WO1998017282A1 - Procedes d'utilisation d'un octosulfate de saccharose pour le traitement ou la prevention d'une infection a virus enveloppe - Google Patents

Procedes d'utilisation d'un octosulfate de saccharose pour le traitement ou la prevention d'une infection a virus enveloppe Download PDF

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Publication number
WO1998017282A1
WO1998017282A1 PCT/US1997/019181 US9719181W WO9817282A1 WO 1998017282 A1 WO1998017282 A1 WO 1998017282A1 US 9719181 W US9719181 W US 9719181W WO 9817282 A1 WO9817282 A1 WO 9817282A1
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virus
sucrose octasulfate
pharmaceutically acceptable
viral
patient
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PCT/US1997/019181
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English (en)
Inventor
Manuel A. Navia
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Vertex Pharmaceuticals Incorporated
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Priority to AU49955/97A priority Critical patent/AU4995597A/en
Publication of WO1998017282A1 publication Critical patent/WO1998017282A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of sucrose octasulfate and pharmaceutically acceptable salts thereof, including sucralfate, the basic aluminum salt of sucrose octasulfate, to treat or prevent viral infections caused by enveloped viruses.
  • Anionic, sulfated polysaccharides such as heparin, heparan sulfate, dermatan sulfate, pentosan sulfate and others have been shown to exhibit antiviral activity [M. Baba et al., Proc. Natl. Acad. Sci. USA. 85, pp. 6132-36 (1988)]. They have also been identified as in vitro inhibitors of enveloped viruses, including the HIV virus [M. Witvrouw et al., Antiviral Chem. Chemother., 5, pp. 345-59 (1994)], herpes simplex type 1 and type 2 viruses [Witvrouw et al., supra; B.
  • anionic sulfated polysaccharides have been proposed as systemic antiviral agents with broad specificty against the enveloped viruses as a class.
  • Anionic sulfated polysaccharides suffer from poor bioavailablilty following oral ingestion and demonstrate toxicity upon continuous intravenous infusion [Witvrouw et al., supra1. They also exhibit significant anticoagulant activity [R. Nagashima, J. Clin. Gastroenterol. , 3, pp. 103-10 (1981); F. A. Ofosue et al., Brit. J. He atol..
  • heparin is a well-recognized and potent anticoagulant drug that is widely used clinically in the control of blood clotting. Increased bleeding in the course of antiviral therapy is an unacceptable side effect, given that enveloped viruses targeted by these agents are transmitted through contact with blood and other bodily fluids. Accordingly, these anionic sulfated polysaccharides have limited use as antiviral therapeutics or prophylactics. None have been approved for use as drugs, either in systemic or in topical form.
  • the anticoagulant and antiviral activity observed for the anionic sulfated polysaccharides both appear to be critically dependent on the degree of polymerization of those molecules. Anticoagulant and antiviral activity decreases rapidly as the size of the polymer decreases.
  • the anticoagulant activity of disaccharide fragments of heparin is no greater than negative controls [R. Nagashima, supra; R. J. Linhardt et al., J. Biol. Chem L.i./ 257, pp. 7310-13 (1982)]
  • the antiviral activity of dextran sulfate is obliterated when that compound is digested down to disaccharide units [N. R. Hart an et al., AIDS Res. Hum. Retroviruses, 6, pp. 805-12 (1990)].
  • sucrose octasulfate One particular anionic sulfated polysaccharide, sucrose octasulfate, and its well-known basic aluminum salt, sucralfate, have been used therpaeutically.
  • United States Patent 3,432,489 describes these compounds.
  • Sucralfate has been used for treating gastrointestinal ulcers or inflammed tissue.
  • European patent application EP 0 640 346 refers to the use of sulphated mono- and di-saccharides to prevent inflammation. That application also refers to the use of sulphated saccharides to indirectly prevent viral infection by acting on the cell to be infected. Sucralfate, however has never been suggested to be able to kill virus directly.
  • Sucralfate is an extremely safe drug, with a remarkably benign side-effects profile. Animal studies have shown that 1 gram/kg of body weight over 24 months is tolerated without toxicity. Sucralfate is one of a handful of drugs that has no known lethal dose.
  • sucrose octasulfate and pharmaceutically acceptable salts thereof including the basic aluminum salt sucralfate
  • sucrose octasulfate and pharmaceutically acceptable salts thereof including the basic aluminum salt sucralfate
  • sucrose octasulfate and its salts can directly kill enveloped viruses by interacting with the positively charged coat of those viruses.
  • sucrose octasulfate and sucralfate are devoid of anticoagulant activity [R. Nagashima, J. Clin. Gastroenterol, 3, pp. 117-27 (1981) ] .
  • sucralfate ideal for use in preventing sexually transmitted enveloped viral diseases, such as herpes and HIV, even in a pregnant patient.
  • sucrose octasulfate ideal for use in preventing sexually transmitted enveloped viral diseases, such as herpes and HIV, even in a pregnant patient.
  • the present invention provides methods for treating or preventing enveloped viral infection in a patient using sucrose octasulfate or a pharmaceutically acceptable salt thereof. The methods may also be used to prevent transmission of enveloped virus during casual contact (including touching and kissing), sexual contact or during childbirth.
  • the invention also provides methods for using sucrose octasulfate or its salts to disinfect various devices that come into contact with bodily fluids, such as contraceptive devices (condoms, sponges, diaphragms) , surgical gloves, surgical tools, napkins and tissues.
  • contraceptive devices condoms, sponges, diaphragms
  • surgical gloves surgical tools, napkins and tissues.
  • the invention also provides methods for disinfecting liquid preparations, such as blood, plasma, sperm and ova, as well as laboratory and clinical samples, with sucrose octasulfate and its salts.
  • the invention further provides methods of preventing transmission of enveloped viral infection in veterinary settings and in the production of animals for food.
  • the invention also provides pharmaceutical combinations comprising sucrose octasulfate or a pharmaceutically acceptable salt thereof, together with an antiviral agent or a contraceptive agent.
  • the present invention capitalizes on the favorable properties of sucrose octasulfate, including its ability to be administered in high doses without toxicity or side effects; its affinity for damaged epithelium which is known to be a preferred site for viral entry; and its ability to form non-covalent gels or remain in a liquid state depending upon the particular salt used.
  • This latter property allows a choice between a long-acting, slow release dosage form of the sucrose octasulfate (gel) , and a rapidly cleared, high activity dosage form (liquid) , depending upon the particular anti-viral use desired.
  • Other formulation options are described below.
  • the present invention provides methods utilizing sucrose octasulfate or pharmaceutical salts thereof for the prevention or treatment of an enveloped virus infection through the direct interaction of those compounds with the virus.
  • the sucrose octasulfate salts used in the methods of this invention are characterized by several advantages. They do not disrupt the integrity of the target epithelial surface. Accordingly, they do not increase the risk of viral infection. In addition, they have no known toxic or tumorigenic effects. In addition, they have no anticoagulant activities, contraceptive effects, or other reproductive impairments.
  • sucrose octasulfate or its pharmaceutically acceptable salts exert their therapeutic and prophylactic effects by interacting with the positively-charged regions of viral envelope proteins, such as the V3 region of gpl20 on HIV.
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof will inhibit the ability of such virus to enter an uninfected cell.
  • the invention provides a pharmaceutical combination for the prophylaxis or treatment of an enveloped viral infection in a patient comprising: an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said patient via direct interaction with said virus; an antiviral agent selected from a reverse transcription inhibitor, a viral protease inhibitor, a viral polymerase inhibitor and an anionic sulfated polysaccharide polymer comprising at least three repeating units; and a pharmaceutically acceptable carrier.
  • sucrose octasulfate or pharmaceutically acceptable salt thereof useful in these combinations may be obtained commercially or may be synthesized by conventional techniques (see United States patent 3,432,489, the disclosure of which is incorporated herein by reference) .
  • these compounds may be conveniently synthesized from commercially available starting materials.
  • compositions of sucrose octasulfate useful in the combinations of this invention may include organic or inorganic, acid or base salts.
  • the combinations comprise a base salt of sucrose octasulfate derived from alkaline or alkali earth metal.
  • a base salt of sucrose octasulfate derived from alkaline or alkali earth metal.
  • an aluminum or potassium salt of sucrose octasulfate is employed.
  • the aluminum salt better known as sucralfate, forms a gel.
  • the potassium salt is completely soluble.
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof as used in the combinations of this invention may be chemically modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are well recognized in the art and include those which increase topical delivery or binding affinity to epithelial surfaces, or those which are compatible with the chemistry of the target surface.
  • the antiviral agent present in the combination of this invention may be selected from a wide range of known reverse transcription inhibitors, viral protease inhibitors, viral polymerase inhibitors or anionic sulfated polysaccharide polymers comprising at least three repeating units.
  • a viral polymerase inhibitors is employed, it is preferably selected from zidovudine ("AZT") , dianosine, zalcitabine, lamivudine, stavudine, nevirapine, 1592U88, or PMEA.
  • a viral protease inhibitor is employed in the combinations of this invention, it is preferably selected from saquinavir, ritonavir, indinavir, nelfinavir or VX-478.
  • a viral polymerase inhibitor is used, it is preferably selected from acyclovir, brivudin, cidofovir, famciclovir, fiacitabine, fialuridine, foscarnet, FTC, ganciclovir, GG- 167, idoxuridine, imiquimod, lobucavir, n-docosanol, netivudine, penciclovir, pirodavir, ribavirin, sorivudine, trifluridine, valaciclovir, dideoxycytidine, 5-azacytidine, or vidarabine.
  • the additional second antiviral agent is AZT, VX-478, acyclovir or famciclovir.
  • any conventional pharmaceutically acceptable carrier or adjuvant may be utilized in the combinations of this invention.
  • These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium, trisilicate, polyvinyl pyrrolidone, cellulose-based substances and polyethylene glycol.
  • Adjuvants for topical or gel base forms may be selected from the group consisting of sodium carboxymethylcellulose, polyacrylates, polyoxyethylene-polyoxpropylene-block polymers, polyethylene glycol, natural and synthetic gum bases, and wood wax alcohols.
  • Formulations may include any excipient or carrier which may be added to sucrose octasulfate or pharmaceutical salts thereof, without affecting its biological effect.
  • Pharmaceutical combinations of the present invention may be administered to epithelial surfaces or the body, or may be adminstered by parenteral techniques or by an implanted resevoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the combinations of the present invention may be topically administered to any epithelial surface.
  • An "epithelial surface” is defined as an area of tissue that covers external surfaces of a body, or which and lines hollow structures including, but not limited to, cutaneous and mucosal surfaces.
  • Such epithelial surfaces include oral, pharyngeal, esophogeal, pulmonary, ocular, aural, nasal, buccal, lingual, vaginal, cervical, genitourinary, alimentary, and anorectal surfaces.
  • compositions of the present invention may be formulated in a variety of conventional forms employed for topical administration. These include, for example, semi-solid and liquid dosage forms, such as liquid solutions or suspensions, suppositories, douches, enemas, gels, creams, emulsions, lotions, slurries, powders, sprays, lipsticks, foams, pastes, toothpastes, ointments, salves, balms, douches, drops, troches, chewing gums, lozenges, mouthwashes, rinses. Standard and well-understood formulation strategies for topical agents can be applied to sucrose octasulfate or a pharmaceutically acceptable salt thereof in order to enhance the persistence and residence time of the drug, and to improve the prophylactic efficacy achieved.
  • semi-solid and liquid dosage forms such as liquid solutions or suspensions, suppositories, douches, enemas, gels, creams, emulsions, lotions, slurries
  • the sucrose octasulfate combination is formulated into a topical cream or gel.
  • Such formulations are particularly useful, for example, for treatment or prevention of vaginal enveloped viral infections and treatment of viral infections of the oral cavity, including cold sores caused by herpes labialis .
  • topical formulations may be used to treat or prevent enveloped viral infections of eye, the skin, or the lower intestinal tract. Suitable topical formulations are may be readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical combinations of this invention may also be administered by nasal aerosol or inhalation.
  • Such combinations are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the pharmaceutical combinations may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical combinations may be formulated in an ointment such as petrolatum.
  • the pharmaceutical combinations of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • Sucrose octasulfate is a particularly preferred pharmaceutical salt of sucrose octasulfate in the combinations of this invention due to its formation of an anionic gel in dilute acid and its ability to bind to and protect ulcerated areas of the gastrointestinal tract.
  • the pharmaceutical combinations of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, gums, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Sterile injectable forms of the combinations of this invention may be aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • the antiviral agent is present in amounts ranging from 50% to 100% of the amounts normally administered for that agent when it is used in a monotherapy.
  • the remaining part of the combination will be made up of carrier and, if appropriate, water.
  • Sucrose octasulfate or a pharmaceutically acceptable salt thereof will represent some percentage of the total dose in other dosage forms, including liquid solutions or suspensions, suppositories, douches, enemas, gels, creams, emulsions, lotions, slurries, powders, sprays, lipsticks, foams, pastes, toothpastes, ointments, salves, balms, douches, drops, troches, lozenges, mouthwashes, rinses and others.
  • Creams and gels are typically limited by the physical chemical properties of the delivery medium to concentrations less than 20% (e.g., 200mg/gm) . For special uses, far less concentrated preparations can be prepared, (e.g., lower percent formulations for pediatric applications) .
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof over many decades of clinical use as an anti-ulcerant [W. R. Garnett, Clin. Pharm. , 1, pp. 307-14
  • sucrose octasulfate the minimum amount present in the combinations of this invention that is effective in treating or preventing viral disease due to direct interaction with the virus should produce be 1 x 10 mg/ml. If sucralfate is employed the minimum effective concentration should be 1 x 10 mg/ml.
  • the invention provides a pharmaceutical combination for preventing conception and for the prophylaxis or treatment of an enveloped viral infection in a patient comprising: an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said patient via direct interaction with said virus; an amount of a contraceptive effective to prevent conception; a pharmaceutically acceptable carrier.
  • the sucrose octasulfate component can be in any salt form mentioned above.
  • it is the aluminum salt sucralfate.
  • the contraceptive agent is selected from nonoxynol-9, nonoxynol-11, octoxynol, sodium docusate, HPA-23, gossypol, menfegol, arildone, gramicidin, magainins, defensins, melittin, or amphotercin B.
  • the contraceptive agent is nonoxynol-9.
  • the carrier employed in the sucrose octasulfate/contraceptice agent combinations of this invention should be compatible with vaginal administration and/or coating of contraceptive devices.
  • the choice of particular carrier for these uses is well known in the art.
  • These combinations may be utilized in solid, semi-solid and liquid dosage forms, such as diaphragm jelly, douches, foams, ointments, creams, balms, gels, salves, pastes, slurries, vaginal suppositories, sexual lubricants, and coatings for devices such as condoms, contraceptive sponges, cervical caps and diaphragms.
  • the invention provides a method for treating or preventing an enveloped virus infection in a patient comprising the step of administering to said patient a composition comprising: an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said patient via direct interaction with said virus; and a pharmaceutically acceptable carrier.
  • a composition comprising: an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said patient via direct interaction with said virus; and a pharmaceutically acceptable carrier.
  • sucrose octasulfate form and of carrier are the same as described above for sucrose octasulfate/antiviral agent combinations.
  • this method comprises the additional step of administering to said patient, either as part of the same dosage form or as a separate dosage form, an antiviral agent selected from a reverse transcription inhibitor, a viral protease inhibitor, a viral polymerase inhibitor and an anionic sulfated polysaccharide polymer comprising at least three repeating units.
  • an antiviral agent selected from a reverse transcription inhibitor, a viral protease inhibitor, a viral polymerase inhibitor and an anionic sulfated polysaccharide polymer comprising at least three repeating units.
  • the methods comprises the additional step of administering to said patient, either as part of the same dosage form or as a separate dosage form, an amount of a contraceptive effective to prevent conception.
  • sucrose octasulfate and for the contaceptive agent are the same as those described above for the sucrose octasulfate/ contraceptive agent pharmaceutical combinations.
  • Combinational therapies utilized in the methods of this invention may also exert an additive or synergistic effect, particularly when the viricidal activity of each component operates via a different mechanism.
  • the reduction in effective therapeutic dose achieved with such combinations may be additive or synergistic.
  • dramatically lower doses of both the conventional antiviral agent and of sucrose octasulfate or a pharmaceutically acceptable salt thereof will lead to effective therapy nonetheless.
  • the occurrence of any side effects associated with the added conventional antiviral agent may be reduced or avoided — where, as stated above, the toxicity of sucrose octasulfate or its basic aluminum salt, sucralfate is known to be minimal from prior clinical experience.
  • Another advantage of such combination therpy regimens is that they may delay the emergence of viral resistance.
  • a patient according to this invention is an animal, including a human.
  • Animal patients include, but are not limited to, other mammals, birds, and fish.
  • the patient is a human.
  • the methods of this invention are carried out for a period of time sufficient to prevent viral replication in a patient or to prevent transmission of enveloped virus from an infected patient to another patient through the direct interaction of sucrose octasulfate or its salts with the virus.
  • Such enveloped viruses include, for example, virus from the genera Retroviridae , Herpesviridae, Orthomyxoviridae, Paramyxoviridae, Hepadnaviridae , Flaviviridae , Togaviridae, Rhabdoviridae, Poxviridae, Arenaviridae, Coronoviridae, Bunyaviridae and Filoviridae.
  • Retroviridae that may be treated or prevented using the methods of this invention include, for example, human immunodeficiency virus type 1 and the human immunodeficiency virus type 2 lentiviruses, foamy viruses and human T-cell leukemia viruses.
  • Herpesviridae that may be treated or prevented using the methods of this invention include, for example, herpes simplex type 1 and herpes simplex type 2 viruses, varicella-zoster viruses, cytomegaloviruses, lymphoproliferative herpesviruses and Epstein-Barr virus.
  • Orthomyxoviridae that may be treated or prevented using the methods of this invention include, for example, influenza A, influenza B and influenza C viruses.
  • Paramyxoviridae that may be treated or prevented using the methods of this invention include, for example, respiratory syncytial virus, mumps virus, parainfluenza viruses and measles-like viruses.
  • Hepadnaviridae that may be treated or prevented using the methods of this invention include, for example, hepatitis B virus.
  • Flaviviridae that may be treated or prevented using the methods of this invention include, for example, hepatitis C virus, yellow fever virus, dengue virus and tick-borne encephalitis viruses.
  • Togaviridae that may be treated or prevented using the methods of this invention include, for example, rubella virus .
  • Rhabdoviridae that may be treated or prevented using the methods of this invention include, for example, rabies virus and vesicular stomatitis virus.
  • Poxviridae that may be treated or prevented using the methods of this invention include, for example, vertebrate and avian poxviruses and vaccinia viruses.
  • Arenaviridae that may be treated or prevented using the methods of this invention include, for example, the arenaviruses.
  • Coronaviridae that may be treated or prevented using the methods of this invention include, for example, the coronaviruses.
  • Bunyaviridae that may be treated or prevented using the methods of this invention include, for example, the hantaviruses.
  • Filoviridae that may be treated or prevented using the methods of this invention include, for example, Marburg, Reston and Ebola viruses.
  • the enveloped viral infection to be treated is one wherein the virus if from the genera Retroviridae, Herpesviridae, Orthomyxoviridae, Paramyxoviridae, Hepadnaviridae, Flaviviridae, or Rhabdoviridae. More preferably, the virus is type 1 or type 2 human immunodeficiency virus, type 1 or type 2 herpes simplex virus, varicella zoster virus,
  • Epstein-Barr virus Epstein-Barr virus, cytomegalovirus, influenza type A, B, or C virus, respiratory scincytial virus, mumps virus, hepatitis B virus, hepatitis C virus, encephalitis virus, rabies virus, or dengue fever-inducing virus.
  • the virus is type 1 or type 2 human immunodeficiency virus or type 1 or type 2 herpes simplex virus.
  • compositions of this invention are also useful in the treatment or prevention of respiratory complications in neonates resulting from paramyxovirus infection, measles, German measles, conjunctivitis, other non-sexually transmitted enveloped virus-induced diseases, herpes-associated Karposi's sarcoma, other viral-assocated cancers, encephalitis and yellow fever.
  • the methods of this invention are used to treat an epithelial surface of a patient.
  • the epithelial surface is selected from oral, pharyngeal, esophogeal, pulmonary, ocular, aural, nasal, buccal, lingual, vaginal, cervical, genitourinary, alimentary, or anorectal surfaces.
  • the methods of this invention are useful to prevent and treat infections that cause oral and esophageal sores.
  • Oral sores may arise by infection from a number of enveloped viruses including
  • Herpesviridae including herpes simplex type I and type II viruses, and Retroviridae such as the human immunodeficiency viruses.
  • Sucrose octasulfate or a pharmaceutically acceptable form thereof, used in this embodiment may be in several forms including solid, semi-solid and liquid dosage forms, including liquid solutions or suspensions, troches, lozenges, mouthwashes, rinses, pastes toothpastes, ointments, salves, balms, lipsticks, gels, creams, emulsions, lotions, slurries, powders, sprays, foams, and drops .
  • the methods of this invention are useful for treating and preventing infections that cause genital sores.
  • Genital sores may arise from infection by a number of enveloped viruses including Herpesviridae such as the herpes simplex type I and type II viruses, retroviridae such as the human immunodeficiency viruses.
  • Sucrose octasulfate or a pharmaceutically acceptable salt thereof, used in this embodiment may be incorporated into several forms including solid, semi-solid and liquid dosage forms, diaphragm jelly, douches, sprays, foams, lotions, ointments, creams, balms, powders, gels, salves, pastes, slurries, suppositories, sexual lubricants, and including coatings or for devices such as condoms, diaphragms, feminine napkins, and tampons.
  • the methods of this invention are useful for treating and preventing respiratory infections.
  • Respiratory infections be caused by a number of enveloped viruses including Orthomyxoviridae such as the influenza virus, Paramyxoviridae such as the respiratory syncytial virus, parainfluenza virus, hantavirus, and cytomegalovirus.
  • Sucrose octasulfate or pharmaceutically acceptable salt thereof, used in this embodiment may be in several forms including solid, semi- solid and liquid dosage forms, including liquid solutions or suspensions, troches, lozenges, mouthwashes, rinses, pastes toothpastes, ointments, salves, balms, lipsticks, gels, creams, emulsions, lotions, slurries, powders, sprays, foams, and drops.
  • the invention provides a method for preventing vertical transmission of an enveloped virus from a mother to a child during childbirth, which comprises the step of treating said mother prior to or during labor with a composition comprising: an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said child via direct interaction with said virus; and a pharmaceutically acceptable carrier.
  • This method is carried out by topically administering to the mother's birth canal during or prior to labor a therapeutically effective concentration of sucrose octasulfate or a pharmaceutically acceptable salt thereof.
  • Recent data suggests a correlation between maternal viral load and extended contact with vaginal and cervical secretions by the neonate, with the incidence of vertical transmission of HIV to newborns [T.
  • sucrose octasulfate composition or combination utilized should be compatible with the treatment of neonates.
  • carrier and antiviral agent if utilized for use in childbirth is well known in the art.
  • the invention provides a method for disinfecting a health care device which is designed to come into contact with a patient, said method comprising the step of contacting the health care device with a composition comprising an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce the viral titer on said health care device prior to said device coming into contact with said patient.
  • the device is selected from a contraceptive device, a plastering material, a bandage, a sponge, a napkin, a strip, a tissue, a protective external covering used in medicine, a surgical device, a dental device, a laboratory device, surgical gloves, a surgical gown, and a surgical mask.
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof may be mixed with a talcum lubricant powder used to line surgical gloves.
  • the amounts of sucrose octasulfate salts, as well as the antiviral agent (if present), carriers and adjuvants that are necessary for the coating or treatment of said devices that are necessary to treat the aforementioned devices and biological materials for the purpose of disinfecting said devices prior to coming into contact with animals will be dependent on the type, size, surface area, consistency, intended use of this device.
  • the devices will be prepared in such a way as to be treated with a therapeutically or prophylactically effective amount and for a period of time sufficient to prevent the transmission of an enveloped virus from said device.
  • One skilled in the art will be able to determine the most appropriate formulations for treatment of said devices.
  • the invention provides a method for disinfecting a biological fluid comprising the step of contacting said fluid with an amount of sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce the viral titer in said biological fluid.
  • the biological fluid is selected from blood, plasma, ova, or semen.
  • the sucrose octasulfate or salt thereof may be added directly to the biological fluid.
  • it may be coupled to a solid support comprising, for example, plastic or glass beads, or a filter, which is placed in contact with those samples.
  • Sucrose octasulfate and its salts are particularly advantageous for purifying blood because of its lack of anticoagulant activity.
  • the invention provides a method for preventing the transmission of an enveloped viral infection between animals, birds or fish, comprising the step of contacting a food, water, or living environment of said animals, birds or fish with an amount of a sucrose octasulfate or a pharmaceutically acceptable salt thereof, sufficient to reduce or prevent viral replication in said animals, birds or fish via direct interaction with said virus.
  • sucrose octasulfate or pharmaceutically acceptable salts thereof for living things depends upon the target virus, previous therapy, the extent of desired treatment, the target area of treatment, the body weight of patient, drug combinations, severity of the disease, the patient's health status and response to the sucrose octasulfate and the judgment of the treating physician.
  • the sucrose octasulfate may be administered to the patient in any pharmaceutically acceptable topical dosage form, at one time or over a series of treatments.
  • a maintenance dose of the sucrose octasulfate or a pharmaceutically acceptable salt thereof alone or in combination with a second antiviral agent may be administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • Example l cell lines and Materials Sucralfate was purchased as a powder from Spectrum Chemical Manufacturing. Corp. (Gardena, CA) or as a tablet from Marion Merril Dow (Kansas City, Mo) . Sucrose octasulfate powder was purchased from U.S. Pharmacopeial Convention, Inc., Rockville, MD.
  • Sucralfate stock suspensions were prepared by dissolving lg of sucralfate powder in 4mL of RPMI-1640 medium with 0.01 N HC1 added. The sucralfate stock suspension (at 250 mg/ml) was stored at 4°C prior to use. Sucrose octasulfate solutions were prepared by dissolving 100 mg sucrose octasulfate in 4mL of RPMI-1640 medium; the 25 mg/mL sucrose octasulfate solutions were also stored as above . Human monocytes and cell lines (C8166, H9, U-937) were prepared in RPMI-1640 media, supplemented with 20% fetal calf serum. Peripheral blood mononuclear cells (PBMCs) were grown in the same medium to which IL-2 (5%, Cellular Products) and phytohemagglutinin (5 ⁇ g/mL) had been added.
  • PBMCs Peripheral blood mononuclear cells
  • HTLV-IIIB was provided by R.C. Gallo, NCI, Bethesda, MD. HIV-1 18a and 18c was provided by Dr. V.A. Johnson, University of Alabama, Birmingham, AL. HIV-1-9400232 (HIV-194) , is a low passage clinical isolate obtained from a participant in an AIDS clinical trial.
  • Example 2 Cvtotoxicity Assays Given that sucralfate suspensions interfere visually with the determination of cell viability by trypan blue staining, cytotoxic effects of the drug were determined by monitoring cellular proliferation, as assayed by 3H- thymidine incorporation.
  • One ⁇ Ci thymidine DuPont-NEN, Boston, MA
  • 3 H- thymidine cultures were incubated for 4-6 hours at 37°C and 3 H-TdR incorporation was determined.
  • TCID 50 is defined as the viral titer that will infect 50% of the cells in a tissue culture experiment.
  • 100 ⁇ L aliquots of the sucralfate or sucrose octasulfate dilutions were added to each well.
  • supernatants from the test cultures were assayed for viral replication as described below. HIV virus replication assays were performed essentially as according to D.D.
  • a sample containing unlabelled p24 antigen was mixed with a fixed amount of 125 ⁇ labelled p24 and a fixed limiting amount of rabbit anti-p24 antibody.
  • the samples were incubated overnight at room temperature.
  • a goat anti-rabbit immunoglobulin preparation was then added to the test mixture, to precipitate the anti-p24 antibody.
  • the samples were centrifuged and the supernatant was aspirated. Pelletted 125 I labelled p24 was quantitated for each sample by gamma counting and comparison to a standard curve .
  • sucralfate and sucrose octasulfate were determined.
  • IC50 values concentration of sucralfate and sucrose octasulfate required to inhibit 50% of viral replication.
  • TC50 values indicate the concentration of sucralfate or sucrose octasulfate that inhibited 50% of cellular proliferation as measured by tritiated thymidine incorporation (see protocol Example 2, results Table 1) .
  • the inhibitory activity of sucralfate tablet and sucralfate powder can be compared within cell lines on Table 1.
  • sucralfate tablet is approximately 4.5 fold more effective against an acutely infected H9 cell line than a chronically infected cell line.
  • Sucralfate powder and sucrose octasulfate both were more effective against acutely infected H9 cells than chronically infected H9 cells .
  • sucralfate tablet suspension inhibited HIV replication more effectively in HIV 18C and HIV 194 isolates than in HIV 18a isolate.
  • sucralfate tablet suspensions did not have different effects on the level of HIV infection in monocytes challenged with HIV 18a or HIV 18c (see IC50 values, Table 1) . Therefore, the treatment or prophylaxis of HIV infection using sucralfate and sucrose octasulfate will need to be adjusted depending on the targeted cell and viral strain.
  • Example 4 Svner ⁇ istic Effect of AZT and Sucrose Octasulfate A ⁇ ainst HTV 2 x 10 5 PBMCs in 100 ⁇ L were exposed to 100 TCID 50 of HIV-1 inoculum (isolates 18c and 18c) in 50 ⁇ L without subsequent washing of cells.
  • sucrose octasulfate or AZT suspensions were added to each well for a final concentration of 4 nM, InM, 0.25nM, 0.064nM, or 0.016nM of AZT or a final concentration 4 mg/ml, 1 mg/ml, 0.25 mg/ml, 0.064 mg/ml, or 0.016 mg/ml of sucrose octasulfate.
  • AZT was tested in combination with sucrose octasulfate such that 4 nM AZT was tested with 4 mg/ml sucrose octasulfate, 1 nM AZT was tested with 1 mg/ml of sucrose octasulfate, and so on. Viral replication was assayed by quantitating HIV p24 antigen production four days after infection (see Example 3) .
  • sucrose octasulfate alone inhibited the infection of 50% of the cells (IC50) at 0.99 mg/ml.
  • AZT inhibited the infection of 50% of the cells (IC50) at 3.35 nM.
  • Sucrose octasulfate and AZT combined was able to inhibit 50% of the tested cells at a concentration of 0.65 nM AZT and 0.35-0.45 mg/ml sucrose octasulfate. Therefore, the results indicate that five fold less AZT and approximately 2.5 fold less sucrose octasulfate are required to achieve 50% viral inhibition than by either AZT or sucrose octasulfate alone. In a similar study using HIV isolate 18c, ten fold less AZT and five fold less sucrose octasulfate was needed to achieve 50% viral inhibition than when either one was used alone.
  • Sucralfate was dissolved in solutions with varying pH prior to addition to cells. Inhibition of viral replication was measured four days after infection by p24 antigen production (see Example 3) . Sucralfate dissolved in a solution of pH 6.0 was more inhibitory than sucralfate dissolved in pH 3.0 (compare IC50 values, Table 2). Sucralfate was also found to be more soluble at pH 5.61-6.40 than pH 3.0. Therefore, the activity of sucralfate appears related to its solubility. TABLE 2 p24 Antigen ng/mL (Day 4 after infection)
  • HSV-1 (strain HSV-690) and HSV-2 (strain SKB-1) and the AS49/20S cell line were obtained from Dr. Adriana Weinberg, University of Colorado Health Sciences.
  • Trisodium phosphonoformate (PFA) a viral polymerase inhibitor, was used as a positive control.
  • HSV-1 or HSV- 2 (MOI 0.005 pfu/cell) and sucralfate or sucrose octasulfate was added to AS49/20S cells, incubated at 37°C in 5% C0 2 , and observed for evidence of cytopathic effect (CPE) over a period of 0 to 48 hours after viral innoculation.
  • CPE cytopathic effect
  • sucralfate and sucrose octasulfate inhibited 50% of CPE in HSV-1 infected cells at approximately 0.125 to 2 mg/ml. Severity of CPE depended upon the point of addition of drug or viral challenge of HSV-1. For example, in Tables 3a-c, sucralfate and sucrose octasulfate were more effective against HSV-1 when added simultaneously with virus than when added after the virus was allowed to contact the cell (compare IC50 values of preinfected cells and cells not preinfected) .
  • sucrose octasulfate over a final concentration range of 0 to 8 mg/ml was tested essentially as described above. However, viral activity was quantitated by counting the number of plaques formed for each infection (see results in Table 4, below) .
  • HSV-2 like HSV-1, was more effectively inhibited by sucrose ocatasulfate or sucralfate when the cells were not pre-treated with virus (See Table 4, compare IC50 values of preinfected cells and cells not preinfected) .
  • sucrose octasulfate inhibited 50% of plaque formation by HSV-2 when no drug was added. No significant toxicity was observed at the concentrations and formulations of sucralfate or sucrose octasulfate as recited in Table 3 or Table 4.

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Abstract

La présente invention concerne l'utilisation d'un octosulfate de saccharose et de sels pharmaceutiquement acceptables de ceux-ci comportant, un sucralfate, le sel basique d'aluminium d'octosulfate de saccharose, seul ou en combinaison avec d'autres agents, dans des compositions topiques et des procédés de traitement ou de prévention d'infections virales. Selon un mode de réalisation préféré de cette invention, une composition topique comprenant un octosulfate de saccharose et de sels pharmeutiquement acceptables de ceux-ci tel qu'un sucralfate, est utilisée dans des procédés de traitement ou de prévention d'infections provoquées par des virus enveloppés, tels qu'un virus de l'immunodéficience humaine (VIH), un virus de l'herpès et d'autres virus enveloppés.
PCT/US1997/019181 1996-10-23 1997-10-23 Procedes d'utilisation d'un octosulfate de saccharose pour le traitement ou la prevention d'une infection a virus enveloppe WO1998017282A1 (fr)

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WO1999015566A1 (fr) * 1997-09-23 1999-04-01 Dalhousie University Composition et preparation pharmaceutique la contenant pour le traitement de l'herpes et autres maladies virales apparentees
DE19841795A1 (de) * 1998-09-12 2000-03-16 Beiersdorf Ag Kombinationen von Antiadhäsiva (Sterole und Sterolderivate) und Mikrobiziden
DE19841794A1 (de) * 1998-09-12 2000-03-16 Beiersdorf Ag Kombinationen von Antiadhäsiva (Ceramide und Sphingosine und Derivate) und Mikrobiziden
DE19841796A1 (de) * 1998-09-12 2000-03-16 Beiersdorf Ag Kombinationen von Antiadhäsiva (Kohlenhydrate) und Mikrobiziden
EP1239923A2 (fr) * 1999-12-20 2002-09-18 New Pharma Research Sweden AB Compositions veterinaires stabilisees, contenant plusieurs agents antiviraux
JP2008239541A (ja) * 2007-03-27 2008-10-09 Kanmonkai:Kk 魚介類の感染予防剤
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