AU4486489A – Composition for inhibiting transmission of aids
– Google Patents
AU4486489A – Composition for inhibiting transmission of aids
– Google Patents
Composition for inhibiting transmission of aids
Info
Publication number
AU4486489A
AU4486489A
AU44864/89A
AU4486489A
AU4486489A
AU 4486489 A
AU4486489 A
AU 4486489A
AU 44864/89 A
AU44864/89 A
AU 44864/89A
AU 4486489 A
AU4486489 A
AU 4486489A
AU 4486489 A
AU4486489 A
AU 4486489A
Authority
AU
Australia
Prior art keywords
silver
composition according
topical composition
virus
aids
Prior art date
1988-10-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
AU44864/89A
Other versions
AU622945B2
(en
Inventor
Charles L. Fox Jr.
Shanta M. Modak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Columbia University of New York
Original Assignee
Columbia University of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1988-10-18
Filing date
1989-10-17
Publication date
1990-05-14
1989-10-17
Application filed by Columbia University of New York
filed
Critical
Columbia University of New York
1990-05-14
Publication of AU4486489A
publication
Critical
patent/AU4486489A/en
1992-04-30
Application granted
granted
Critical
1992-04-30
Publication of AU622945B2
publication
Critical
patent/AU622945B2/en
2009-10-17
Anticipated expiration
legal-status
Critical
Status
Ceased
legal-status
Critical
Current
Links
Espacenet
Global Dossier
Discuss
239000000203
mixture
Substances
0.000
title
claims
description
47
230000005540
biological transmission
Effects
0.000
title
claims
description
16
230000002401
inhibitory effect
Effects
0.000
title
claims
description
9
208000030507
AIDS
Diseases
0.000
claims
description
26
GHXZTYHSJHQHIJ-UHFFFAOYSA-N
Chlorhexidine
Chemical compound
C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1
GHXZTYHSJHQHIJ-UHFFFAOYSA-N
0.000
claims
description
23
229960003260
chlorhexidine
Drugs
0.000
claims
description
22
230000000840
anti-viral effect
Effects
0.000
claims
description
21
230000001568
sexual effect
Effects
0.000
claims
description
19
230000000699
topical effect
Effects
0.000
claims
description
14
229960003600
silver sulfadiazine
Drugs
0.000
claims
description
12
UEJSSZHHYBHCEL-UHFFFAOYSA-N
silver(1+) sulfadiazinate
Chemical compound
[Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1
UEJSSZHHYBHCEL-UHFFFAOYSA-N
0.000
claims
description
12
GGCZERPQGJTIQP-UHFFFAOYSA-N
sodium;9,10-dioxoanthracene-2-sulfonic acid
Chemical compound
[Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1
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0.000
claims
description
12
229960003964
deoxycholic acid
Drugs
0.000
claims
description
9
229940123208
Biguanide
Drugs
0.000
claims
description
8
239000006185
dispersion
Substances
0.000
claims
description
7
XNCOSPRUTUOJCJ-UHFFFAOYSA-N
Biguanide
Chemical compound
NC(N)=NC(N)=N
XNCOSPRUTUOJCJ-UHFFFAOYSA-N
0.000
claims
description
6
NDVLTYZPCACLMA-UHFFFAOYSA-N
silver oxide
Chemical compound
[O-2].[Ag+].[Ag+]
NDVLTYZPCACLMA-UHFFFAOYSA-N
0.000
claims
description
6
SQGYOTSLMSWVJD-UHFFFAOYSA-N
silver(1+) nitrate
Chemical compound
[Ag+].[O-]N(=O)=O
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0.000
claims
description
6
229930006000
Sucrose
Natural products
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claims
description
5
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Sucrose
Chemical compound
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description
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detergent
Substances
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claims
description
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claims
description
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239000005720
sucrose
Substances
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claims
description
5
XLYOFNOQVPJJNP-UHFFFAOYSA-N
water
Substances
O
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claims
description
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Hepatitis B virus
Species
0.000
claims
description
4
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1,3-dihydropyrrolo[2,3-b]pyridin-2-one
Chemical compound
C1=CN=C2NC(=O)CC2=C1
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0.000
claims
description
3
JKFYKCYQEWQPTM-UHFFFAOYSA-N
2-azaniumyl-2-(4-fluorophenyl)acetate
Chemical compound
OC(=O)C(N)C1=CC=C(F)C=C1
JKFYKCYQEWQPTM-UHFFFAOYSA-N
0.000
claims
description
3
229910021607
Silver chloride
Inorganic materials
0.000
claims
description
3
229910021612
Silver iodide
Inorganic materials
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claims
description
3
238000003780
insertion
Methods
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claims
description
3
230000037431
insertion
Effects
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claims
description
3
150000003839
salts
Chemical class
0.000
claims
description
3
CQLFBEKRDQMJLZ-UHFFFAOYSA-M
silver acetate
Chemical compound
[Ag+].CC([O-])=O
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0.000
claims
description
3
229940071536
silver acetate
Drugs
0.000
claims
description
3
LKZMBDSASOBTPN-UHFFFAOYSA-L
silver carbonate
Substances
[Ag].[O-]C([O-])=O
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0.000
claims
description
3
229910001958
silver carbonate
Inorganic materials
0.000
claims
description
3
YSVXTGDPTJIEIX-UHFFFAOYSA-M
silver iodate
Chemical compound
[Ag+].[O-]I(=O)=O
YSVXTGDPTJIEIX-UHFFFAOYSA-M
0.000
claims
description
3
229940045105
silver iodide
Drugs
0.000
claims
description
3
HKZLPVFGJNLROG-UHFFFAOYSA-M
silver monochloride
Chemical compound
[Cl-].[Ag+]
HKZLPVFGJNLROG-UHFFFAOYSA-M
0.000
claims
description
3
229910001961
silver nitrate
Inorganic materials
0.000
claims
description
3
229910001923
silver oxide
Inorganic materials
0.000
claims
description
3
LMEWRZSPCQHBOB-UHFFFAOYSA-M
silver;2-hydroxypropanoate
Chemical compound
[Ag+].CC(O)C([O-])=O
LMEWRZSPCQHBOB-UHFFFAOYSA-M
0.000
claims
description
3
CLDWGXZGFUNWKB-UHFFFAOYSA-M
silver;benzoate
Chemical compound
[Ag+].[O-]C(=O)C1=CC=CC=C1
CLDWGXZGFUNWKB-UHFFFAOYSA-M
0.000
claims
description
3
MNMYRUHURLPFQW-UHFFFAOYSA-M
silver;dodecanoate
Chemical compound
[Ag+].CCCCCCCCCCCC([O-])=O
MNMYRUHURLPFQW-UHFFFAOYSA-M
0.000
claims
description
3
208000019802
Sexually transmitted disease
Diseases
0.000
claims
description
2
239000012052
hydrophilic carrier
Substances
0.000
claims
description
2
239000007764
o/w emulsion
Substances
0.000
claims
description
2
150000003378
silver
Chemical class
0.000
claims
2
LTYHQUJGIQUHMS-UHFFFAOYSA-M
silver;hexadecanoate
Chemical compound
[Ag+].CCCCCCCCCCCCCCCC([O-])=O
LTYHQUJGIQUHMS-UHFFFAOYSA-M
0.000
claims
2
208000006454
hepatitis
Diseases
0.000
claims
1
231100000283
hepatitis
Toxicity
0.000
claims
1
FHHPUSMSKHSNKW-SMOYURAASA-M
sodium deoxycholate
Chemical group
[Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1
FHHPUSMSKHSNKW-SMOYURAASA-M
0.000
claims
1
230000002195
synergetic effect
Effects
0.000
claims
1
241000700605
Viruses
Species
0.000
description
40
241000725303
Human immunodeficiency virus
Species
0.000
description
30
210000004027
cell
Anatomy
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26
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drug
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16
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drug
Substances
0.000
description
16
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method
Methods
0.000
description
13
KXGVEGMKQFWNSR-LLQZFEROSA-N
deoxycholic acid
Chemical compound
C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1
KXGVEGMKQFWNSR-LLQZFEROSA-N
0.000
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12
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effects
Effects
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11
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testing method
Methods
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11
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material
Substances
0.000
description
10
238000002360
preparation method
Methods
0.000
description
10
LOKCTEFSRHRXRJ-UHFFFAOYSA-I
dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride
Chemical compound
P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+]
LOKCTEFSRHRXRJ-UHFFFAOYSA-I
0.000
description
7
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infectious disease
Diseases
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7
230000002147
killing effect
Effects
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description
7
239000002953
phosphate buffered saline
Substances
0.000
description
7
241001430294
unidentified retrovirus
Species
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7
241001465754
Metazoa
Species
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6
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spleen
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Candida albicans
Species
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5
241000699670
Mus sp.
Species
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description
5
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candida albicans
Drugs
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5
150000001875
compounds
Chemical class
0.000
description
5
238000002474
experimental method
Methods
0.000
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5
230000003612
virological effect
Effects
0.000
description
5
241000282414
Homo sapiens
Species
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description
4
241000700584
Simplexvirus
Species
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4
IQFYYKKMVGJFEH-XLPZGREQSA-N
Thymidine
Chemical compound
O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1
IQFYYKKMVGJFEH-XLPZGREQSA-N
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chemical substances by application
Substances
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239000011248
coating agent
Substances
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coating method
Methods
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deoxycholate
Drugs
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238000002347
injection
Methods
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injection
Substances
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medium
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stock solution
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DNA
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Homo
Species
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Polyethylene glycol
Substances
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dilution
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Beta-D-1-Arabinofuranosylthymine
Natural products
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Fusicsaeure
Natural products
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Hank’s balanced salt solution
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Human alphaherpesvirus 1
Species
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Mus
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Neisseria
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RNA-directed DNA polymerase
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Sodium azide
Chemical compound
[Na+].[N-]=[N+]=[N-]
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anti bacterial agent
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beta-L-thymidine
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chlorhexidine
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fusidic acid
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Classifications
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
A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
A—HUMAN NECESSITIES
A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
A01N47/44—Guanidine; Derivatives thereof
A—HUMAN NECESSITIES
A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
A01N59/16—Heavy metals; Compounds thereof
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
A61K31/13—Amines
A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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
A61K31/16—Amides, e.g. hydroxamic acids
A61K31/18—Sulfonamides
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
A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K33/00—Medicinal preparations containing inorganic active ingredients
A61K33/24—Heavy metals; Compounds thereof
A61K33/38—Silver; Compounds thereof
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P31/12—Antivirals
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P31/12—Antivirals
A61P31/14—Antivirals for RNA viruses
A61P31/18—Antivirals for RNA viruses for HIV
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P37/00—Drugs for immunological or allergic disorders
A61P37/02—Immunomodulators
A61P37/04—Immunostimulants
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
Description Composition for Inhibiting Transmission of AIDS
Background of the Invention
The present invention relates to composition for inhibiting the transmission of Acquired
Immunodeficiency Syndrome (AIDS).
AIDS is a fatal catastrophic disease that
presently infects millions of people worldwide.
Although initially concentrated in central Africa and in certain high risk groups in other geographic areas including the United States, AIDS is now spreading to other areas and is appearing in individuals who are not members of the recognized risk groups. As a result, major efforts are being made to develop methods of preventing the transmission of AIDS, methods of curing AIDS once contracted, and methods of ameliorating the symptoms of AIDS. To date, however, AIDS has proven difficult to treat or prevent.
AIDS is caused by a virus. This virus has been referred to by a number of names in the literature, including HIV (human immunodeficiency virus), LAV (lymphadenopathy-associated virus), ARV (AIDS-related virus) and HTLV-III (human T-cell leukemia virus-Ill). For simplicity, the virus causing AIDS will be
referred to herein as the AIDS virus.
It is generally known that viruses can be divided into two groups based upon the nature of the virus’ genetic material. Some viruses are DNA viruses, that is there genetic material is deoxyribonucleic acid, while others are RNA (ribonucleic acid) viruses. The RNA viruses can further be divided into two groups, those in which replication of the viral genome
proceeds by making an RNA copy directly from the RNA genome and those in which a DNA intermediate is
involved. This latter type of RNA virus is called a retrovirus.
The AIDS virus is a retrovirus. Thus, like other retroviruses, it has an enzyme called reverse
transcriptase (or RNA-dependent DNA polymerase) which catalyzes transcription of viral RNA into double helical DNA. This DNA sequence is integrated into the genome of the infected cell where it is known as a provirus. Subsequent transcription of this provirus by the transcription mechanism of the infected cell produces new viral RNA for packaging into new virus particles.
Because the AIDS virus may lie dormant in an infected cell in the form of a provirus for extended periods of time, it has been difficult to establish the precise routes by which AIDS is spread. It is known, however, that AIDS can be transmitted to a person by transfusing that person with blood
containing the AIDS virus. AIDS can also be
transmitted to a person through homosexual or
heterosexual intercourse with a partner infected with the AIDS virus. Transmission of the AIDS virus is facilitated by preexisting sexually transmitted diseases (STD’s) other than AIDS, for example
gonorrhea. Further, scientists suspect that the AIDS virus is spread easily during sexual intercourse due to tearing of tissue which would abet entry of the AIDS virus into the blood stream.
In response to the growing threat of AIDS transmission, the use of condoms during sexual intercourse has been suggested as a means of
preventing transmission of the AIDS virus. Improper use of condoms, or their perforation during
intercourse renders them only partially effective. Accordingly, there is a pressing need for a better method of inhibiting the transmission of the AIDS virus in humans during sexual intercourse and during surgical procedures on infected patients. It is an
object of the present invention to provide such a method.
Summary of the Invention
The present invention provides an inexpensive, easily available and convenient composition for inhibiting the transmission of the AIDS virus in humans for example, as a result of sexual intercourse. The invention relies upon a dual mode of action of particular compounds and combinations thereof which results in a rapid killing action within minutes.
These compounds are effective to reduce the
infectivity of the AIDS virus and also kill the causative organisms of many other STD ‘ s af ter short exposure. The method of the invention is therefore useful to reduce the immediate risk of AIDS
transmission. It also reduces future risk of AIDS transmission by eliminating STD causing organisms which increase the risk of AIDS.
Silver salts, such as silver sulfadiazine (AgSD), are among the compounds found to be effective
antiviral agents against retroviruses including the AIDS virus. Such materials had previously been recognized as antibacterial agents useful in treating burns in man and animal. C.L. Fox, Jr., U.S. Patent No. 3,761,590. AgSD has also been shown to be
effective against certain viruses such as herpes simplex and herpes zoster and against the causative organisms of many STD’s including Candida albicans, Treponema pallidum and gonorrhea. U.S. Patent No.
4,415,565 of Wysor shows further antiviral activity of AgSD against certain RNA viruses, but none of these are retroviruses. Thus, while AgSD is a well studied material, there was no basis to expect that it would have activity against the AIDS retrovirus which has proven so difficult to inhibit or destroy.
Biguanides, such as chlorhexidine, have also been found to be effective when used at sufficiently high levels as inhibitors of the AIDS virus.
We have also found that combinations of these compounds with each other and with other antibacterial agents lead to an unexpected enhancement of the antiviral activity of AgSD and also in a rapid killing action. Specifically, AgSD in combination with chlorhexidine, a broad spectrum antibacterial, is substantially more effective for reducing the
infectivity of the AIDS virus than AgSD alone, despite the fact the chlorhexidine alone has no effect on infectivity of AIDS virus under the same conditions. Increased effectiveness was also noted for
combinations of AgSD with detergents such as
deoxycholate.
In view of these findings, the invention
contemplates inhibiting the transmission of AIDS comprising topically applying an effective antiviral amount of biguanide or a silver salt such as silver sulfadiazine, alone or in combination. Other agents such as deoxycholate may also be used. The composition is advantageously administered to a sexual canal of a human prior to or during sexual intercourse.
This application can be carried out by introducing a cream or foam into the sexual canal, or by coating the inhibitory composition onto a condom or other device that is inserted into the sexual canal.
Brief Description of the Figure
Fig. 1 is a graph of the rate of incorporation of radiolabeled thymidine by hepatitis B virus following exposure of the virus to AgSD alone or in combination with other agents.
Detailed Description of the Invention
As noted above, the composition of the present invention is effective to inhibit the transmission of
AIDS virus in humans and other mammals which applied topically in an effective antiviral amount. The composition comprises a biguanide, alone or in
combination with other active ingredients.
As used in this application, the term sexual canal refers to either a vaginal or an anal canal.
The antiviral composition used in the method of the invention comprises biguanide, such as
chlorhexidine or a salt thereof.
The composition may also include a silver salt. While the examples hereinbelow use one specific silver salt, AgSD, other silver salts may also be used.
Other suitable silver salts include silver acetate, silver benzoate, silver carbonate, silver chloride, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver
palmitate, and silver salts of proteins.
The antiviral composition of the invention preferably also comprises one or more additional ingredients which enhance the antiviral effectiveness of the silver salt. Thus, the antiviral composition may contain detergents such as deoxycholate or
benzalkonium chloride. Suitable salts of these materials may also be used.
The antiviral composition may also include other materials which are effective against STD-causing organisms which will reduce the long term risk of AIDS infection. Examples of such materials include
nonoxynol, which is effective against gonococcus and quinolones which are effective against numerous STD- causing organisms. It should be noted that
chlorhexidine and the detergents noted above are also effective against a variety of STD-causing organisms, including herpes simplex virus (HSV) and Candida albicans.
The antiviral compositions for use in the
invention can be applied as (a) a dispersion in a water-dispersible hydrophilic carrier; (b) as a
dispersion in a substantially water insoluble carrier; (c) as a dispersion in a semi-soft or cream-like water-dispersible or water-soluble oil-in-water emulsion carrier; or (d) as a dispersion in an aqueous sucrose carrier, e.g. an approximately 25%-50% by weight aqueous sucrose solution. Specific examples of formulating silver sulfadiazine in various carriers are provided in U.S. Patent No. 3,761,590 which is incorporated herein by reference. The carrier will preferably contain from about 0.1 to about 10% by weight of the silver salt and up to 2% of other active agents.
The antiviral composition useful in the method of the invention can be contained in a squeezable tube having an applicator nozzle. This facilitates topical application of the composition to the sexual canal prior to intercourse by inserting the nozzle into the sexual canal and squeezing the tube to force the antiviral composition into the sexual canal.
Alternatively, the antiviral can be applied with any of various known applicators for delivering drugs into a sexual canal. The antiviral composition can also be topically applied during sexual intercourse by coating the penis itself or coating a condom with a lubricant material, such as K-Y Jelly (Johnson & Johnson), that contains the silver salt.
The antiviral composition of the invention may also be introduced into the sexual canal as a coating on a device intended for insertion in the sexual canal. Examples of such devices include condoms, medical gloves, and diaphragms. Such devices may be coated or impregnated with the antiviral composition by spraying the completed device or by incorporating the antiviral composition during manufacture.
Specific techniques for preparing the devices are described in U.S. Patent Application Serial No.
154,920, filed February 11, 1988, and its
combination-in-part filed October 14, 1988, both of which are incorporated herein by reference.
The experimental results which demonstrate the effectiveness of the claimed method are set forth below. These tests involve the AIDS virus, a
recognized model system for the AIDS virus or a recognized STD organism. Further, although the tests with the AIDS virus itself are necessarily in vitro tests in view of the catastrophic consequences of AIDS, these in vitro tests are highly predictive of and correlate with in vivo efficacy. They thus support the surprising finding that compositions containing biguanides with or without silver salts can be used to inhibit transmission of AIDS as a result of sexual intercourse.
Example 1
The effectiveness of AgSD against the AIDS virus J1 in vitro was assessed by testing the infectivity of samples of HTLV-III in H9 cells after exposure to AgSD for 10 minutes. Due to the relatively low titers achievable with the AIDS virus, it was necessary to devise means for separating the bulk of the AgSD from the virus to be assayed. After a number of
preliminary experiments, it was found that the best method of those investigated was to rapidly pass the AgSD/AIDS virus mixture over a Sephadex G-25M column, recover the AIDS virus containing void volume and precipitate the virus using polyethylene glycol (PEG).
To determine recovery of the virus using this method, a control preparation containing virus but no AgSD was similarly processed.
It was also necessary tc confirm that this procedure was effective to remove all of the AgSD.
This was accomplished using «Stop Controls». This involved processing AgSD alone through the column, precipitating the same fraction with PEG and then adding active AIDS virus to the precipitate. If the titer of the stop control had been similar to the
control preparation containing virus but no AgSD it would have indicated that little or no AgSO was present in the precipitate. In fact, however, the titer was substantially lower in the stop controls (Samples 4 and 6) than in the corresponding test samples without silver sulfadiazine (Samples 1 and 2). This indicates that some of the silver sulfadiazine is not being separated. While this means that virus killing occurred over a longer period than the ten minute contact time, it also suggests that the
virucidal activity is fairly strong to persist even at the reduced levels.
The specific tests conducted are summarized in Table 1. For each sample to which virus was added initially, the virus sample was a stock solution prepared from a 10,000 fold concentrate of HTLV-III obtained from Bionetics Research. This material was diluted 1:10 with Conditioned Infection Medium (CIM) to form a stock solution with an actual virus titer of 10 55.5/ml. Two AgSD stock preparations were also prepared, a 1% by weight in 50% by weight aqueous sucrose preparation and an 0.5% by weight in 25% by weight aqueous sucrose preparation.
To conduct the tests, 60 μl aliquots of the virus stock were placed in microfuge tubes as samples 1-3 and 6 as indicated in Table 1. This was mixed with 540 μl of the respective AgSD preparations in tubes 3 and 5 and with 540 μl of CIM in tubes 1 and 2. Tubes 4 and 6 each received 600 μl of the respective AgSD preparations, but no virus. Each tube was then mixed with a vortex mixer and allowed to incubate for 10 minutes at rcom temperature.
To separate the AgSD from the virus, the contents of each tube containing AgSD then centrifuged in a microfuge for 1 minute, and the supernatants were collected. These supernatants and the entire sample of tube 2 were then introduced onto a Sephadex-25M column. The columns used had a fitted disc at the top
of the column and a void volume of approximately 1 ml. These columns are normally stored in sodium azide and had been prepared by washing under sterile conditions with 18 successive 4 ml portions of CIM medium on the day prior to the experiment.
Each of the samples was placed on the column until it passed through the fitted disc. The column was then eluted with 4 ml of CIM medium. The first 3 ml of eluent was discarded and the last ml was
collected into a sterile microfuge tube containing 0.35 ml of 30% PEG 6000 in phosphate buffer. These tubes were held at 0°C for at least 30 minutes and then centrifuged for 1 minute in a microfuge. The pellets were collected and resuspended in either 0.5 ml CIM (samples 2, 3 and 5) or in an HTLV-III
containing medium made by diluting 0.7 parts of the virus stock with 6.3 parts of CIM.
Each of the six samples thus prepared was assayed in quadruplicate with 10-fold dilutions in CIM for its ability to infect H9 cells. This was done by adding 50 μl of a preparation containing 2.4 X 106/ml H9 cells that had been conditioned in CIM for 1 hour at 37°C to each 100 μl of sample or dilution. This culture was fed 25 μl of CIM on days 4, 7 and 10. On day 4, cytotoxicity was evaluated by visual
examination of the cultures.
The results of these observations are shown in Table 1. As can be clearly seen, AgSD substantially reduced the infectivity of AIDS virus tested without any observation of cytotoxicity.
Example 2
The effect of AgSD, chlorhexidine and sodium deoxycholate, both individually and in combination, on the infectivity of the ARV-2 strain of AIDS virus was tested in H9 cells using lower concentrations of drug such as can be practically coated onto a glove or condom or other device. These concentrations were below the level that produced substantial observable
cytotoxicity, even during incubation with the virus, and yet were effective at killing the virus.
A stock solution of virus containing 3 to 5 X 104 infectious virus particles/ml was preincubated with the various drugs as indicated in Table 2 for 15 minutes. The virus sample was then diluted 4-fold in order to reduce the concentrations of the drugs below levels toxic to H9 cells (see Example 3 below) and mixed with 250,000 H9 cells in a total volume of 1 ml. After 24 hours, the cells were assayed to determine the percentage of the culture expressing viral
antigen. This time interval was selected as it allows for only a single round of viral infection to have occurred such that the number of cells infected was a direct reflection of the number of infectious virions present in the original sample.
As can be seen from Table 2, AgSD alone at these low concentrations was only slightly effective, but better results were obtained when AgSD was used in combination with either sodium deoxycholate and chlorhexidine. Of particular significance is the marked reduction in infectivity observed for the combination of AgSD (5 μg/ml) and chlorhexidine
(5 μg/ml) since chlorhexidine (10 μg/ml) did not itself reduce viral infectivity.
Example 3
The toxicity of the various agents used in the antiviral compositions of the invention to human T4- lymphocytes (H9 cells and marophages which are the carriers of the AIDS virus may be relevant to the effectiveness of a drug. This is because killing these cells when present in semen or vaginal fluids may lead to release of virus making it more
susceptible to the effects of the drug. With this in mind, the effect of short exposure (10 minutes) of
AgSD and other drugs on H9 cells was tested by
treating a suspension of H9 cells (1.6 X 106/ml in HBSS) with 50 and 100 ml/ml of each drug or drug
combination. After incubating for 10 minutes, the cells were washed twice in thirty volumes of HBSS; resuspended in RPMI 10% FCS + NaPyruvate and plated into 24 well plates at 4 X 105 cells/ml. Cell
viability was determined after 24 hours and is
reported as numbers of viable cells per ml and viable percentage (live cells/live cells + dead cells) in Table 3A. As can be seen, each of the agents tested kills some of the cells, although the most significant killing is observed for 100 μl/ml AgSD and the
combination of AgSD and sodium deoxycholate.
The effectiveness of killing of macrophages was also tested as shown in Table 3B. In the experiment, peritonial normal mouse macrophages were enriched by attaching to petri dishes and adjusted to a cell concentration of 5 to 10 x 106/ml. 0.1ml aliquots of this suspension were plated in microtiter plates and 10μ and 5μ of each of four samples was added. The control plate received PBS only. After 20 minutes of incubation in a CO incubator, the cells were tested for viability using tryphan-blue dye. The percent kill is shown in Table 3B.
Example 4
In vivo tests were performed using Rauscher
Leukemia Virus (RLV), a recognized retrovirus model (see, e.g.. Nature 323, 467-469 (1986); Rupecht et al., Proc. Nat’l. Acad. Sci. USA 82, 7733-7737
(1985)) which is used by the FDA in testing drugs for use in treating AIDS. RLV was introduced into
Balb/CICR mice in which it infects the spleen. The level of virus infectivity was quantified by
determining the weight increase of the mouse spleen after 20 days from infection.
A preliminary experiment was first carried out to determine the effect of the drugs to be tested on the spleen. Nine sets of five mice each (6 week old female mice) received 0.25 ml injections into the tail
vein of one of an extract of a glove treated with one of the following solutions:
1. Silver Sulfadiazine (2%)
2. Sodium Deoxycholate (2%) 3. Chlorhexidine (2%)
4. Silver Sulfadiazine (1%) +
Sodium Deoxycholate (1%)
5. Silver Sulfadiazine (1%) +
Chlorhexidine (1%) 6. Fusidic Acid (2%)
7. Fusidic Acid (1%) +
Chlorhexidine (1%)
8. Saline incubated glove
9. Saline-no glove Each treatment was prepared by incubating 1.5 ml Dulbecco’s Phosphate Buffered Saline (PBS) for 10 minutes at 37°C in the finger tip of a latex glove. After incubation, as much as possible of the material was removed from the glove. 0.4 ml of PBS was then introduced into the glove and this was the sample which was introduced into the animals. The animals that did not receive a clean stick during the
injection were excluded from the study. Thus two of the groups only had four animals each that were considered.
Eight days after injection each of the animals was sacrificed and the spleen weights determined for each animal. No increase in spleen weight was observed in any of tne groups.
An additional eleven groups of 5 mice each were then used to test the effectiveness of these same compounds against infectivity of RLV. Each treatment was prepared by incubating 0.4 ml sterile PBS
containing RVB3 (a strain of RLV) for 10 minutes in a glove tip which had previously had one of drugs or straight PBS incubated in it as described above.
Three additional controls, a PBS containing glove with no virus, a virus sample not incubated in a glove, and a PBS sample not incubated in a glove were also run. The mice in this case were sacrificed 20 days after injection and spleen weights determined as shown in Table 4. Each of the materials tested showed a substantial reduction in virus infectivity.
Example 5
The combination of AgSD with chlorhexidine and deoxycholate was also found to be particularly
effective against several STD-causing organisms. As shown in Tables 5A and 5B silver sulfadiazine in combination with chlorhexidine or sodium deoxycholate is particularly effective against Candida albicans. Similarly, these combinations are effective to kill Gonococcus (Table 6) and herpes virus (Tables 7A and 7B).
Example 6
The effect of AgSD alone or in combination with chlorhexidine or sodium deoxycholate on DNA synthesis by Hepatitis B Virus was studied by measuring the rate of incorporation of radiolabeled thymidine. As a result, it was found that the AgSD interferes with the RNA-dependent DNA polymerase of Hepatitis B virus, an interference which is enhanced by using it in
combination with either chlorhexidine or sodium deoxycholate (Fig. 1).
Example 7
The effect of chlorohexidine on HIV-I was tested using a 4% chlorohexidine gluconate (CHG) hand scrub (HIBICLENS®) and an 0.5% CHG-containing hand rinse
(HIBISTAT®). In each case, an HIV-I preparation was exposed to dilutions of one of the two materials for 10 minutes after which the viral preparation was used to infect C3-44 cells. The presence of HIV-I
infection was monitored by indirect immunofluorescense by detecting viral p24 antigen expression and by reverse transciptase activity in culture fluid as a measure of virus production. The results of this experiment showed that, chlorohexidine gluconate at concentrations of 0.04%, 0.05% and higher were
effective to prevent HIV-I infection, while
concentrations of 0.01% and lower were not. Thus, it appears that a threshold level of chlorohexidine is necessary for activity and that the results in
Example 2 can be attributed to the use of
chlorohexidine at a level below this threshold.
TABLE 5B
.Antibacterial Efficacy of Drug Coated Gloves
against Candida albicans
Treated glove fingers were draped over the top of culture tubes with the treated side forming the inside of the cup shape. Then 3.0ml of TSB containing 10 organisms of Candida albicans was dispensed in each finger and all placed in the water bath shaker at 37°C. Samples were removed at 15 minutes, 1 hour, 2 hours, and 4 hours. They were diluted 1- 10 and plated on blood agar in 2.0ml amounts.
TABLE 7A Toxicitv of Drugs for HSV
One ml HSV at 3×106/ml was incubated with 200 μlitres of drugs each 500μg/ml stock solution. After 20 minutes at R.T., the virus was titered on monolayers of vero cells, incubated for 2 hours, then overlayed with methyl cellulose. Virus titers were read after 48 hours. No drug toxicity* was seen in rows titer read in.
TABLE 7B Effect on HSV-1 of Interaction with Drug Treated Gloves
HSV-1 was diluted to 3×106 PFU/ml in DME 10% FCS. One ml of virus was placed in sterile drug treated gloves, incubated for 10 min. at room temperature then titered on Vero cells.
Claims (16)
Claims
1. A topical composition for inhibiting transmission of sexually transmitted diseases including AIDS and hepatitis characterized in that the
composition comprises an effective antiviral amount of a biguanide.
2. A topical composition according to claim 1,
characterized in that the biguanide is
chlorhexidine or a salt thereof.
3. A topical composition according to claims 1-2, characterized in that the composition further comprises a silver salt in an amount which with the biguanide exhibits synergistic antiviral activity.
4. A topical composition according to claim 3,
characterized in that the silver salt is selected from among silver sulfadiazine, silver acetate, silver benzoate, silver carbonate, silver
chloride, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, and silver salts of proteins.
5. A topical composition according to claim 4,
characterized in that the silver salt is silver sulfadiazine.
6. A topical composition according to claims 1-5, characterized in that the composition further comprises a detergent.
7. A topical composition according to claim 6,
characterized in that the detergent is sodium deoxycholate.
8. A topical composition according to claims 1-7, characterized in that the composition is a dispersion in a water dispersible hydrophilic carrier.
9. A topical composition according to claims 1-7, characterized in that the composition is a dispersion in a semi-soft or cream-like, water dispersible or water soluble oil-in-water
emulsion.
10. A topical composition according to claims 1-7, characterized in that the composition is a dispersion in an aqueous sucrose solution.
11. A topical composition according to claims 3-10, characterized in that the composition comprises 0.1 to 10 percent by weight of the silver salt.
12. A topical composition for inhibiting transmission of hepatitis B virus, characterized in that the composition comprises an effective antiviral amount of a silver salt.
13. A topical composition according to claim 12,
characterized in that the silver salt is selected from among silver sulfadiazine, silver acetate, silver benzoate, silver carbonate, silver
chloride, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, and silver salts of proteins.
14. A device for insertion in a sexual canal,
characterized in that the device is coated with a composition accorded to any of claims 1-13.
15. A device for insertion in a sexual canal, characterized in that the device is impregnated with a composition according to any one to claims 1-13.
16. A device according to claims 14-15, characterized in that the device is a condom.
AU44864/89A
1988-10-18
1989-10-17
Composition for inhibiting transmission of aids
Ceased
AU622945B2
(en)
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US262165
1988-10-18
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US4952411A
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1987-02-25
1988-10-18
Method of inhibiting the transmission of AIDS virus
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Composition for inhibiting transmission of aids
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(en)
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EP0439513B1
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Method of inhibiting the transmission of aids virus
1988
1988-10-18
US
US07/262,165
patent/US4952411A/en
not_active
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1989-10-17
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1989-10-17
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1990-05-03
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1992-04-30
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