WO1999043333A1

WO1999043333A1 - Therapeutic and prophylactic uses of negatively charged substituted disaccharides

Info

Publication number: WO1999043333A1
Application number: PCT/US1999/004432
Authority: WO
Inventors: Manuel A. Navia; Thomas C. Quinn
Original assignee: The Althexis Company; Usa, Secretary Department Of Health And Human Services
Priority date: 1998-02-27
Filing date: 1999-02-26
Publication date: 1999-09-02
Also published as: AU2798299A

Abstract

The present invention relates to the compositions and methods of using negatively charged substituted disaccharides, e.g., sucrose octasulfate, or salts thereof alone or in combination with other agents, in treating or preventing infections by N. gonorrhoeae.

Description

THERAPEUTIC AND PROPHYLACTIC USES OF NEGATIVELY CHARGED SUBSTITUTED DISACCHARIDES

Field of the Invention

The invention relates to the use of negatively charged substituted disaccharides, e.g., sucrose octasulfate, to treat or prevent infections caused by N. gonorrhoeae.

Background of the Invention

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.

Since the 1960s there has been an alarming increase in the number of cases of gonorrhea in the United States. This increase has coincided with the widespread introduction of birth control pills, the hormones of which cause more basic pH values in the vaginal tract which removes the normal protection afforded against infection by acid- sensitive bacteria, such as N. gonorrhoeae. Gonorrhea is normally contracted from someone who is asymptomatic or who has symptoms but does not seek treatment. The rate of gonorrhea infection for males is about 35 percent after a single exposure to an infected female and rises to about 75 percent after multiple sexual contacts with the same individual (Atlas, R.M. ( 1984) Microbiology: Fundamentals and Applications, McMillan Publishing Co., Ν.Y).

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. et al. ( 1983) N. Engl. J. Mecj. 309: 576-583). 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.

Summary of the Invention

In general, 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. In a preferred embodiment, 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. In in vivo embodiments, the negatively charged substituted disaccharide can be administered to a subject. In preferred embodiments, 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.

In preferred in vivo embodiments, 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.

In preferred in vivo embodiments, the cell, e.g., the epithelial cell, 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.

In preferred in vivo embodiments, the cell, e.g., an epithelial 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. Preferably, 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. Most preferably, the cell is a columnar epithelial cell of the endocervix.

In preferred embodiments, the cell is, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell. Most preferably, the cell is a mucosal cell.

In preferred embodiments, the cell is a mammalian cell, e.g., a human or non- human cell, most preferably, the cell is a human cell.

In preferred embodiments, the composition of the negatively charged substituted disaccharide does not include a contraceptive substance.

In preferred embodiments, 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. Preferably, the salt of the negatively charged substituted disaccharide includes an aluminum hydroxide ion or a potassium ion.

In preferred embodiments, the negatively charged substituted disaccharide is sucrose octasulfate. Preferably, the sucrose octasulfate is associated with a counter ion, e.g., a potassium or an aluminum hydroxide ion, to form a salt. 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.

In preferred embodiments, sucrose octasulfate compounds can be represented by the general formula:

CH20-RX)

wherein R is SO3. Preferably, the 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., Al₂(OH)₅. Preferably, X_j-Xg are the same cation. In most preferred salts of sucrose octasulfate, 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.

In other embodiments, the negatively charged substituted disaccharide is represented by the general formula:

ORX,

)— o-Y T

RX- ORX₄ ORX, ^

wherein R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group. Preferably, R is SO3 or PO4. In preferred embodiments, 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.

In certain embodiments, 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] .

In preferred embodiments, the methods described herein use a composition which includes a mixture of salts of negatively charged substituted disaccharides having different substituents at positions Xj-Xg. For example, 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. In another aspect, 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. gonorrhoeae organism in a subject. 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. In a preferred embodiment, 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.

In preferred embodiments, 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.

In preferred embodiments, 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. Preferably, 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. Most preferably the epithelial surface is a columnar epithelial cell surface of the endocervix.

In preferred embodiments, the method treats or prevents infection of a cell, e.g., a mucosal, submucosal, epidermal, dermal or subcutaneous cell. Most preferably, the cell is a mucosal cell.

In preferred embodiments, 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.

In preferred embodiments, 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 Ν. gonorrhoeae organism.

In preferred embodiments, 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.

CH20-RX]

0-RX3 H

0- X4

wherein R is SO3. Preferably, the 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. Preferably, Xj-Xg are the same cation. In most preferred salts of sucrose octasulfate, 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] . In other embodiments, the negatively charged substituted disaccharide is represented by the general formula:

ORX,

O -ORX_g

^W -o-χ f \._DY i O ORRXX,

^0RX ₄ ORX₆

wherein R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group. Preferably, R is SO3 or PO4. In preferred embodiments, 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.

In certain embodiments, 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.

In preferred embodiments, the methods described herein use a composition which includes a mixture of salts of negatively charged substituted disaccharides having different substituents at positions X_j-Xg. For example, 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.

In preferred embodiments, the negatively charged substituted disaccharide is administered: topically, orally, parenterally, intravaginally, intrarectally, or in aerosol form. Preferably, the negatively charged substituted disaccharide is administered, e.g., self-administered, by topical application. For example, 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. In preferred embodiments, 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.

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.

In preferred embodiments, 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 most preferred quinolone is ciprofloxacin.

In preferred embodiments, 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. Exemplary penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin. Exemplary cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole.

In preferred embodiments, 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. Examples of 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. In preferred embodiments, 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. For example, in treating urinary tract infections, 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.

In preferred embodiments, 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. Preferable, sulfated polysaccharides can have a molecular weight of 5,000 to 1 ,000,000, more preferably from 50,000 to 500,000. In addition, 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.

In preferred embodiments, 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.

In another aspect, 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. In preferred embodiments, the first and second subjects are humans. In a preferred embodiment, 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.

In preferred embodiments, 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

contacted with the negatively charged substituted disaccharide. Preferably, the contacting step occurs on the surface of the body, or in a body cavity, of the first subject, the second subject or both.

In preferred embodiments, 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.

In preferred embodiments, 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.

In preferred embodiments, the first subject is N. gonorrhoeae infected. However, it is stressed that 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.

In preferred embodiments, 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.

In preferred embodiments, the second subject is an N. gonorrhoeae-free female.

In preferred embodiments, the first subject is an N. gonorrboeαe-infected male and the second subject is an Ν. gonorrhoeae-free female, or a female infected by a different strain of N. gonorrhoeae than is the first subject.

In preferred embodiments, the first subject is an N. gøworrAoeαe-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.

In preferred embodiments, the second subject is an N. gonorrhoeae-free male. In preferred embodiments, the first subject is an N. gø/iorrbøeαe-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.

In preferred embodiments, the first or second subject is pregnant.

In preferred embodiments, the first subject is an N. go«orrbøeαe-infected mother and the second subject is a child.

In preferred embodiments, 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.

In preferred embodiments, the negatively charged substituted disaccharide can be administered prior to physical contact, e.g., casual contact, sexual contact or contact during child birth. For example, 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.

In preferred embodiments, the negatively charged substituted disaccharide can be administered topically, orally, parenterally, intravaginally, infrarectally, or in aerosol form. Preferably, the sucrose octasulfate can be administered, e.g., self-administered, by topical application. For example, 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.

In preferred embodiments, 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. For example, 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. The device can additionally include a contraceptive agent, e.g., a spermicidal agent, e.g., nonoxynol-9, in an amount sufficient to prevent conception. In preferred embodiments, 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.

In preferred embodiments, 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.

CH20-RX

wherein R is SO3. Preferably, the 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; Νa, 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. Preferably, Xj-Xg are the same cation. In most preferred salts of sucrose octasulfate, 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)5Jg.

ORX,

-ORX

X^O O— O ORRXX,

ORX₄ ORX₆

wherein R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group. Preferably. R is SO3 or PO4. In preferred embodiments, 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. In certain embodiments, 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.

In preferred embodiments, the methods described herein use a composition which includes a mixture of salts of negatively charged substituted disaccharides having different substituents at positions X_j-Xg. For example, 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.

In preferred embodiments, 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.

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.

In preferred embodiments, 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 preferred quinolone is ciprofloxacin.

In preferred embodiments, 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. Exemplary penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin. Exemplary cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole. In preferred embodiments, 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. Examples of 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.

In preferred embodiments, 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. For example, in treating urinary tract infections, 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.

In preferred embodiments, 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. Preferable, sulfated polysaccharides can have a molecular weight of 5,000 to 1 ,000,000, more preferably from 50,000 to 500,000. In addition, 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.

In another aspect, 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.

In preferred embodiments, the device, tissue or liquid preparation come into contact with a subject body, before or after disinfection.

In preferred embodiments, 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.

In preferred embodiments, the liquid preparation is: blood, plasma, semen, sperm, or a laboratory clinical sample.

In preferred embodiments, 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.

In another aspect, 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.

In preferred embodiments, the cell, e.g., the epithelial 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. Preferably, 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.

CH20-RX1

wherein R is SO3. Preferably, the 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. Preferably, X_j -Xg are the same cation. In most preferred salts of sucrose octasulfate, 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.

ORX₅ /⁰^^^~0RX°

ORX₄ < x₆ ^ORX7

wherein R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group. Preferably, R is SO3 or PO4. In preferred embodiments, 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. In certain embodiments, 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.

In preferred embodiments, the compositions of the present invention can include a mixture of salts of negatively charged substituted disaccharides having different substituents at positions Xj-Xg. For example, 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.

In preferred embodiments, the antibacterial agent is administered, either as part of the same dosage form or as a separate dosage form.

In preferred embodiments, the DNA topoisomerase inhibitor is a quinolone, e.g., ciprofloxacin, ofloxacin, norfloxacin or nalidixic acid. A most preferred quinolone is ciprofloxacin.

In preferred embodiments, 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. Exemplary penicillin compounds include penicillin G, phenoxymethyl penicillin, methicillin, oxacillin, naficillin, ampicillin, amoxicillin, and carbenicillin. Exemplary cephalosphorin compounds include cephalothin, cephtriaxone, cefazolin, cefalexin, cephradine, cefoxitin, and cefamandole.

In preferred embodiments, the protein synthesis inhibitor is an inhibitor of ribosomal 30S or 50S subunit, or other protein synthesis inhibitor. Examples of 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.

In preferred embodiments, the metabolic inhibitor is a folic acid metabolic inhibitor, e.g., timethoprim or sulfonilamides.

In preferred embodiments, the anionic sulfated polysaccharide polymer are long chain polymers of sugars linked to sulfates and optionally other functional groups. Preferable, sulfated polysaccharides can have a molecular weight of 5,000 to 1,000,000, more preferably from 50,000 to 500,000. In addition, from 10 to 100% of the available binding sites are sulfated, more preferably, from 50 to 100%. Examples of preferred sulfated polysaccharides include carrageenans, chondroitin sulfate, dextran sulfate, lentinan sulfate, curdlan sulfate, heparin sulfate, and de-N- sulfated heparin. In another aspect, 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.

In preferred embodiments, the cell, e.g., the epithelial cell, is located on a body surface or a body cavity, e.g., genitourinary, vaginal, cervical, or anorectal surface. Preferably, the cell is a genitourinary epithelial cell, e.g., lining bladder or urinary duct, or a vaginal or cervical epithelial cell. Most preferably the epithelial surface cell is a columnar epithelial cell surface of the endocervix.

In preferred embodiments, the negatively charged substituted disaccharide is sucrose octasulfate. Preferably, 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.

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.

wherein R is SO3. Preferably, the 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. Preferably, X_]-Xg are the same cation. In most preferred salts of sucrose octasulfate, 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 .

ORX₅ o- \V O^ T ^{- 0RX}8

ORX₄ ORX, ^0RX?

wherein R is a negatively charged substituent, preferably a small, negatively charged substituent, wherein small means approximately the size of an SO3 group. Preferably, R is SO3 or PO4. In preferred embodiments, 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.

In certain embodiments, 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.

In preferred embodiments, the compositions of the present invention can include a mixture of salts of negatively charged substituted disaccharides having different substituents at positions Xi-Xg. For example, 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.

In preferred embodiments, 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. Most preferably, the contraceptive agent is nonoxynol-9.

In another aspect, the invention features, a device, in association with a negatively charged substituted disaccharide, e.g, sucrose octasulfate. Preferably, 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.

In preferred embodiments, the device is a contraceptive device, e.g., a male or female condom, or a diaphragm.

In preferred embodiments, the device is a waterproof enclosure which contains sucrose octasulfate, preferably compounded for vaginal or rectal applications.

In preferred embodiments, the device is a sponge, a tampon, a film, or a suppository, e.g., a vaginal or rectal suppository.

In preferred embodiments, the device is an article of clothing, e.g., underwear.

In preferred embodiments, the device is a device for administering sucrose octasulfate to a body cavity, e.g., the vagina, cervix, or rectum. In preferred embodiments, the device is a time release device.

In still another aspect, 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. For example, both agents can be pre-mixed, preferably in a pharmaceutically acceptable carrier. Alternatively, 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.

The terms "negatively charged substituted disaccharide" and "substituted disaccharide" are used interchangeably herein.

The term "pharmaceutically acceptable composition" 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). In preferred embodiments, these pharmaceutical compositions can include at least one antibacterial agent other than the negatively charged substituted disaccharide or a salt thereof. In certain embodiments, compositions of the present invention can also include anti -contraceptive agents.

As used herein, "inhibition of 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.

As used herein, "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.

As used herein, 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.

As used herein, "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. As used herein, "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.

As used herein, the language "subject" is intended to include human and non- human animals. In preferred embodiments, 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. gøπørrbøeαe-infected partner. In certain, embodiments, the subject is an N. gonorrhoeae -infected mother, or a child, e.g., a newborn, or an infant. The term "non- human animals" of the invention includes all vertebrates, e.g., mammals and non- mammals, such as non-human primates, ruminants, birds, amphibians, reptiles.

As used herein, the term "associated with" refers to contacted with, e.g., packaged with, impregnated with, coated, or the like.

As used herein, the term "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.

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 forms non-covalent gels, or remains in a liquid state depending upon the particular salt used, sucrose octasulfate has good bioavailability. 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-bacterial use desired. Accordingly, these compounds do not increase the risk of bacterial infection and can be administered in high doses without toxicity or side effects. The absence of contraceptive, and/or teratogenic activity demonstrated for sucralfate to date makes this compound ideal for use in preventing sexually transmitted N. gonorrhoeae infections, even in a pregnant subject, or a subject that seeks to avoid contraception for, e.g., cultural or religious reasons.

Other features and advantages of the invention will be apparent from the following description and from the claims.

Detailed Description

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. The most typical mode of human transmission is through heterosexual vaginal intercourse. However, 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. For example, 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.

Without being bound by theory, it is believed that the negatively charged substituted disaccharides, e.g., sucrose octasulfate, or their pharmaceutically acceptable salts, exert their therapeutic and prophylactic effects by a direct antimicrobial effect. As used herein, the phrase "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. Alternatively, 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. It has been recently suggested that 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. Chemical S^ynthesis of Negatively Charged Substituted Disaccharide

The negatively charged substituted disaccharide of the invention, for example, 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). For example, sucrose octasulfate can be conveniently synthesized from commercially available starting materials.

It should also be understood that 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. Such 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.

Pharmaceutical Compositions

The invention provides pharmaceutically acceptable 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.

As described in detail below, 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, and as a disinfecting lavage of the newborn.

The phrase "pharmaceutically-acceptable carrier" as used herein 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. Some examples of 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 hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical compositions. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These 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.

In some cases, 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.

Pharmaceutical 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.

The phrases "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.

The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean 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.

In some methods, the compositions of the invention can be topically administered to any epithelial surface. An "epithelial surface" according to this invention 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.

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, carbonate, bicarbonate, citrate, gluconate, lactate, acetate, gluceptate or tartrate).

Such 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.

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. 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. 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. For ophthalmic applications, 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. Alternatively, for ophthalmic uses, 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.

Ordinarily, 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. A compound may also be administered as a bolus, electuary or paste. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When 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, such as dragees, capsules, pills and granules, 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. These 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. Examples of embedding compositions which can be used 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. In addition to the active ingredient, 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.

Besides inert diluents, the oral compositions can also include 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.

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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, 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. 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). For example, 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. In particular, 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.

Given the low toxicity of 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. Thus, for most forms of the negatively charged substituted disaccharide, e.g., sucrose octasulfate, 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.

For prophylactic applications, 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. 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.

Uses and Methods Methods described herein can be performed in culture, e.g., in vitro or ex vivo, or can be performed in a subject, e.g., as part of an in vivo therapeutic protocol. The therapeutic regimen can be carried out on a human or other animal subject. The 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. Alternatively, human fallopian tube organ cultures (HFTOC) can also be used (Cooper, M.D. et al. (1990) J. Gen. Microbiol. 136: 1109-1115).

While the negatively charged substituted disaccharide, e.g., sucrose octasulfate, can be utilized alone to treat or prevent N. gonorrhoeae infections, the subject compounds can be combined with other 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.

The identification of those subjects, e.g., persons who are in need of prophylactic treatment is within the ability and knowledge of one skilled in the art. 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 Ν. gonorrhoeae organism: E.g., a hetero-, homo- or bisexual person who engages in physical, e.g., casual or sexual contact, with an Ν. gønørrboeαe-infected partner.

The invention provides methods of using the negatively charged substituted disaccharide to prevent vertical transmission of an Ν. gonorrhoeae infection from a mother to a child during childbirth. For example, 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. Alternatively, the neonate can be disinfected with a pharmaceutical composition which includes the negatively charged substituted disaccharide, e.g., sucrose octasulfate. For example, 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. For convenience, 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. Preferably, 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. For example, negatively charged substituted disaccharide or a pharmaceutically acceptable salt thereof, may be mixed with a talcum lubricant powder used to line surgical gloves.

According to another embodiment, 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. Preferably, the biological fluid is selected from blood, plasma, ova, sperm or semen. Because of its benign nature, the negatively charged substituted disaccharide or salt thereof may be added directly to the biological fluid. Alternatively, 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.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are set forth for illustrative purposes only and are not to be construed as limiting this invention in any manner. 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.

A MacFarland standard of N. gonorhoeae (10^ gonococci (GC)/ml) was prepared in Trypticase Soy (T-soy) Broth. 50 ul of the T-soy broth (50GC) were added to the potassium sucrose octasulfate and sucralfate series of dilutions to determine if there was a time-dependent effect, the N. gooorrboeoe-inoculated potassium sucrose octasulfate and sucralfate dilution series were incubated at 37°C in 5% CO2 for 0 hr, 1 hr and 2 hr. Following incubation, GC agar plates enriched with IsoVitaleX were inoculated, and incubated for 2 days at 37°C in 50% CO2. At the end of the period, plates were examined for growth. Controls without potassium sucrose octasulfate or sucralfate were run against each of the above experiments.

From these experiments, 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.

Table 1 : Determination of MIC after 0, 1 hr. and 2 hr. incubations with potassium sucrose octasulfate and sucralfate

Procedure Solution MIC

1 potassium sucrose .00003 mg/ml octasulfate

1 sucralfate .00003 mg/ml

These data demonstrate a dramatic and immediate inhibitory effect on the growth of N. gonorrhoeae by contact with potassium sucrose octasulfate or sucralfate prior to plating and further incubation under favorable growth conditions. No growth of N. gonorrhoeae was detected at any of the times testing, i.e., the inhibitory effect, was observed at 0 hr, 1 hr and 2 hr of incubation.

Example 2: Reduced Inhibitory Effect on N. gonorrhoeae Growth Using Potassium Sucrose Octasulfate and Sucralfate

In this experiment, 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. N. gonorrhoeae were inoculated onto the plates with a calibrated loop (50 ul = 50GC), and the plates were incubated for 2 days at 37°C in 5% CO2- Controls plates without potassium sucrose octasulfate or sucralfate were run against each of the above experiments. After two days, the experimental and control plates were examined for N. gonorrhoeae growth. As shown below in Table 2, the MIC for potassium sucrose octasulfate was 3 mg/ml, and for sucralfate was 30 mg/ml. Heavy growth was observed in all the control plates.

Table 2: Reduced inhibitory effect of potassium sucrose octasulfate and sucralfate in GC agar

Procedure Solution MIC

2 potassium sucrose 30 mg/ml octasulfate

2 sucralfate 3.0 mg/ml

These results show that potassium sucrose octasulfate and sucralfate in solid form, i.e., when mixed with the agar base, produced very little inhibitory effect on N. gonorrhoeae growth. The results summarized in Tables 1-2 indicate that both potassium sucrose octasulfate and sucralfate have a powerful and immediate inhibitory effect on N. gonorrhoeae infectivity on contact, when the bacteria are exposed to these compounds in liquid form.

All of the above-cited references and publications are hereby incorporated by reference. Other embodiments are within the following claims.

Claims

We claim:

1. A method for inhibiting infection of a cell, by an N. gonorrhoeae organism, comprising: contacting the cell, or the N. gonorrhoeae organism, with a negatively charged substituted disaccharide, in an amount effective to reduce or prevent infectivity by the N. gonorrhoeae organism.

2. The method of claim 1, wherein the negatively charged substituted disaccharide acts via a direct antimicrobial effect on the N. gonorrhoeae organism.

3. The method of claim 1, wherein said method is an in vivo method.

4. The method of claim 1, wherein said method is an in vitro method.

5. The method of claim 1, wherein 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 with the cell.

6. The method of claim 1, wherein said negatively charged substituted disaccharide is sucrose octasulfate.

7. The method of claim 6, wherein said sucrose octasulfate is associated with a potassium ion or an aluminum hydroxide ion to form a salt of sucrose octasulfate.

8. The method of claim 7, wherein said salt of sucrose octasulfate is potassium sucrose octasulfate.

9. The method of claim 7, wherein said salt of sucrose octasulfate is sucralfate.

10. A method for treating or preventing, infection with an N. gonorrhoeae organism, or treating or preventing a disorder or disease caused by the N. gonorrhoeae organism in a human subject, comprising administering to the subject, an amount of a negatively charged substituted disaccharide effective to treat or prevent infection of the subject with the N. gonorrhoeae organism, or to treat or prevent a disorder or disease caused by the N. gonorrhoeae organism.

1 1. The method of claim 10, wherein the negatively charged substituted disaccharide acts via a direct antimicrobial effect on the N. gonorrhoeae organism.

12. The method of claim 10, wherein 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.

13. The method of claim 10, wherein the method treats or prevents infection of an epithelial surface, the surface of a body cavity, an oral, pharyngeal, esophageal, pulmonary, ocular, aural, nasal, buccal, lingual, genitourinary, vaginal, cervical, alimentary, or anorectal surface.

14. The method of claim 10, wherein the salt of the negatively charged substituted disaccharide is sucrose octasulfate.

15. The method of claim 14, wherein said sucrose octasulfate is associated with a potassium ion or an aluminum hydroxide ion to form a salt of sucrose octasulfate.

16. The method of claim 15, wherein said salt of sucrose octasulfate is potassium sucrose octasulfate.

17. The method of claim 15, wherein said salt of sucrose octasulfate is sucralfate.

18. A method for inhibiting transmission, or decreasing the risk of transmission, of an N. gonorrhoeae organism or infection from a first human subject, to a second human subject comprising: administering to the first, the second, or both subjects, an amount of a negatively charged substituted disaccharide sufficient to inhibit transmission, or decrease the risk of transmission.

19. The method of claim 18, wherein the N. gonorrhoeae organism is contacted with said negatively charged substituted disaccharide

20. The method of claim 19, wherein the N. gonorrhoeae organism is contacted with the negatively charged substituted disaccharide on the surface of the body, or in a body cavity, of the first subject, the second subject, or both.

21. The method of claim 19, wherein 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 with the second subject

22. The method of claim 18, wherein the negatively charged substituted disaccharide is administered to either the first or the second subject prior to physical contact.

23. The method of claim 18, wherein 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.

24. The method of claim 18, wherein the second subject is an N. gonorrhoeae- free female.

25. The method of claim 18, wherein the first subject is an N. gonorrhoeae- infected male and the second subject is an Ν. gonorrhoeae-free female, or a female infected by a different species of N. gonorrhoeae than is the first subject.

26. The method of claim 18, wherein die first subject is an N. gonorrhoeae- infected female and the second subject is an Ν. gonorrhoeae-free female, or a female infected by a different species of N. gonorrhoeae than is the first subject.

27. The method of claim 18, wherein the second subject is an N. gonorrhoeae- free male.

28. The method of claim 18, wherein the first subject is an N. gonorrhoeae- infected male and the second subject is an N. gonorrhoeae-free male, or a male infected by a different species of N. gonorrhoeae than is the first subject.

29. The method of claim 18, wherein the first or second subject is pregnant.

30. The method of claim 18, wherein the first subject is an N. gonorrhoeae infected mother and the second subject is a child.

31. The method of claim 18, which prevents transmission from an N. gonorrhoeae infected mother to a child during birth.

32. The method of claim 18, further comprising the step of identifying a subject at risk of being infected or reinfected by an N. gonorrhoeae organism and providing the subject with the negatively charged substituted disaccharide or with a device associated with the negatively charged substituted disaccharide.

33. The method of claim 18, wherein the negatively charged substituted disaccharide is administered prior to sexual contact.

34. The method of claim 18, wherein the negatively charged substituted disaccharide is administered prior to contact during birth.

35. The method of claim 18, wherein 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.

36. The method of claim 18, wherein die negatively charged substituted disaccharide acts via a direct antimicrobial effect on the N. gonorrhoeae organism.

37. The method of claim 18, wherein the negatively charged substituted disaccharide is sucrose octasulfate.

38. The method of claim 37, wherein said sucrose octasulfate is associated with a potassium ion or an aluminum hydroxide ion to form a salt of sucrose octasulfate.

39. The method of claim 38, wherein said salt of sucrose octasulfate is potassium sucrose octasulfate.

40. The method of claim 38, wherein said salt of sucrose octasulfate is sucralfate.

41. A method for disinfecting a device, a tissue, or a liquid preparation, which is contaminated with N. gonorrhoeae, comprising: 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.

42. A composition for inhibiting infection of a cell by an N. gonorrhoeae organism, comprising: an amount of a negatively charged substituted disaccharide, sufficient to inhibit the infectivity by an N. gonorrhoeae organism; and one or more of an antibacterial agent selected from the group consisting of a DNA topoisomerase inhibitor, a protein synthesis inhibitor, a membrane transport inhibitor, and an anionic sulfated polysaccharide polymer.

43. A composition for preventing conception and for inhibiting infection of a cell by an N. gonorrhoeae organism, comprising: 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.

44. A device, in association with an amount of a negatively charged substituted disaccharide sufficient to inhibit infection by an N. gonorrhoeae organism.