WO1999043333A1 - Utilisations therapeutiques et prophylactiques de disaccharides substitues de charge negative - Google Patents

Utilisations therapeutiques et prophylactiques de disaccharides substitues de charge negative Download PDF

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Publication number
WO1999043333A1
WO1999043333A1 PCT/US1999/004432 US9904432W WO9943333A1 WO 1999043333 A1 WO1999043333 A1 WO 1999043333A1 US 9904432 W US9904432 W US 9904432W WO 9943333 A1 WO9943333 A1 WO 9943333A1
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Prior art keywords
gonorrhoeae
negatively charged
subject
organism
substituted disaccharide
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PCT/US1999/004432
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English (en)
Inventor
Manuel A. Navia
Thomas C. Quinn
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The Althexis Company
Usa, Secretary Department Of Health And Human Services
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Publication date
Application filed by The Althexis Company, Usa, Secretary Department Of Health And Human Services filed Critical The Althexis Company
Priority to AU27982/99A priority Critical patent/AU2798299A/en
Publication of WO1999043333A1 publication Critical patent/WO1999043333A1/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
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose

Definitions

  • the invention relates to the use of negatively charged substituted disaccharides, e.g., sucrose octasulfate, to treat or prevent infections caused by N. gonorrhoeae.
  • negatively charged substituted disaccharides e.g., sucrose octasulfate
  • Gonorrhea is a sexually transmitted diseased caused by the Gram negative diplococcus, Neisseria gonorrhoeae, often referred to as gonococcus.
  • N. gonorrhoeae infects a diverse array of mucosal surfaces, including cells lining the epithelium of the urethra, cervix, anal canal, pharynx, and conjunctivae (Britigan et al. (1985) N. Engl. J. Med. 312: 1683-1694).
  • the host defenses and physiology of these tissues are quite diverse, but the gonococcus seems to have adapted to survive in these diverse environments.
  • N. gonorrhoeae infections have been implicated in a number of diseases, such as male or female infertility, ectopic pregnancy, puerperal and perinatal morbidity, and infant blindness. Some of these complications remain common today, particularly in the developing world. In most cases, gonorrhea is primarily a localized disease. However, the infection may spread to contiguous parts and, in some instances, infection may be disseminated to other parts of the body. In men, gonorrhea can result in a characteristic painful, purulent urethral discharge with dysuria and, sometimes, urinary frequency. Asymptomatic rectal infection is common among homosexual men, particularly in homosexual men who engage in promiscuous behavior (Quinn, T.C.
  • N. gonorrhoeae In women, the usual sites of infection by N. gonorrhoeae include the cervix, urethra, rectum, and pharynx, in decreasing frequency.
  • Female infections with N. gonorrhoeae exhibit a wide variety of symptoms, including inflammation with some pain and swelling, abnormal vaginal discharge, and abnormal menstrual bleeding.
  • Locally invasive neonatal ocular infection is a common cause of neonatal conjunctivitis and a major cause of preventable infant blindness in developing countries with a high prevalence of gonorrhea (Barnes, R.C. and K.K. Holmes (1984) Epidemiol. Rev. 6: 1-30). Transmission in these cases typically occurs from an infected mother to an infant during passage through the vaginal tract.
  • the invention features, a method for inhibiting infection of a cell, e.g., an epithelial cell, e.g., a surface epithelial cell, by an N. gonorrhoeae organism.
  • the method includes: contacting the cell, or the N. gonorrhoeae organism, with a negatively charged substituted disaccharide, e.g., sucrose octasulfate, in an amount effective to reduce or prevent infectivity by the N. gonorrhoeae organism.
  • the negatively charged substituted disaccharide acts via a direct antimicrobial effect on the N. gonorrhoeae organism.
  • the substituted disaccharide can be provided as a pharmaceutically acceptable salt, or as a composition, e.g., a pharmaceutical composition, which includes the substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the method can be practiced in vivo or in vitro.
  • the negatively charged substituted disaccharide can be administered to a subject.
  • the subject is a mammal.
  • a preferred mammal is a human, e.g., a person at risk of being infected or reinfected by the N. gonorrhoeae organism.
  • the N. gonorrhoeae organism is contacted with the negatively charged substituted disaccharide and such contact occurs, or is initiated, prior to contact of the N. gonorrhoeae organism with the subject, e.g., prior to contact of the N. gonorrhoeae organism with a body surface, e.g., an epithelial surface, or prior to entry of the N. gonorrhoeae organism into a body cavity of the subject.
  • the cell e.g., the epithelial cell
  • the negatively charged substituted disaccharide is contacted with the negatively charged substituted disaccharide and such contact occurs, or is initiated, prior to contact of the N. gonorrhoeae organism with the subject.
  • the cell e.g., an epithelial cell
  • the cell is located on a body surface or a body cavity of a subject, e.g., an oral, pharyngeal, esophageal, pulmonary, ocular, aural, nasal, buccal, lingual, genitourinary, vaginal, cervical, alimentary, or anorectal surface.
  • the cell is a genitourinary epithelial cell, e.g., a cell in the lining of the bladder or urinary duct, or a vaginal or cervical epithelial cell.
  • the cell is a columnar epithelial cell of the endocervix.
  • the cell is, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell. Most preferably, the cell is a mucosal cell.
  • the cell is a mammalian cell, e.g., a human or non- human cell, most preferably, the cell is a human cell.
  • the composition of the negatively charged substituted disaccharide does not include a contraceptive substance.
  • the negatively charged substituted disaccharide is associated with a counter ion, e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base, to form a salt, e.g., a neutral salt.
  • a counter ion e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base
  • a salt e.g., a neutral salt.
  • the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.
  • the negatively charged substituted disaccharide is sucrose octasulfate.
  • the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt.
  • a counter ion e.g., a potassium or an aluminum hydroxide ion
  • Preferred salts of sucrose octasulfate include the potassium salt of sucrose octasulfate, also referred to herein as potassium sucrose octasulfate, and the aluminum hydroxide salt of sucrose octasulfate, also referred to herein as sucralfate.
  • sucrose octasulfate compounds can be represented by the general formula:
  • sucrose octasulfate compounds represented by the formula are in the form of a salt, wherein Xj-Xs are cations, and each of Xj-Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al 2 (OH) 5 .
  • X j -Xg are the same cation.
  • each of X j -Xg is a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al (OH) 5 , which can optionally be in hydrated form, e.g., [Al2(OH)5Jg.
  • the negatively charged substituted disaccharide is represented by the general formula:
  • R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group.
  • R is SO3 or PO4.
  • Xi-X are cations, and each of X ] -Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • the stereochemistry is not limiting, e.g., various stereoisomers can be used.
  • Xj-Xg are the same cation, most preferably, a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH)y, wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5] .
  • compositions of the present invention may contain a mixture of a negatively charged substituted disaccharide wherein each of Xj-Xg is an aluminum hydroxide ion, e.g., Al2(OH)5 and another negatively charged substituted disaccharide wherein each of Xj-Xg is a potassium ion.
  • the invention features, a method for treating or preventing, infection with an N. gonorrhoeae organism, or treating or preventing a disorder or disease caused by an N.
  • the method includes: administering to the subject, an amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, effective to treat or prevent infection of the subject by the N. gonorrhoeae organism, or to treat or prevent a disorder or disease caused by the N. gonorrhoeae organism.
  • a negatively charged substituted disaccharide e.g., sucrose octasulfate
  • the negatively charged substituted disaccharide acts via a direct antimicrobial effect.
  • the substituted disaccharide can be provided as a pharmaceutically acceptable salt, or as a composition, e.g., a pharmaceutical composition, which includes the substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the N. gonorrhoeae organism is contacted with the negatively charged substituted disaccharide and such contact occurs, or is initiated, prior to contact of the N. gonorrhoeae organism with the subject, e.g., prior to contact of the N. gonorrhoeae organism with a body surface, e.g., an epithelial surface, or prior to entry of the N. gonorrhoeae organism into a body cavity of the subject.
  • the method treats or prevents infection of an epithelial surface, e.g., the surface of a body cavity, e.g., an oral, pharyngeal, esophageal, pulmonary, ocular, aural, nasal, buccal, lingual, genitourinary, vaginal, cervical, alimentary, or anorectal surface.
  • the epithelial surface is a genitourinary epithelial surface, e.g., the lining of the bladder or urinary duct, or a vaginal or cervical epithelial surface.
  • the epithelial surface is a columnar epithelial cell surface of the endocervix.
  • the method treats or prevents infection of a cell, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell.
  • a cell e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell.
  • the cell is a mucosal cell.
  • the method treats or prevents infection of a cell, or an epithelial surface by contacting the N. gonorrhoeae organism, or the epithelial surface or the cell with the negatively charged substituted disaccharide.
  • the subject is a mammal, e.g., human or non-human.
  • a preferred mammal includes a human, e.g., a person at risk of being infected or reinfected by an ⁇ . gonorrhoeae organism.
  • the disorder or disease is: an eye disease or disorder, e.g., conjunctivitis, blindness; inflammatory disease, e.g., cervicitis, pelvic inflammatory disease; ectopic pregnancy; infertility, e.g.. female or male infertility; genital or urinary infections, e.g., urethritis, proctitis; rectal infections, e.g., anorectal pain, tenesmus, mucoid or bloody rectal discharge; and epididymitis.
  • eye disease or disorder e.g., conjunctivitis, blindness
  • inflammatory disease e.g., cervicitis, pelvic inflammatory disease
  • ectopic pregnancy infertility, e.g.. female or male infertility
  • genital or urinary infections e.g., urethritis, proctitis
  • rectal infections e.g., anorectal pain, tenes
  • the composition of the negatively charged substituted disaccharide does not include a contraceptive substance.
  • the negatively charged substituted disaccharide is associated with a counter ion, e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base, to form a salt, e.g., a neutral salt.
  • a counter ion e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base
  • a salt e.g., a neutral salt.
  • the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.
  • the negatively charged substituted disaccharide is sucrose octasulfate.
  • the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt.
  • a counter ion e.g., a potassium or an aluminum hydroxide ion
  • Preferred salts of sucrose octasulfate include the potassium salt of sucrose octasulfate, also referred to herein as potassium sucrose octasulfate, and the aluminum hydroxide salt of sucrose octasulfate, also referred to herein as sucralfate.
  • sucrose octasulfate compounds can be represented by the general formula:
  • sucrose octasulfate compounds represented by the formula are in the form of a salt, wherein Xi-Xg are cations, and each of Xj-Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • Xj-Xg are the same cation.
  • each of Xj-Xg is a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5] .
  • the negatively charged substituted disaccharide is represented by the general formula:
  • R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group.
  • R is SO3 or PO4.
  • X]-Xg are cations, and each of Xj-Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • the stereochemistry is not limiting, e.g., various stereoisomers can be used.
  • Xj-Xg are the same cation, most preferably, a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5Jg.
  • compositions of the present invention may contain a mixture of a negatively charged substituted disaccharide wherein each of Xj-Xg is an aluminum hydroxide ion, e.g., Al2(OH)5 and another negatively charged substituted disaccharide wherein each of Xj-Xg is a potassium ion.
  • the negatively charged substituted disaccharide is administered: topically, orally, parenterally, intravaginally, intrarectally, or in aerosol form.
  • the negatively charged substituted disaccharide is administered, e.g., self-administered, by topical application.
  • topical application e.g., it can be applied, e.g., self- applied, topically onto the epithelium of a bodily surface, e.g., the vaginal mucosa, cervical mucosa, penis, or anorectal surface.
  • the method further includes administering, either as part of the same dosage form or as a separate dosage form, one or more of an antibacterial agent selected from the group consisting of a DNA topoisomerase inhibitor; a cell wall inhibitor; a protein synthesis inhibitor; a membrane transport inhibitor; a metabolic inhibitor, e.g., a folic acid metabolic inhibitor such as trimethoprim and sulfonilamides; an RNA synthesis inhibitor, e.g., rifamycin; a cell membrane agent, e.g., polymixins.
  • an antibacterial agent selected from the group consisting of a DNA topoisomerase inhibitor; a cell wall inhibitor; a protein synthesis inhibitor; a membrane transport inhibitor; a metabolic inhibitor, e.g., a folic acid metabolic inhibitor such as trimethoprim and sulfonilamides; an RNA synthesis inhibitor, e.g., rifamycin; a cell membrane agent, e.g., polymixins.
  • defensins or magainins
  • an agent affecting electron transport e.g., metronidazole
  • an anionic sulfated polysaccharide polymer e.g., a sulfated polymer comprising at least three repeating units.
  • any combination of one or more classes of an antibacterial agent and an anionic sulfated polysaccharide polymer can be co-administered, e.g., as part of a combinatorial therapy, with a negatively charged substituted disaccharide.
  • a preferred combination of the substituted disaccharide and an antibacterial agent includes a DNA topoisomerase inhibitor, e.g., ciprofloxacin, a cell wall inhibitor, e.g., penicillin, and a protein synthesis inhibitor, e.g., a tetracycline and/or an aminoglycoside, e.g., streptomycin.
  • the negatively charged substituted disaccharide is administered with a DNA topoisomerase inhibitor such as a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin, or nalidixic acid.
  • a DNA topoisomerase inhibitor such as a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin, or nalidixic acid.
  • a most preferred quinolone is ciprofloxacin.
  • the negatively charged substituted disaccharide is administered with a cell wall inhibitor selected from the group consisting of: penicillin, cephalosporin, monobactam, carbapenems, glycopeptides, vancomycin, bacitracin and cycloserine.
  • a cell wall inhibitor selected from the group consisting of: penicillin, cephalosporin, monobactam, carbapenems, glycopeptides, vancomycin, bacitracin and cycloserine.
  • exemplary penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin.
  • cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole.
  • the negatively charged substituted disaccharide is administered with a protein synthesis inhibitor and: the protein synthesis inhibitor is an inhibitor of a ribosomal 3 OS or 50S subunit, or other protein synthesis inhibitor.
  • protein synthesis inhibitors include: tetracyclines, glycylglycines, aminoglycosides, e.g., streptomycin, gentamicin, tobramycin, choramphenicol, clindamycin, macrolides, e.g., erythromycin, chlarithromycin, azithromycin, lincosamides, streptogramins, e.g., streptogramin B, oxazolidinones, GE-2270A (EF-Tu) and everninomycin.
  • the negatively charged substituted disaccharide is administered with an antibacterial agent that is capable of accumulating, e.g., concentrating, in the tissue or organ in which a therapeutic or prophylactic effect is desired.
  • an antibacterial agent that is capable of accumulating, e.g., concentrating, in the tissue or organ in which a therapeutic or prophylactic effect is desired.
  • antibacterial agents which are known to concentrate in the urinary tract, such as methenamine, quinolones, e.g., ciprofloxacin, oxolinic acid or nitrofurantoin, are preferred agents.
  • the negatively charged substituted disaccharide is administered with an anionic sulfated polysaccharide and: the anionic sulfated polysaccharide polymer is a long chain polymer of sugars linked to sulfates and optionally other functional groups.
  • sulfated polysaccharides can have a molecular weight of 5,000 to 1 ,000,000, more preferably from 50,000 to 500,000.
  • from 10 to 100% of the available binding sites are sulfated, more preferably, from 50 to 100%.
  • Exemplary sulfated polysaccharides include carrageenans, chondroitin sulfate, dextran sulfate, lentinan sulfate, curdlan sulfate, heparin sulfate, and de-N- sulfated heparin.
  • the negatively charged substituted disaccharide is administered with a contraceptive agent, either as part of the same dosage form or as a separate dosage form, and: the contraceptive agent is selected from the group consisting of nonoxynol-9, nonoxynol-1 1, octoxynol, sodium docusate, HPA-23, gossypol, menfegol, arildone, gramicidin, magainins, defensins, melittin and amphotercin B. Most preferably, the contraceptive agent is nonoxynol-9.
  • the invention features, a method for inhibiting transmission, or decreasing the risk of transmission, of an N. gonorrhoeae organism or infection from a first subject, e.g., a first subject infected with N. gonorrhoeae, to a second subject.
  • the method includes: administering to the first, the second, or both subjects, an amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, sufficient to inhibit transmission, or decrease the risk of transmission.
  • the first and second subjects are humans.
  • the negatively charged substituted disaccharide acts via a direct antimicrobial effect.
  • the substituted disaccharide can be provided as a pharmaceutically acceptable salt, or as a composition, e.g., a pharmaceutical composition, which includes the substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the N. gonorrhoeae organism, or a body surface, e.g., an epithelial surface, that will be contacted by the N. gonorrhoeae organism, or both, are O 99/43333 -!°- PCT/US99/04432
  • the contacting step occurs on the surface of the body, or in a body cavity, of the first subject, the second subject or both.
  • the N. gonorrhoeae organism is contacted with the negatively charged substituted disaccharide and such contact occurs, or is initiated prior to contact of the N. gonorrhoeae organism with the second subject, e.g., prior to contact of the N. gonorrhoeae organism into a body surface, e.g., an epithelial surface, or prior to entry into a body cavity of the second subject.
  • a body surface e.g., an epithelial surface
  • the negatively charged substituted disaccharide is administered to either the first or the second subject prior to physical contact, e.g., casual contact (including touching and kissing), sexual contact or contact during child birth.
  • the first subject is N. gonorrhoeae infected.
  • the first subject need not be infected with N. gonorrhoeae, as methods of the invention will be used by a subject in prophylactic applications, wherein not every partner will be infected.
  • Preferred first subjects include humans, most preferably, an individual, e.g., a male or female, who engages in homosexual, heterosexual or bisexual sex, or oral contact.
  • the second subject is N. gonorrhoeae uninfected, or is infected with a strain of N. gonorrhoeae which is different from the N. gonorrhoeae infection of the first subject.
  • Preferred second subjects include humans, most preferably, an individual at risk of being infected by an N. gonorrhoeae organism, or an individual at risk of being infected by a different strain of N. gonorrhoeae.
  • the second subject is an N. gonorrhoeae-free female.
  • the first subject is an N. gonorrboe ⁇ e-infected male and the second subject is an ⁇ . gonorrhoeae-free female, or a female infected by a different strain of N. gonorrhoeae than is the first subject.
  • the first subject is an N. g ⁇ worrAoe ⁇ e-infected female and the second subject is an N. gonorrhoeae-free female, or a female infected by a different strain of N. gonorrhoeae than is the first subject.
  • the second subject is an N. gonorrhoeae-free male.
  • the first subject is an N. g ⁇ /iorrb ⁇ e ⁇ e-infected male and the second subject is an N. gonorrhoeae-free male, or a male infected by a different strain of N. gonorrhoeae than is the first subject.
  • the first or second subject is pregnant.
  • the first subject is an N. go «orrb ⁇ e ⁇ e-infected mother and the second subject is a child.
  • the method further includes the step of identifying a subject at risk of being infected or reinfected by an N. gonorrhoeae organism and providing the subject with sucrose octasulfate or with a device associated with the negatively charged substituted disaccharide.
  • the subject can be a first or a second subject who is uninfected, or infected with N. gonorrhoeae.
  • the negatively charged substituted disaccharide can be administered prior to physical contact, e.g., casual contact, sexual contact or contact during child birth.
  • the composition can be administered within 12 hours, preferably within 8 or 6 hours, most preferably within 1 hour of physical contact.
  • the negatively charged substituted disaccharide can be applied prior to contact, but sufficiently close in time to the contact such that transmission of N. gonorrhoeae infection is inhibited.
  • the negatively charged substituted disaccharide can be administered topically, orally, parenterally, intravaginally, infrarectally, or in aerosol form.
  • the sucrose octasulfate can be administered, e.g., self-administered, by topical application.
  • it can be applied topically onto the epithelium of a bodily surface or cavity, e.g., the vaginal mucosa, cervical mucosa, penis, or anorectal surface.
  • either the first subject or the second subject, or both apply the negatively charged substituted disaccharide topically onto the epithelium of a bodily surface or cavity.
  • the substituted disaccharide can be applied as a topical cream, or can be applied as part of a device associated with the substituted disaccharide, e.g., a contraceptive device, e.g., male or female condom, a diaphragm, an infrauterine device, a tampon, a sponge, a film, a foam, a suppository, or an article of clothing, e.g., an underwear.
  • a contraceptive device e.g., male or female condom, a diaphragm, an infrauterine device, a tampon, a sponge, a film, a foam, a suppository, or an article of clothing, e.g., an underwear.
  • the device can additionally include a contraceptive agent, e.g., a spermicidal agent, e.g., nonoxynol-9, in an amount sufficient to prevent conception.
  • a contraceptive agent e.g., a spermicidal agent, e.g., nonoxynol-9
  • the second subject supplies the first subject with the negatively charged substituted disaccharide, or with a device in association with the substituted disaccharide, e.g., a contraceptive device, e.g., a male or female condom, a diaphragm, an intrauterine device, a tampon, a sponge, an article of clothing, e.g., an underwear, or a topical cream.
  • the method is used to prevent vertical transmission of the N. gonorrhoeae organism, e.g., transmission of an N. gonorrhoeae infected mother to a child during birth.
  • the composition of the negatively charged substituted disaccharide does not include a contraceptive substance.
  • the negatively charged substituted disaccharide is associated with a counter ion, e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base, to form a salt, e.g., a neutral salt.
  • a counter ion e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base
  • a salt e.g., a neutral salt.
  • the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.
  • the negatively charged substituted disaccharide is sucrose octasulfate.
  • the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt.
  • a counter ion e.g., a potassium or an aluminum hydroxide ion
  • Preferred salts of sucrose octasulfate include the potassium salt of sucrose octasulfate, also referred to herein as potassium sucrose octasulfate, and the aluminum hydroxide salt of sucrose octasulfate, also referred to herein as sucralfate.
  • sucrose octasulfate compounds can be represented by the general formula:
  • sucrose octasulfate compounds represented by the formula are in the form of a salt, wherein Xj-Xg are cations, and each of Xj-Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; ⁇ a, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g.. an amino acid; Al x (OH) y . wherein x and y are positive integers, e.g., Al2(OH)5.
  • Xj-Xg are the same cation.
  • each of X ] -Xg is a potassium ion, e.g., K n .
  • n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5Jg.
  • the negatively charged substituted disaccharide is represented by the general formula:
  • R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group.
  • R is SO3 or PO4.
  • Xj-Xg are cations, and each of Xj-Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • the stereochemistry is not limiting, e.g., various stereoisomers can be used.
  • X ] -Xg are the same cation, most preferably, a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5Jg.
  • compositions of the present invention may contain a mixture of a negatively charged substituted disaccharide wherein each of X j -Xg is an aluminum hydroxide ion, e.g., Al2(OH)5 and another negatively charged substituted disaccharide wherein each of Xi-Xg is a potassium ion.
  • the method further includes administering, either as part of the same dosage form or as a separate dosage form, one or more of an antibacterial agent selected from the group consisting of a DNA topoisomerase inhibitor; a cell wall inhibitor; a protein synthesis inhibitor; a membrane transport inhibitor; a metabolic inhibitor, e.g., a folic acid metabolic inhibitor such as trimethoprim and sulfonilamides; an RNA synthesis inhibitor, e.g., rifamycin; a cell membrane agent, e.g., polymixins, defensins, or magainins; an agent affecting electron transport, e.g., metronidazole; or an anionic sulfated polysaccharide polymer, e.g., a sulfated polymer comprising at least three repeating units.
  • an antibacterial agent selected from the group consisting of a DNA topoisomerase inhibitor; a cell wall inhibitor; a protein synthesis inhibitor; a membrane transport inhibitor;
  • any combination of one or more classes of an antibacterial agent and an anionic sulfated polysaccharide polymer can be co-administered, e.g., as part of a combinatorial therapy, with sucrose octasulfate.
  • a preferred combination of a negatively charged substituted disaccharide and an antibacterial agent includes a DNA topoisomerase inhibitor, e.g., ciprofloxacin, a cell wall inhibitor, e.g., penicillin, and a protein synthesis inhibitor, e.g., a tetracycline and/or an aminoglycoside, e.g., streptomycin.
  • the negatively charged substituted disaccharide is administered with a DNA topoisomerase inhibitor such as a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin, or nalidixic acid.
  • a DNA topoisomerase inhibitor such as a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin, or nalidixic acid.
  • a preferred quinolone is ciprofloxacin.
  • the negatively charged substituted disaccharide is administered with a cell wall inhibitor selected from the group consisting of: penicillin, cephalosporin, monobactam, carbapenems, glycopeptides, vancomycin, bacitracin and cycloserine.
  • a cell wall inhibitor selected from the group consisting of: penicillin, cephalosporin, monobactam, carbapenems, glycopeptides, vancomycin, bacitracin and cycloserine.
  • exemplary penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin.
  • cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole.
  • the negatively charged substituted disaccharide is administered with a protein synthesis inhibitor and: the protein synthesis inhibitor is an inhibitor of a ribosomal 30S or 50S subunit, or other protein synthesis inhibitor.
  • protein synthesis inhibitors include: tetracyclines, glycylglycines, aminoglycosides, e.g., streptomycin, gentamicin, tobramycin, choramphenicol, clindamycin, macrolides, e.g., erythromycin, chlarithromycin, azithromycin, lincosamides, streptogramins, e.g., streptogramin B, oxazolidinones, GE-2270A (EF-Tu) and eveminomycin.
  • the negatively charged substituted disaccharide is administered with an antibacterial agent that are capable of accumulating, e.g., concentrating, in the tissue or organ in which a therapeutic or prophylactic effect is desired.
  • an antibacterial agent that are capable of accumulating, e.g., concentrating, in the tissue or organ in which a therapeutic or prophylactic effect is desired.
  • antibacterial agents which are known to concentrate in the urinary tract, such as methenamine, quinolones, e.g., ciprofloxacin, oxolinic acid or nitrofurantoin, are preferred agents.
  • the negatively charged substituted disaccharide is administered with an anionic sulfated polysaccharide and: the anionic sulfated polysaccharide polymer is a long chain polymer of sugars linked to sulfates and optionally other functional groups.
  • sulfated polysaccharides can have a molecular weight of 5,000 to 1 ,000,000, more preferably from 50,000 to 500,000.
  • from 10 to 100% of the available binding sites are sulfated, more preferably, from 50 to 100%.
  • Exemplary sulfated polysaccharides include carrageenans, chondroitin sulfate. dextran sulfate, lentinan sulfate, curdlan sulfate, heparin sulfate, and de-N- sulfated heparin.
  • the invention features, a method for disinfecting a device, a tissue, or a liquid preparation, which is contaminated with N. gonorrhoeae.
  • the method includes: contacting the device, tissue, or liquid preparation, with an amount of a negatively charged substituted disaccharide sufficient to eliminate or attenuate the infectivity of the N. gonorrhoeae organism.
  • the device, tissue or liquid preparation come into contact with a subject body, before or after disinfection.
  • the device is: a contraceptive device (e.g., a condom, a sponge, a diaphragm, a film, or a suppository), a surgical glove, a surgical tool, a napkin or a tissue.
  • a contraceptive device e.g., a condom, a sponge, a diaphragm, a film, or a suppository
  • a surgical glove e.g., a surgical tool, a napkin or a tissue.
  • the liquid preparation is: blood, plasma, semen, sperm, or a laboratory clinical sample.
  • the tissue is an organ, e.g., a kidney, a liver, a tissue or a cell to be transplanted into the body of a recipient, e.g, an ova, a stem cell, e.g., a bone marrow stem cell.
  • the invention features, a composition for inhibiting infection of a cell by an N. gonorrhoeae organism, including: an amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, sufficient to inhibit the infectivity by the N. gonorrhoeae organism; and one or more of an antibacterial agent, e.g., a DNA topoisomerase inhibitor, a cell wall inhibitor, a protein synthesis inhibitor, a membrane transport inhibitor, a metabolic inhibitor, an RNA synthesis inhibitor, or an anionic sulfated polysaccharide polymer, e.g., a polymer comprising at least three repeating units.
  • the negatively charged substituted disaccharide can be provided as a pharmaceutically acceptable salt of the disaccharide, or as a composition, e.g., a pharmaceutical composition, which includes the negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the cell is, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell. Most preferably, the cell is a mucosal cell.
  • the cell e.g., the epithelial cell
  • the cell is located on a body surface or a body cavity, e.g., an oral, pharyngeal, esophageal, pulmonary, ocular, aural, nasal, buccal, lingual, genitourinary, vaginal, cervical, alimentary, or anorectal surface.
  • the cell is a genitourinary epithelial cell, e.g., a cell in the lining bladder or urinary duct, or a vaginal or cervical, e.g., endocervical, epithelial cell.
  • the composition of the negatively charged substituted disaccharide does not include a contraceptive substance.
  • the negatively charged substituted disaccharide is associated with a counter ion, e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base, to form a salt, e.g., a neutral salt.
  • a counter ion e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base
  • a salt e.g., a neutral salt.
  • the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.
  • the negatively charged substituted disaccharide is sucrose octasulfate.
  • the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt.
  • a counter ion e.g., a potassium or an aluminum hydroxide ion
  • Preferred salts of sucrose octasulfate include the potassium salt of sucrose octasulfate, also referred to herein as potassium sucrose octasulfate, and the aluminum hydroxide salt of sucrose octasulfate, also referred to herein as sucralfate.
  • sucrose octasulfate compounds can be represented by the general formula:
  • sucrose octasulfate compounds represented by the formula are in the form of a salt, wherein X j -Xg are cations, and each of X j -Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al (OH)5.
  • X j -Xg are the same cation.
  • each of X]-Xg is a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5]g.
  • the negatively charged substituted disaccharide is represented by the general formula:
  • R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group.
  • R is SO3 or PO4.
  • X]-Xg are cations, and each of X j -Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • the stereochemistry is not limiting, e.g., various stereoisomers can be used.
  • X -Xg are the same cation, most preferably, a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5Jg.
  • compositions of the present invention can include a mixture of salts of negatively charged substituted disaccharides having different substituents at positions Xj-Xg.
  • compositions of the present invention may contain a mixture of a negatively charged substituted disaccharide wherein each of Xj-Xg is an aluminum hydroxide ion, e.g., Al2(OH)5 and another negatively charged substituted disaccharide wherein each of X j -Xg is a potassium ion.
  • the antibacterial agent is administered, either as part of the same dosage form or as a separate dosage form.
  • the DNA topoisomerase inhibitor is a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin or nalidixic acid.
  • a quinolone e.g., ciprofloxacin, ofloxacin, norfloxacin or nalidixic acid.
  • a most preferred quinolone is ciprofloxacin.
  • the cell wall inhibitor is, e.g., an inhibitor of cross- linkages of the peptidoglycan layer of the bacterial cell wall, such as penicillin, cephalosporin, monobactam, carbapenems, glycopeptides, vancomycin, bacitracin and cycloserine.
  • penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin.
  • cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole.
  • the protein synthesis inhibitor is an inhibitor of ribosomal 30S or 50S subunit, or other protein synthesis inhibitor.
  • protein synthesis inhibitors include: tetracyclines, glycylglycines, aminoglycosides, e.g., streptomycin, gentamicin, tobramycin, choramphenicol, clindamycin, macrolides, e.g., erythromycin, chlarithromycin, azithromycin, lincosamides, streptogramins, e.g., streptogramin B, oxazolidinones, GE-2270A (EF-Tu) and everninomycin.
  • a preferred protein synthesis inhibitor is streptomycin.
  • the metabolic inhibitor is a folic acid metabolic inhibitor, e.g., timethoprim or sulfonilamides.
  • the anionic sulfated polysaccharide polymer are long chain polymers of sugars linked to sulfates and optionally other functional groups.
  • sulfated polysaccharides can have a molecular weight of 5,000 to 1,000,000, more preferably from 50,000 to 500,000.
  • from 10 to 100% of the available binding sites are sulfated, more preferably, from 50 to 100%.
  • preferred sulfated polysaccharides include carrageenans, chondroitin sulfate, dextran sulfate, lentinan sulfate, curdlan sulfate, heparin sulfate, and de-N- sulfated heparin.
  • the invention features, a composition for preventing conception and for inhibiting infection of a cell by an N. gonorrhoeae organism, including: an amount of a negatively charged substituted disaccharide, sufficient to inhibit infectivity of the cell by the N. gonorrhoeae organism; and an amount of a contraceptive agent effective to prevent conception.
  • the negatively charged substituted disaccharide can be provided as a pharmaceutically acceptable salt of the disaccharide, or as a composition, e.g., a pharmaceutical composition, which includes the negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the cell is, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell. Most preferably, the cell is a mucosal cell.
  • the cell e.g., the epithelial cell
  • the cell is located on a body surface or a body cavity, e.g., genitourinary, vaginal, cervical, or anorectal surface.
  • the cell is a genitourinary epithelial cell, e.g., lining bladder or urinary duct, or a vaginal or cervical epithelial cell.
  • the epithelial surface cell is a columnar epithelial cell surface of the endocervix.
  • the negatively charged substituted disaccharide is associated with a counter ion, e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base, to form a salt, e.g., a neutral salt.
  • a counter ion e.g., cation, e.g., an alkaline or alkali earth metal ion, or an organic base
  • a salt e.g., a neutral salt.
  • the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.
  • the negatively charged substituted disaccharide is sucrose octasulfate.
  • the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt, e.g., a neutral salt.
  • sucrose octasulfate examples include the potassium salt of sucrose octasulfate, also referred to herein as potassium sucrose octasulfate, and the aluminum hydroxide salt of sucrose octasulfate, also referred to herein as sucralfate.
  • sucrose octasulfate compounds can be represented by the general formula:
  • sucrose octasulfate compounds represented by the formula are in the form of a salt, wherein X j -Xg are cations, and each of X j -Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al (OH) 5 .
  • X ] -Xg are the same cation.
  • each of X j -Xg is a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5J .
  • the negatively charged substituted disaccharide is represented by the general formula:
  • R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group.
  • R is SO3 or PO4.
  • Xj-Xg are cations, and each of X ] -Xg can, e.g., be chosen individually from the group of: alkaline or alkali earth metal ions; Na, K, Ca, Mg, Ba, Al, and Mn; an organic base, e.g., an amino acid; Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5.
  • the stereochemistry is not limiting, e.g., various stereoisomers can be used.
  • Xi-Xg are the same cation, most preferably, a potassium ion, e.g., K n , wherein n is a positive integer, e.g., Kg; or an aluminum hydroxide ion, e.g., Al x (OH) y , wherein x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5]g.
  • a potassium ion e.g., K n
  • n is a positive integer
  • x e.g., Kg
  • an aluminum hydroxide ion e.g., Al x (OH) y
  • x and y are positive integers, e.g., Al2(OH)5, which can optionally be in hydrated form, e.g., [Al2(OH)5]g.
  • compositions of the present invention can include a mixture of salts of negatively charged substituted disaccharides having different substituents at positions Xi-Xg.
  • compositions of the present invention may contain a mixture of a negatively charged substituted disaccharide wherein each of X] -Xg is an aluminum hydroxide ion, e.g., Al2(OH)5 and another negatively charged substituted disaccharide wherein each of X j -Xg is a potassium ion.
  • the contraceptive agent is administered, either as part of the same dosage form or as a separate dosage form.
  • exemplary contraceptive agents include: nonoxynol-9, nonoxynol-1 1 , octoxynol, sodium docusate, HPA-23, gossypol, menfegol, arildone, gramicidin, magainins, defensins, melittin and amphotercin B.
  • the contraceptive agent is nonoxynol-9.
  • the invention features, a device, in association with a negatively charged substituted disaccharide, e.g, sucrose octasulfate.
  • a negatively charged substituted disaccharide e.g, sucrose octasulfate.
  • the device is associated with an amount of the negatively charged substituted disaccharide sufficient to inhibit infection by an N. gonorrhoeae organism.
  • the device can additionally include a spermicidal agent such as nonoxynol-9, in an amount of a contraceptive agent sufficient to prevent conception.
  • the device is a contraceptive device, e.g., a male or female condom, or a diaphragm.
  • the device is a waterproof enclosure which contains sucrose octasulfate, preferably compounded for vaginal or rectal applications.
  • the device is a sponge, a tampon, a film, or a suppository, e.g., a vaginal or rectal suppository.
  • the device is an article of clothing, e.g., underwear.
  • the device is a device for administering sucrose octasulfate to a body cavity, e.g., the vagina, cervix, or rectum.
  • the device is a time release device.
  • the invention features compositions and kits for co- administering the negatively charged substituted disaccharide, e.g., sucrose octasulfate, or a pharmaceutically acceptable salt thereof and an antibacterial or a contraceptive agent.
  • both agents can be pre-mixed, preferably in a pharmaceutically acceptable carrier.
  • the agents can be provided separately in the form of a kit comprising (i) a first pharmaceutical composition including the negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, and (ii) a second pharmaceutical composition including an antibacterial or a contraceptive agent in a pharmaceutically acceptable carrier.
  • compositions refers to compositions which comprise a therapeutically-effective amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, or a "pharmaceutically acceptable” salt thereof, formulated together with one or more pharmaceutically acceptable carrier(s).
  • these pharmaceutical compositions can include at least one antibacterial agent other than the negatively charged substituted disaccharide or a salt thereof.
  • compositions of the present invention can also include anti -contraceptive agents.
  • inhibiting infectivity by N. gonorrhoeae refers to a reduction in the number of N. gonorrhoeae organisms which infect a cell or non-microbial organism. The term includes both total inhibition or reductions which are less than total inhibition.
  • preventing refers to a reduction or a delay in the occurrence of infection by N. gonorrhoeae.
  • the term includes both total inhibition and reductions which are less than total inhibition.
  • a "therapeutically effective amount" of a negatively charged substituted disaccharide e.g., sucrose octasulfate, or a pharmaceutically acceptable salt thereof refers to an amount of a compound which is effective, upon single or multiple dose administration to a subject, at inhibiting infection by N. gonorrhoeae.
  • inhibiting transmission refers to totally or partially reducing the number of viable N. gonorrhoeae organisms which contact or enter a subject's body or cells.
  • a prophylactically effective amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, or a pharmaceutically acceptable salt thereof refers to an amount of a compound which is effective, upon single- or multiple- dose administration to the subject, in preventing or delaying the occurrence of infection by an N. gonorrhoeae organism.
  • the language "subject” is intended to include human and non- human animals.
  • the subject is a person, e.g., a person at risk of being infected or reinfected by an N. gonorrhoeae organism: E.g., a hetero-, homo- or bisexual person who engages in physical, e.g., casual or sexual contact, with an N. g ⁇ rrb ⁇ e ⁇ e-infected partner.
  • the subject is an N. gonorrhoeae -infected mother, or a child, e.g., a newborn, or an infant.
  • non- human animals includes all vertebrates, e.g., mammals and non- mammals, such as non-human primates, ruminants, birds, amphibians, reptiles.
  • association with refers to contacted with, e.g., packaged with, impregnated with, coated, or the like.
  • contacting refers to any physical association of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, with a cell, e.g., an epithelial cell, or an N. gonorrheae organism, including close juxtaposition, coating, or the like.
  • a negatively charged substituted disaccharide e.g., sucrose octasulfate
  • a cell e.g., an epithelial cell, or an N. gonorrheae organism, including close juxtaposition, coating, or the like.
  • the methods described herein are characterized by one or more of the following advantages: (1) the negatively charged substituted disaccharide, e.g., sucrose octasulfate, minimizes disruption of the integrity of the epithelial cell surface to which it is applied; (2) the negatively charged substituted disaccharide, e.g., sucrose octasulfate, has little, if any, toxic or tumorigenic effects; (3) the negatively charged substituted disaccharide, e.g., sucrose octasulfate, has little, if any, anticoagulant activities (in contrast to larger anionic sulfated polysaccharides), contraceptive effects, or other reproductive or teratogenic effects; (4) the negatively charged substituted disaccharide, e.g., sucrose octasulfate, has affinity for damaged epithelium, which is known to be a preferred site for bacterial entry; and (5) the negatively charged substituted disaccharide, e.g.,
  • sucrose octasulfate gel
  • liquid high activity dosage form
  • the invention provides methods and compositions including a negatively charged substituted disaccharide, e.g., sucrose octasulfate, or pharmaceutical salts thereof for the prevention or treatment of infection by N. gonorrhoeae.
  • a negatively charged substituted disaccharide e.g., sucrose octasulfate
  • pharmaceutical salts thereof for the prevention or treatment of infection by N. gonorrhoeae.
  • the most typical mode of human transmission is through heterosexual vaginal intercourse.
  • other modes of transmission for example, homosexual rectal sex, or vertical transmission from a mother to a child during birth are known to occur. It is believed that the mechanism of N. gonorrhoeae infectivity involves adherence of the free organism to epithelial mucosal cells.
  • infection of a female recipient is believed to occur by adherence of the free organism to vaginal or cervical epithelial cells, and then subsequently the epithelial cells of upper genital tract, e.g., the uterus or the Fallopian tubes.
  • the negatively charged substituted disaccharides e.g., sucrose octasulfate, or their pharmaceutically acceptable salts
  • direct antimicrobial effect refers to the binding of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, to a surface, e.g., an outer membrane protein, on the N. gonorrhoeae organism, such that the adherence of the N. gonorrhoeae organism to a cell, e.g., an epithelial cell, is reduced or blocked.
  • the negatively charged substituted disaccharide can bind to, e.g. coat, the cell, e.g., the epithelial cell, that is exposed to the N. gonorrhoeae organism, thus reducing or blocking the adherence of the N. gonorrhoeae organism to the cell.
  • adherence of N. gonorrhoeae organism to a cell surface may be mediated by a heparin sulfate (HS) glycosaminoglycan (GAG) (Rostand, K.S. et al. (1997) Infect. Immun. 66: 1-8. Therefore, by competing with the HS glycosaminoglycan for binding to either the N. gonorrhoeae organism or the cell, or both, the negatively charged substituted disaccharide may block bacterial adherence to the cell.
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof can be obtained commercially, or may be synthesized by conventional techniques (see US patent 3,432,489, EP 230023, EP 0640346).
  • sucrose octasulfate can be conveniently synthesized from commercially available starting materials.
  • the negatively charged substituted disaccharide 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 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.
  • compositions which include a therapeutically-effective amount of a negatively charged substituted disaccharide, e.g., sucrose octasulfate, and one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • a composition can also include an antibiotic or a contraceptive agent.
  • the pharmaceutical compositions can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or infrarectally, for example, as a pessary, cream, foam, or suppository; (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound; or (6) as a liquid suspension, foam, gel, ointment, or spray that can be used to lavage the birth canal before and during labor, e.g., prior to breaking the amniotic sac, through delivery,
  • oral administration for
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the negatively charged substituted disaccharide from one organ, or portion of the body, to another organ, or portion of the body without affecting its biological effect.
  • Each carrier should be “acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (1 1) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • compositions of the present invention may be administered to epithelial surfaces of the body orally, parenterally, topically, rectally nasally, intravaginally, intracisternally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal or vaginal suppositories.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a negatively charged substituted disaccharide and/or an antibacterial or a contraceptive agent, drug or other material other than directly into the central nervous system, such that it enters the subject's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • compositions of the invention can 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, esophageal, pulmonary, ocular, aural, nasal, buccal, lingual, vaginal, cervical, genitourinary, alimentary, and anorectal surfaces.
  • compositions can 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.
  • 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.
  • Conventionally used carriers for topical applications include pectin, gelatin and derivatives thereof, polylactic acid or polyglycolic acid polymers or copolymers thereof, cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, or oxidized cellulose, guar gum, acacia gum, karaya gum, fragacanth gum, bentonite, agar, carbomer, bladderwrack, ceratonia, dextran and derivatives thereof, ghatti gum, hectorite, ispaghula husk, polyvinypyrrolidone, silica and derivatives thereof, xanthan gum, kaolin, talc, starch and derivatives thereof, paraffin, water, vegetable and animal oils, polyethylene, polyethylene oxide, polyethylene glycol, polypropylene glycol, glycerol, ethanol, propanol, propylene glycol (glycols, alcohols), fixed oils, sodium, potassium, aluminium, magnesium or calcium salts (such as chloride
  • compositions can be particularly useful, for example, for treatment or prevention of vaginal N. gonorrhoeae infections, or infections of the oral cavity, including infections of eye, the skin, or the lower intestinal tract.
  • Standard composition strategies for topical agents can be applied to negatively charged substituted disaccharide 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.
  • a rectal suppository for topical application to be used in the lower intestinal tract or vaginally, a rectal suppository, a suitable enema, a gel, an ointment, a solution, a suspension or an insert can be used.
  • Topical transdermal patches may also be used.
  • Transdermal patches have the added advantage of providing controlled delivery of the compositions of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • compositions of the invention can be administered in the form of suppositories for rectal or vaginal administration.
  • suppositories for rectal or vaginal administration.
  • These can be prepared by mixing the agent with a suitable non-irritating carrier which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vagina to release the drug.
  • suitable non-irritating carrier which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vagina to release the drug.
  • suitable non-irritating carrier which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vagina to release the drug.
  • Such materials include cocoa butter, beeswax, polyethylene glycols, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, films, or spray compositions containing such carriers as are known in the art to be appropriate.
  • the carrier employed in the negatively charged substituted disaccharide /contraceptive agent should be compatible with vaginal administration and/or coating of contraceptive devices.
  • Combinations can be in solid, semi-solid and liquid dosage forms, such as diaphragm, jelly, douches, foams, films, 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 pharmaceutical compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the compositions can be formulated in an ointment such as petrolatum.
  • Exemplary ophthalmic compositions include eye ointments, powders, solutions and the like.
  • Powders and sprays can contain, in addition to the negatively charged substituted disaccharide and/or antibiotic or contraceptive agent(s), carriers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of the invention can also be orally administered in any orally- acceptable dosage form including, but not limited to, capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or fragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the negatively charged substituted disaccharide and/or antibiotic or contraceptive agent(s) as an active ingredient.
  • capsules, cachets, pills, tablets, lozenges using a flavored basis, usually sucrose and acacia or fragacanth
  • powders granules, or
  • a compound may also be administered as a bolus, electuary or paste.
  • 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.
  • Tablets, and other solid dosage forms may be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active negatively charged substituted disaccharide and/or antibiotic or contraceptive agent(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and fragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and fragacanth, and mixtures thereof.
  • Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a nontoxic 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 negatively charged substituted disaccharide 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 for example are typically limited by the physical chemical properties of the delivery medium to concentrations less than 20% (e.g., 200 mg/gm). For special uses, far less concentrated preparations can be prepared, (e.g., lower percent formulations for pediatric applications).
  • the pharmaceutical composition of the invention can comprise negatively charged substituted disaccharide in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the total preparation.
  • a preferred concentration thereof in the preparation is 0.5-50%, especially 0.5-25%, such as 1-10%. It can be suitably applied 1-10 times a day, depending on the type and severity of the condition to be treated or prevented.
  • sucrose octasulfate or a pharmaceutically acceptable salt thereof over many decades of clinical use as an anti-ulcerant [W.R. Garnett, Clin. Pharm. 1 :307-314 (1982); R.N. Brogden et al., Drugs 27:194-209 (1984); D.M. McCarthy, New EngJMed., 325:1017-1025 (1991), an upper limit for the therapeutically effective dose is not a critical issue.
  • the minimum amount present in the combinations of this invention that is effective in treating or preventing bacterial disease due to direct interaction with the organism should produce be 1 x 10 "4 mg/ml. If sucralfate is employed the minimum effective concentration should be 1 x 10"3 mg/ml.
  • the pharmaceutical composition of the invention can be applied prior to physical contact.
  • the timing of application prior to physical contact can be optimized to maximize the prophylactic effectiveness of the compound.
  • the timing of application will vary depending on the mode of administration, the epithelial surface to which it is applied, the surface area, doses, the stability and effectiveness of composition under the pH of the epithelial surface, the frequency of application, e.g., single application or multiple applications.
  • the timing of application can be determined such that a single application of composition is sufficient.
  • One skilled in the art will be able to determine the most appropriate time interval required to maximize prophylactive effectiveness of the compound.
  • compositions of the present invention can be initially tested in vitro using N. gonorrhoeae grown on specialized media, e.g., in broth or in agar form, as described in the Examples herein.
  • human fallopian tube organ cultures HFTOC
  • looper M.D. et al. (1990) J. Gen. Microbiol. 136: 1109-1115).
  • the negatively charged substituted disaccharide e.g., sucrose octasulfate
  • the subject compounds can be combined with other agents, e.g., such as antibacterial agents.
  • agents e.g., such as antibacterial agents.
  • Some of the co-administered agents particular those with cytotoxic effects or which lack specficity for the treated cells, may be given in smaller doses due to an additive, and sometimes synergistic effect with negatively charged substituted disaccharide.
  • Choices and preferences for the various antibacterial agents are the same as disclosed above for negatively charged substituted disaccharide/antibacterial agent pharmaceutical combinations.
  • Combinational therapies utilized in the methods described herein may also exert an additive or synergistic effect, particularly when the anti-bacterial activity of each component operates via a different mechanism.
  • the reduction in effective therapeutic dose achieved with such combinations may be additive or synergistic.
  • Methods described herein should be carried out for a period of time sufficient to inhibit, e.g., block or prevent, bacterial adherence or infectivity in a subject, or to prevent transmission of N. gonorrhoeae from an infected subject to another subject.
  • the timing of application prior to physical contact can be optimized to maximize the prophylactic effectiveness of the compound.
  • the timing of application will vary depending on the epithelial surface to which it is applied, the surface area, doses, the stability and effectiveness of composition under the pH of the epithelial surface, the frequency of application, e.g., single application or multiple applications. Preferably, the timing of application can be determined such that a single application of composition is sufficient. One skilled in the art will be able to determine the most appropriate time interval required to maximize prophylactive effectiveness of the compound.
  • candidate subjects e.g., persons who are in need of prophylactic treatment
  • One skilled in the art can identify such candidate subjects, by the use of, for example, clinical tests, physical examination and medical history.
  • Particularly likely candidate subjects are persons at risk of being infected or reinfected by an ⁇ . gonorrhoeae organism: E.g., a hetero-, homo- or bisexual person who engages in physical, e.g., casual or sexual contact, with an ⁇ . g ⁇ n ⁇ rrboe ⁇ e-infected partner.
  • the invention provides methods of using the negatively charged substituted disaccharide to prevent vertical transmission of an ⁇ . gonorrhoeae infection from a mother to a child during childbirth.
  • the method can include a method of treating the mother prior to or during labor with an amount of negatively charged substituted disaccharide, e.g., sucrose octasulfate, sufficient to reduce or prevent N. gonorrhoeae infection of the child.
  • the method can be carried out by topically administering to the mother's birth canal during or prior to labor a therapeutically effective concentration of the substituted disaccharide or a pharmaceutically acceptable salt thereof.
  • the neonate can be disinfected with a pharmaceutical composition which includes the negatively charged substituted disaccharide, e.g., sucrose octasulfate.
  • a pharmaceutical composition which includes the negatively charged substituted disaccharide, e.g., sucrose octasulfate.
  • a lotion or oinment e.g., an eye lotion or oinment, including the negatively charged substituted disaccharide can be used as a disinfecting lavage of the newborn.
  • the composition of the negatively charged substituted disaccharide utilized should be compatible with the treatment of neonates.
  • the choice of carrier and antibacterial agent if utilized for use during childbirth is known in the art.
  • Treatment or prophylaxis can be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage should be increased by small increments until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • Compounds which are determined to be effective for the prevention or treatment of infection in vitro may also be useful in treatment of infection in humans.
  • Those skilled in the art of treating bacterial infections in humans will know, based upon the data obtained in in vitro studies, the dosage and route of administration of the compound to humans.
  • the invention also provides methods for disinfecting a health care device which is designed to come into contact with a subject.
  • the device is selected from a contraceptive device, a plastering material, a bandage, a sponge, a napkin, a strip, a tissue protective external covering used in medicine, a surgical device, a dental device, a laboratory device, surgical gloves, a surgical gown, and a surgical mask.
  • a contraceptive device a plastering material
  • a bandage a sponge
  • a napkin a strip
  • tissue protective external covering used in medicine
  • a surgical device a dental device, a laboratory device, surgical gloves, a surgical gown, and a surgical mask.
  • negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof may be mixed with a talcum lubricant powder used to line surgical gloves.
  • the invention provides a method for disinfecting a biological fluid comprising the step of contacting said fluid with an amount of negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof, sufficient to reduce the gonorrhoeae infectivity in said biological fluid.
  • the biological fluid is selected from blood, plasma, ova, sperm or semen.
  • the negatively charged substituted disaccharide 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.
  • Negatively charged substituted disaccharides and their salts are particularly advantageous for purifying blood because of their lack of anticoagulant activity.
  • Example 1 Sucralfate and the Potassium Salt of Sucrose Octasulfate Inhibits Infection of N. gonorrhoeae In Vitro Materials and Methods
  • Sucralfate can be purchased as liquid suspension from Hoeschst Marion Roussel (Kansas City, MO). Potassium sucrose octasulfate powder can be purchased from U.S. Pharmacopeial (USP) Convention, Inc. (Rockville, M.D). A stock solution of potassium sucrose octasulfate can be prepared by dissolving 1 gram of potassium sucrose octasulfate powder in 3 ml of phosphate buffered saline (PBS). A stock solution of sucralfate can be prepared by adding 1 ml of the sucralfate suspension to 9 ml of PBS. Stock solutions can be stored at 4°C prior to use. Serial dilutions were prepared from the potassium sucrose octasulfate and sucralfate stock solutions, to final concentrations of 30 mg/ml to 0.0003 mg/ml in PBS without antibiotics.
  • the minimum inhibitory concentration (MIC) for potassium sucrose octasulfate and for sucralfate i.e., the lowest concentration of the two compounds in which there is no growth of N. gonorrhoeae, was determined to be 0.00003 mg/ml (see Table 1). In contrast, heavy growth was observed in the control plates.
  • Example 2 Reduced Inhibitory Effect on N. gonorrhoeae Growth Using Potassium Sucrose Octasulfate and Sucralfate
  • GC agar base enriched with IsoVitaleX was prepared, while still a broth, for each of the serial dilutions of the potassium sucrose octasulfate and sucralfate stock solutions that were described in the previous Example. Those dilutions were carried out as described in the previous Example.
  • the GC agar base samples were allowed to dry over night to form agar plates.

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Abstract

La présente invention concerne des compositions et des procédés dans lesquels on utilise des disaccharides substitués de charge négative, par exemple de l'octasulfate de saccharose, ou des sels de ceux-ci seuls ou combinés à d'autres substances pour traiter ou prévenir les infections par le N. gonorrhoeae.
PCT/US1999/004432 1998-02-27 1999-02-26 Utilisations therapeutiques et prophylactiques de disaccharides substitues de charge negative WO1999043333A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030395A1 (fr) * 2000-10-10 2002-04-18 Pharmacia & Upjohn Company Composition antibiotique topique destinee au traitement d'une infection oculaire
WO2002089818A1 (fr) * 2001-05-03 2002-11-14 Farmigea S.P.A. Utilisation de sucralfate pour traiter l'erosion cervicale
FR2824474A1 (fr) * 2001-05-11 2002-11-15 Fabre Pierre Dermo Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc
US7128928B2 (en) 2002-02-22 2006-10-31 Pharmacia Corporation Ophthalmic formulation with novel gum composition
WO2014060138A1 (fr) * 2012-10-17 2014-04-24 Interalia S.R.L. Compositions comprenant un sel d'argent d'octasulfate de saccharose et un sel de potassium d'octasulfate de saccharose pour la protection des épithéliums de muqueuse

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640346A1 (fr) * 1987-12-21 1995-03-01 BM Research A/S Utilisations de sucres sulfates contre inflammation
US5538954A (en) * 1994-06-24 1996-07-23 A/S Dumex (Dumex Ltd.) Salts of tetracyclines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640346A1 (fr) * 1987-12-21 1995-03-01 BM Research A/S Utilisations de sucres sulfates contre inflammation
US5538954A (en) * 1994-06-24 1996-07-23 A/S Dumex (Dumex Ltd.) Salts of tetracyclines

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030395A1 (fr) * 2000-10-10 2002-04-18 Pharmacia & Upjohn Company Composition antibiotique topique destinee au traitement d'une infection oculaire
US6551584B2 (en) 2000-10-10 2003-04-22 Pharmacia & Upjohn Company Topical antibiotic composition for treatment of eye infection
WO2002089818A1 (fr) * 2001-05-03 2002-11-14 Farmigea S.P.A. Utilisation de sucralfate pour traiter l'erosion cervicale
FR2824474A1 (fr) * 2001-05-11 2002-11-15 Fabre Pierre Dermo Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc
WO2002092045A1 (fr) * 2001-05-11 2002-11-21 Pierre Fabre Dermo-Cosmetique Composition cosmetique a base de sucralfate et de sulfates de cuivre et de zinc
US7128928B2 (en) 2002-02-22 2006-10-31 Pharmacia Corporation Ophthalmic formulation with novel gum composition
WO2014060138A1 (fr) * 2012-10-17 2014-04-24 Interalia S.R.L. Compositions comprenant un sel d'argent d'octasulfate de saccharose et un sel de potassium d'octasulfate de saccharose pour la protection des épithéliums de muqueuse

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