wallal virus, Warrego virus and Wongorr virus are also RNA viruses.
  • Retroviruses include alpharetroviruses (for example, Rous sarcoma virus and avian leukemia virus), betaretroviruses (for example, mouse mammary tumor virus, Mason-Pfizer monkey virus and Jaagsiekte sheep retrovirus), gammaretroviruses (for example, murine leukemia virus and feline leukemia virus, deltraretroviruses (for example, human T cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1 and STLV-2), epsilonretriviruses (for example, Walleye dermal sarcoma virus and Walleye epidermal hyperplasia virus 1), reticuloendotheliosis virus (for example, chicken syncytial virus, lentiviruses (for example, human immunodeficiency virus (HIV) type 1 , human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immuno
  • DNA viruses examples include polyomaviruses (for example, simian virus 40, simian agent 12, B virus, JC virus, Merkel Cell polyoma virus, bovine polyoma virus and lymphotrophic papovavirus), papillomaviruses (for example, human papillomavirus, bovine papillomavirus, adenoviruses (for example, adenoviruses A-F, canine adenovirus type I, canined adeovirus type 2), circoviruses (for example, porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (for example, canine parvovirus), erythroviruses (for example, adeno-associated virus types 1-8), betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, pefudensoviruses, herpes viruses 1 ,2,
  • viruses include, but are not limited to, the animal counterpart to any above listed human virus.
  • the provided compounds can also decrease infection by newly discovered or emerging viruses. Such viruses are continuously updated on http://en.wikipedia.org/wiki/Virus and www.virology.net.
  • bacterial infections include, but are not limited to infections caused by the following bacteria: Listeria (sp.), Franscicella tularensis,
  • Mycobacterium tuberculosis Rickettsia (all types), Ehrlichia, Chlamydia. Further examples of bacteria that can be targeted by the present methods include M.
  • tuberculosis M. bovis
  • M. bovis strain BCG BCG substrains
  • M. avium M.
  • Campylobacter species Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Clostridium tetani, other Clostridium species, Yersinia enterolitica, and other Yersinia species.
  • parasitic infections include, but are not limited to infections caused by the following parasites: Cryptosporidium, Plasmodium (all species), American trypanosomes ( ⁇ .
  • African trypanosomes Acanthamoeba, Entaoeba histolytica, Angiostrongylus, Anisakis, Ascaris, Babesia, Balantidium, Baylisascaris, lice, ticks, mites, fleas, Capillaria, Clonorchis, Chilomastix mesnili, Cyc!spora, Diphyllobothrium, Dipylidium caninum, Fasciola, Giardia, Gnathosioma,
  • Hetetophyes Hymenolepsis, Isospora, Loa loa, Microsporidia, Naegleria, Toxocara, Onchocerca, Opisthorchis, Parago imus, Baylisascaris, Strongyloides, Taenia, Trichomonas and Trichuris.
  • protozoan and fungal species contemplated within the present methods include, but are not limited to, Plasmodium falciparum, other Plasmodium species, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma cruzi, other trypanosomal species, Leishmania donova i, other Leishmania species, Theileria annulata, other Theileria species, Eimeria tenella, other Eimeria species, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, and Candida species.
  • the provided compounds can also decrease infection by newly discovered or emerging bacteria, parasites or fungi, including multidrug resistant strains of same.
  • compositions disclosed herein can also be used to treat multiple infections in the same individual simultaneously.
  • the compositions can also be used to treat various individuals with different pathogenic infections.
  • the compositions disclosed herein can be used to treat an individual with both influenza virus as well as rhinovirus infection.
  • the compositions disclosed herein can be used to treat one individual with influenza virus, and another individual with rhinovirus infection.
  • a compound can be single compound or a mixture, cocktail or combination of two or more compounds, for example, two or more compounds having a structure selected from the group consisting of formula I, II, III and IV, as defined above. It is understood that any compound set forth herein and derivatives of same can be utilized in the methods set forth herein.
  • the compounds set forth herein can be used alone or in combination with other therapeutic agents such as antiviral compounds, antibacterial agents, antifungal agents, antiparasitic agents, anti-inflammatory agents, anti-cancer agents, etc.
  • the compounds set forth herein can be used in combination with antiviral agents that directly target the virus or the host, including for example viral entry inhibitors, un- coating inhibitors, reverse transcription inhibitors, integrase inhibitors,
  • antiviral compounds examples include, but are not limited to, amantadine, rimantadine, ribavirin, zanamivir (Relenza®) and oseltamivir (Tamiflu®) for the treatment of flu and its associated symptoms.
  • Antiviral compounds useful in the treatment of rhinovirus infection include pleconaril and BTA-798.
  • Antiviral compounds useful in the treatment of HIV include, but are not limited to, Combivir® (lamivudine-zidovudine), maraviroc, Crixivan® (indinavir), Emtriva®
  • antiviral compounds useful in the treatment of Ebola and other filoviruses include ribavirin and cyanovirin-N (CV-N).
  • CV-N cyanovirin-N
  • Zovirax®(acyclovir), Valtrex® (valacyclovir), Cytovene® (ganciclovir) and Valcyte® (valganciclovir) are is available.
  • Antibacterial agents include, but are not limited to, antibiotics (for example, penicillin and ampicillin), sulfa Drugs and folic acid Analogs, Beta-Lactams, aminoglycosides, tetracyclines, macrolides, lincosamides, streptogramins, fluoroquinolones, rifampin, mupirocin, cycloserine, aminocyclitol and oxazolidinones.
  • antibiotics for example, penicillin and ampicillin
  • sulfa Drugs and folic acid Analogs Beta-Lactams
  • aminoglycosides aminoglycosides
  • tetracyclines aminoglycosides
  • macrolides macrolides
  • lincosamides lincosamides
  • streptogramins fluoroquinolones
  • rifampin mupirocin
  • cycloserine aminocyclitol and oxazolid
  • Antifungal agents include, but are not limited to, amphotericin, nystatin, terbinafine, itraconazole, fluconazole, ketoconazole, and griselfulvin.
  • Antiparasitic agents include, but are not limited to, anthelmintics, antinematodal agents, antiplatyhelmintic agents, antiprotozoal agents, amebicides, antimalarials, antitrichomonal agents, aoccidiostats and trypanocidal agents.
  • the compositions disclosed herein can also be used to treat or prevent asthma and/or chronic obstructive pulmonary disease (COPD) or associated conditions.
  • COPD chronic obstructive pulmonary disease
  • the compositions can be administered to the patient with or without symptoms of viral infection that exacerbates or causes asthma and/or COPD. Typically, administration occurs as soon as symptoms of infection occur but can be administered at any point after or before infection that treats or prevents the condition.
  • Rhinovirus infection has also been associated with nearly half of all COPD exacerbations, including secondary infections resulting from the viral infection (Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, et al.
  • Epstein-Barr Virus (EBV)
  • EBV Epstein-Barr Virus
  • PTLD lymphoproliferative disorders
  • AIDS-related lymphomas PTLD consists of a heterogenous group of B-cell neoplasias that arise in a setting of immunosuppression and are associated with EBV infection especially in patients lacking antibodies to this virus.
  • the incidence of PTLD ranges from 1% for renal transplant recipients, but can be as high as 9% for heart/lung and 12% for pancreas transplant patients.
  • recent studies indicate that EBV may be related to the development of COPD (McManus et al. High levels of Epstein-Barr virus in COPD. Eur Respir J. 2008 Jun;31(6): 1221-6).
  • compositions disclosed herein such as Sulindac
  • EBV diseases and disorders associated with EBV, for example COPD.
  • Methods of introduction include, but are not limited to, mucosal, topical, intradermal, intrathecal, intratracheal, intranasal, via nebulizer, via inhalation, intramuscular, otic delivery (ear), eye delivery (for example, eye drops), buccal (cheek), intraperitoneal, vaginal, rectal, intravenous, subcutaneous, intranasal, and oral routes.
  • the compounds can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (for example, nasal mucosa, oral mucosa, rectal, vaginal and intestinal mucosa, etc.) and can be administered together with other biologically active agents. Administration can be systemic or local.
  • Pharmaceutical compositions can be delivered locally to the area in need of treatment, for example by topical application or local injection.
  • the compositions disclosed herein can be given via nasal inhaler.
  • the nose can be an important route for the delivery of various substances aimed at treating various ailments.
  • the nose including its various nasal membranes, cavities and passageways, traditionally has been used as a route for the delivery of substances aimed at treating upper respiratory ailments, such as sinusitis, allergic conditions, reactive airway diseases, and rhinitis.
  • substances delivered to a user through their nose are delivered in aerosol or aqueous form through nasal delivery devices, including pressurized metered dose nasal inhalers, nasal spray containers, and dry powder inhalers.
  • nasal delivery devices including pressurized metered dose nasal inhalers, nasal spray containers, and dry powder inhalers.
  • substances delivered to the nose to treat the above noted ailments can be, for example, delivered to the area of the nose having a rich blood vessel plexus. This area of the nose typically is found on the lateral sidewall to the interior of the nose, and encompasses the squamous epithelisum prior to the transitional region to the nasal turbinates.
  • the nasal delivery device can take the form of a spray- pump container or bottle.
  • it can take the form of a pressurized metered dose nasal inhaler, or it can take the form of a simple squeeze-type bottle.
  • the substance can exit the container in the form of a dry powder or as a spray, in aerosol or aqueous form.
  • aerosol means a suspension of fine solid or liquid particles in a gas, including air.
  • the inhalant can also comprise anti-cholinergic agents, adrenegically acting
  • the nasal inhaler can be used with any substance which is capable of being introduced into a chamber and thereafter dispensed through an air exit passageway in response to the inhalation of a patient, the compression of the chamber, the actuation of the container, and/or some combination of those activities.
  • the amount of substance in each dosage can be metered, such that the amount remains relatively constant upon each actuation, or it can vary depending on the actuation force applied by the user. It should be understood that, just as the nasal inhaler can be used without the user affirmatively inhaling, the inhaler also can be used without an actuation of the container. For example, the user can entrain the substance, e.g., a dry powder, into the chamber by generating an air flow through inhalation or compression of the chamber.
  • the substance e.g., a dry powder
  • compositions disclosed herein can also be given in an inhaler to be administered to the lungs.
  • inhalers There are several different types of inhalers. The most common is the pressurized metered-dose inhaler (MDI). In MDIs, medication is most commonly stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension.
  • MDI pressurized metered-dose inhaler
  • medication is most commonly stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension.
  • DPIs dry powder inhalers
  • nebulizers which instead supply the aerosol as a mist created from an aqueous formulation.
  • compositions and formulations suitable for pharmaceutical delivery of the therapeutic agents herein disclosed are conventional.
  • Remington 's Pharmaceutical Sciences, by Martin, Mack Publishing Co., Easton, PA, 15th Edition (1975) describes compositions and formulations suitable for pharmaceutical delivery of the therapeutic agents herein disclosed.
  • the nature of the carrier will depend on the mode of administration being employed.
  • parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, sesame oil, glycerol, ethanol, combinations thereof, or the like, as a vehicle.
  • the carrier and composition can be sterile, and the formulation suits the mode of administration.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, sodium saccharine, cellulose, magnesium carbonate, or magnesium stearate.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Embodiments of the disclosure including medicaments can be prepared with conventional pharmaceutically acceptable carriers, adjuvants and counterions as would be known to those of skill in the art.
  • the amount of therapeutic agent effective in decreasing or inhibiting infection can depend on the nature of the pathogen and its associated disorder or condition, and can be determined by standard clinical techniques. Therefore, these amounts will vary depending on the type of virus, bacteria, fungus, parasite or other pathogen.
  • the dosage can be anywhere from 0.01 mg/kg to 100 mg/kg. This includes 0.01, 0.02, 0.03, 0.04.
  • Sulindac dosages and formulations of Sulindac, and the compounds provided herein, that vary from the 150mg and 200mg doses currently used clinically for Sulindac.
  • Sulindac in doses less than 150mg (e.g. 145, 140, 135, 130, 125, 120, 1 15, 110, 105, 100, 95, 90, 85, 80, 75, 70, 65, 0, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5mg) formulated under GMP for administration to human subjects.
  • the duration of the administration of sulindac can be reduced.
  • the compounds disclosed herein are provided in combination with a safety label with decreased adverse clinical side effect profile compared to Sulindac for inflammation, e.g. at the 150mg or 200mg oral doses for time periods extending beyond the period of acute infections.
  • Multiple dosages can also be administered depending on the type of pathogen, and the subject's condition.
  • in vitro assays can be employed to identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration and in particular for viral infection such as a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa F
  • Caliciviruses Hepatitis A, LaCrosse, California encephalitis, VEE, EEE.WEE, Japanese Encephalitis Virus, yasanur Forest Virus, Yellow Fever, Rabies,
  • Duplicate experiments were performed as follows. Prior to compound exposure cells were seeded into 12-well tissue culture plates and allowed to adhere to the vessel surface. Sulindac was serially diluted and lOOul was added to the growth medium in triplicate wells to obtain the indicated final concentration of compound or solvent. Cells were incubated in the presence of the test compound for 24 hours at 37'C under 5% C0 2 .
  • the pre-treatment medium was then aspirated off the cells, and the specified virus, diluted in serum- and compound-free growth medium, was added to the cells.
  • Virus was allowed to adsorb to the cells at 37°C with the exception of Rhinovirus, which was adsorbed at 33°C, under 5% C0 2 .
  • the viral inoculum was aspirated off the cells and replaced with growth medium supplemented with 2% FBS, 1% L-glutamine, 1% penicillin/streptomycin and the respective concentration of test compound. Cells were incubated under the same conditions for an additional 72 hours.
  • RNA or DNA was extracted using the PureLink 96 Viral RNA/DNA extraction kit (Invitrogen) as directed by the manufacturer. Viral nucleic acid was subjected to reverse transcription to generate cDNA, which was subsequently used as the template for quantitative real-time TaqMan PCR to titrate viral replication using a Mastercycler ep realplex 2 (Eppendorf).
  • test material was evaluated in MRC-5 cells against the 1 A and 14 strains of human rhinovirus (HRV) in parallel with ribavirin as a control compound.
  • HRV human rhinovirus
  • Test material provided by Zirus, Inc. (ZIR03056.1) was received as a dry powder and was solubilized in DMSO at 40mM. The test solution was stored at -20°C and protected from light. ZIR03056.1 was evaluated using a high test concentration of 100 ⁇ and serially diluted in half-log increments for the in vitro antiviral assays. Ribavirin was purchased from Sigma (St. Louis, MO) and used as a protective control compound in the cytoprotection assay.
  • MRC-5 cells human male diploid embryonal lung fibroblast, ATCC
  • DMEM medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 ⁇ g/ml penicillin.
  • the cells were split 1 :2 to assure they were in an exponential growth phase at the time of infection.
  • Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay.
  • the cells were resuspended at lxl 0 4 cells per well in tissue culture medium and added to the microtiter plates in a volume of 100 ⁇ L ⁇ . The plates were incubated at 37°C overnight to allow for cell adherence.
  • viruses used for assays were strains HRV14 (VR- 284) and HRV1A (VR-1559). The viruses were obtained from ATCC and stock virus pools were produced in MRC-5 cells. A pretitered aliquot of virus was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet.
  • Virus was resuspended and diluted into assay medium (DMEM supplemented with 2% FBS, 2 mM L-glutamine, 1 mM sodium pyruvate, 0.1 mM NEAA, 100 U/mL penicillin, and 100 ⁇ g/mL) such that the amount of virus added to each well in a volume of 100 LL was the amount determined to yield 80 to 90% cell killing at 6 days post-infection.
  • assay medium DMEM supplemented with 2% FBS, 2 mM L-glutamine, 1 mM sodium pyruvate, 0.1 mM NEAA, 100 U/mL penicillin, and 100 ⁇ g/mL
  • Each plate contains cell control wells (cells only), virus control wells (cells plus virus), drug toxicity wells (cell plus drug only), drug colorimetric control wells (drug only) as well as experimental wells (drug plus cells plus virus).
  • Efficacy and Toxicity XTT Following incubation at 37°C, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide).
  • XTT- tetrazolium is metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of HRV induced cell killing.
  • XTT/PMS stock was prepared immediately before use by adding 40 ⁇ of PMS per ml of XTT solution.
  • Raw data was collected from the Softmax Pro 4.6 software and imported into a Microsoft Excel XL fit4 spreadsheet for analysis by four parameter curve fit calculations. Both antiviral activity and toxicity with a graphic representation of the data are provided in a Plate Analysis Report (PAR) summarizing the individual compound activity.
  • PAR Plate Analysis Report
  • the PAR for each compound consists of the following: the plate design demonstrating the microtiter plate assay format, the raw optical density data values imported from Softmax, the cell type and virus strain that was used in the assay, the technician responsible for the performance of the antiviral assay, the project number identification, the dates of assay initiation and completion, the mean values for the reagent, virus and cell controls and differential of virus to cell control, summary table of mean optical density values at each compound concentration in the efficacy, toxicity and colorimetric wells along with calculated percentage of reduction values for viral cytopathic effect (CPE) and cell viability; graphical presentation of the percentage of cell viability and percentage of reduced viral CPE at each test concentration.
  • CPE viral cytopathic effect
  • Test compound ZIR03056.1 was evaluated against the 14 and 1A strains of human rhinovirus in MRC-5 cells using a 6 concentration dose response curve. The results of these assays are summarized in Table 1. The graphical representation of these data compares the antiviral efficacy and cellular toxicity expressed as a percentage of the control. Figures 1-2.
  • the ribavirin control compound was evaluated in parallel with the submitted test materials and yielded an EC50 value of 16.1 ⁇ g mL versus HRV14 and 7.6 ⁇ g/mL versus HRVi A .
  • ZIR03056.1 demonstrated similar antiviral activity against the two strains of HRV yielding EC50 values of 2.3 and 5.4 ⁇ versus HRV14 and HRVIA, respectively.
  • cardiovascular thrombotic events There may be an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
  • Gastrointestinal Risk There may be an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
  • Patients with known CV disease or risk factors for CV disease may be at greater risk.
  • the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
  • NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including sulindac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
  • BP Blood pressure
  • NSAIDs can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal.
  • GI gastrointestinal
  • These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.
  • Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic.
  • Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year.
  • NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
  • the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
  • Such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac should be discontinued.
  • NSAIDs Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal
  • anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to sulindac.
  • Sulindac should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma).
  • Emergency help should be sought in cases where an
  • NSAIDs including sulindac
  • SJS Stevens- Johnson syndrome
  • TEN toxic epidermal necrolysis
  • liver function tests and severe skin reactions have occurred during therapy with sulindac. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with sulindac develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with sulindac should be discontinued. The elevated temperature and abnormalities in liver function caused by sulindac characteristically have reverted to normal after discontinuation of therapy. Administration of sulindac should not be reinstituted in such patients.
  • sulindac In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.
  • Sulindac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
  • Anemia is sometimes seen in patients receiving NSAIDs, including sulindac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including sulindac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
  • NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
  • asthma Patients with asthma may have aspirin-sensitive asthma.
  • the use of aspirin in patients with aspirinsensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, sulindac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
  • Sulindac should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving sulindac.
  • the following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between sulindac and these adverse reactions.
  • the adverse reactions which have been observed in clinical trials encompass observations in 1 ,865 patients, including 232 observed for at least 48 weeks. Incidence Greater Than 1% Gastrointestinal
  • the most frequent types of adverse reactions occurring with sulindac are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia**, nausea** with or without vomiting, diarrhea**, constipation**, flatulence, anorexia and gastrointestinal cramps.
  • Liver function abnormalities jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
  • Cardiovascular Congestive heart failure especially in patients with marginal cardiac function; palpitation; hypertension.
  • Urine discoloration Genitourinary Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
  • Musculoskeletal Muscle weakness The Psychiatric Depression; psychic disturbances including acute psychosis.
  • Hypersensitivity Reactions Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea. Hypersensitivity vasculitis.
  • This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions— see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).

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Abstract

Les présentes compositions et méthodes sont liées à l'emploi de ((R-S(=O)0-2-R'0,1-arylène)-méthényl-indén-3-yl)acétyles dans la réduction d'une infection provoquée par un pathogène.
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WO2014026959A1 (fr) 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cistique
WO2017083971A1 (fr) * 2015-11-16 2017-05-26 University Of Manitoba Compositions et méthodes pour le traitement de la grippe
WO2018203762A1 (fr) 2017-05-04 2018-11-08 Wyższa Szkoła Medyczna W Białymstoku Nouvelle utilisation de l'acide 2-[(3z)-6-fluoro-2-méthyl-3-[(4-méthylsulfinylphényl) méthylidène]indén-1-yl] acétique
WO2021202477A1 (fr) * 2020-03-30 2021-10-07 Applied Biology, Inc. Systèmes, méthodes et trousses pour le diagnostic et le traitement d'une infection respiratoire virale
WO2021255218A1 (fr) 2020-06-19 2021-12-23 Charité - Universitätsmedizin Berlin Combinaison pharmaceutique comprenant un protonophore antiviral et un inhibiteur de sérine protéase
US11338010B2 (en) 2020-03-30 2022-05-24 Suzhou Kintor Pharmaceuticals, Inc. Systems, methods, and kits for diagnostics and treatment of viral respiratory infection
CN119587523A (zh) * 2024-12-18 2025-03-11 江汉大学 舒林酸酯基三氟甲基硒在制备抗肠道病毒药物中的应用

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US6232312B1 (en) * 1995-06-07 2001-05-15 Cell Pathways, Inc. Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides
JP2002509884A (ja) * 1998-03-28 2002-04-02 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ザ・ユニバーシティ・オブ・アリゾナ 癌の化学防御におけるｄｆｍｏ及びスリンダクの組合せ
US20030004143A1 (en) * 2001-04-18 2003-01-02 Prior Christopher P. Use of NSAIDs for prevention and treatment of cellular abnormalities of the female reproductive tract

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014026959A1 (fr) 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cistique
US9402821B2 (en) 2012-08-13 2016-08-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
US20160296483A1 (en) * 2012-08-13 2016-10-13 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and Pharmaceutical Compositions for Treatment of Cystic Fibrosis
WO2017083971A1 (fr) * 2015-11-16 2017-05-26 University Of Manitoba Compositions et méthodes pour le traitement de la grippe
WO2018203762A1 (fr) 2017-05-04 2018-11-08 Wyższa Szkoła Medyczna W Białymstoku Nouvelle utilisation de l'acide 2-[(3z)-6-fluoro-2-méthyl-3-[(4-méthylsulfinylphényl) méthylidène]indén-1-yl] acétique
WO2021202477A1 (fr) * 2020-03-30 2021-10-07 Applied Biology, Inc. Systèmes, méthodes et trousses pour le diagnostic et le traitement d'une infection respiratoire virale
US11338010B2 (en) 2020-03-30 2022-05-24 Suzhou Kintor Pharmaceuticals, Inc. Systems, methods, and kits for diagnostics and treatment of viral respiratory infection
WO2021255218A1 (fr) 2020-06-19 2021-12-23 Charité - Universitätsmedizin Berlin Combinaison pharmaceutique comprenant un protonophore antiviral et un inhibiteur de sérine protéase
CN119587523A (zh) * 2024-12-18 2025-03-11 江汉大学 舒林酸酯基三氟甲基硒在制备抗肠道病毒药物中的应用

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