CA2186867C - Methods of using iron chelating compounds to reduce free radical damage in mammals - Google Patents
Methods of using iron chelating compounds to reduce free radical damage in mammals Download PDFInfo
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- CA2186867C CA2186867C CA002186867A CA2186867A CA2186867C CA 2186867 C CA2186867 C CA 2186867C CA 002186867 A CA002186867 A CA 002186867A CA 2186867 A CA2186867 A CA 2186867A CA 2186867 C CA2186867 C CA 2186867C
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- furilmonoxime
- furildioxime
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- 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
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- 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
Abstract
The subject invention involves a method of reducing free radical damage in mammals comprising administering to a mammal a composition comprising a safe and effective amount of a compound selected from 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, 2-furildioxime, 2-furilmonoxime, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one, or a pharmaceutically acceptable salt thereof, or mixtures of the subject compounds and/or their salts.
Description
6 7 pCT~S95/02872 METHODS OF USING IRON CHELATING COMPOUNDS TO REDUCE
FREE RADICAL DAMAGE IN hZAMMALS
The subject invention relates to the field of protecting mammals from free radical damage and conditions accelerated by free radical damage. Specifically, the subject invention relates to novel methods of using certain iron-chelating compounds for reducing o the level of free radicals in mammalian cells.
BACKGROUND OF THE INVENTION
Free radicals, in particular oxygen radicals, in mammalian cells arise from a variety of environmental sources. Such sources include smoke, pollution and radiation in addition to normal cell metabolism and inflammatory processes. Free radicals are known to be i5 damaging to biological tissue. In the body, the potential for damage by free radicals is greatly increased by the presence of iron (and to a lesser extent by the presence of copper), which catalyzes their conversion to less stable and therefore more reactive radical species.
The resulting effects of such radicals on components such as structural proteins, membrane lipids and nucleic acids include alteration or loss of tissue and cell function, cell death, and 2o cancer. Based on a growing body of evidence, it is also believed that the accumulated damage from free radicals, including those produced as by-products in normal metabolism, is responsible for chronological aging. This has been termed the free radical theory of aging.
In vitro and in vivo studies on humans and other mammals also indicate that free radicals play an important role in the activation of certain human immunodeficiency virus 25 (HIV) types. See, for example, Schreck, R., B. Meier, D. N. Manner, W.
Droge and P.A.
Baeuerle, "Dithiocarbamates as Potent Inhibitors of Nuclear Factor xB
Activation in Intact Cells," J. EXD. Med., Vol. 175, pp. 1181-1194, (1992). Certain iron chelators have therefore been considered for the treatment of Acquired Immune Deficiency Syndrome (AIDS). See, for example, Hersh, E. M. et al., "Ditiocarb Sodium (Diethyldithiocarbamate) Therapy in 3o Patients with Symptomatic HIV Infection and Aids," J. A. M. A., Vol. 265, pp.1538-1544, _(1991).
To combat the damaging effects of free radicals, especially oxygen radicals, free radical scavengers and anti-oxidants have been used. These compounds react with the radical species to convert them to stable, nonreactive materials.
35 It is an object of the subject invention to provide methods for reducing free radical damage in mammalian cells.
It is also an object of the subject invention to provide compositions which reduce free radical damage in mammalian cells.
FREE RADICAL DAMAGE IN hZAMMALS
The subject invention relates to the field of protecting mammals from free radical damage and conditions accelerated by free radical damage. Specifically, the subject invention relates to novel methods of using certain iron-chelating compounds for reducing o the level of free radicals in mammalian cells.
BACKGROUND OF THE INVENTION
Free radicals, in particular oxygen radicals, in mammalian cells arise from a variety of environmental sources. Such sources include smoke, pollution and radiation in addition to normal cell metabolism and inflammatory processes. Free radicals are known to be i5 damaging to biological tissue. In the body, the potential for damage by free radicals is greatly increased by the presence of iron (and to a lesser extent by the presence of copper), which catalyzes their conversion to less stable and therefore more reactive radical species.
The resulting effects of such radicals on components such as structural proteins, membrane lipids and nucleic acids include alteration or loss of tissue and cell function, cell death, and 2o cancer. Based on a growing body of evidence, it is also believed that the accumulated damage from free radicals, including those produced as by-products in normal metabolism, is responsible for chronological aging. This has been termed the free radical theory of aging.
In vitro and in vivo studies on humans and other mammals also indicate that free radicals play an important role in the activation of certain human immunodeficiency virus 25 (HIV) types. See, for example, Schreck, R., B. Meier, D. N. Manner, W.
Droge and P.A.
Baeuerle, "Dithiocarbamates as Potent Inhibitors of Nuclear Factor xB
Activation in Intact Cells," J. EXD. Med., Vol. 175, pp. 1181-1194, (1992). Certain iron chelators have therefore been considered for the treatment of Acquired Immune Deficiency Syndrome (AIDS). See, for example, Hersh, E. M. et al., "Ditiocarb Sodium (Diethyldithiocarbamate) Therapy in 3o Patients with Symptomatic HIV Infection and Aids," J. A. M. A., Vol. 265, pp.1538-1544, _(1991).
To combat the damaging effects of free radicals, especially oxygen radicals, free radical scavengers and anti-oxidants have been used. These compounds react with the radical species to convert them to stable, nonreactive materials.
35 It is an object of the subject invention to provide methods for reducing free radical damage in mammalian cells.
It is also an object of the subject invention to provide compositions which reduce free radical damage in mammalian cells.
2 i $ 6 8 6 7 PCT/US95/02872 SUMMARY OF THE INVENTION
The subject invention involves a method of reducing free radical damage in mammals comprising administering to a mammal a composition comprising a safe and effective amount of a compound selected from 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, 2-furildioxime, 2-furilmonoxime, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one, or a pharmaceutically acceptable salt thereof, or mixtures of the subject compounds and/or their salts.
DETAILED DESCRIPTION OF THE INVENTION
1o It has been unexpectedly found that compositions comprising the subject compounds exhibit the ability to reduce levels of free radicals in mammals. While the subject invention is not limited to any particular mode of action, it is believed that the subject compounds may reduce the level of free radicals in mammalian cells by preventing the formation of the most damaging radical species. The subject compounds are believed to bind to iron such that iron ~5 cannot participate in the formation of the above mentioned radical species.
The subject compounds, which act as iron chelators, are unexpectedly effective against both environmentally induced radical production as well as the endogenous radical production arising from metabolism.
As used herein, "alkyl" means a substituted or unsubstituted carbon-containing chain 2o which may be straight or branched; saturated, monounsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (i.e., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain).
As used herein, "topical application" means directly laying on or spreading on outer 25 skin.
As used herein, "pharmaceutically-acceptable" means that salts, drugs, medicaments or inert ingredients which the term describes are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
30 As used herein, "safe and effective amount" means an amount of compound or composition suflrcient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and 35 physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
The subject invention involves a method of reducing free radical damage in mammals comprising administering to a mammal a composition comprising a safe and effective amount of a compound selected from 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, 2-furildioxime, 2-furilmonoxime, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one, or a pharmaceutically acceptable salt thereof, or mixtures of the subject compounds and/or their salts.
DETAILED DESCRIPTION OF THE INVENTION
1o It has been unexpectedly found that compositions comprising the subject compounds exhibit the ability to reduce levels of free radicals in mammals. While the subject invention is not limited to any particular mode of action, it is believed that the subject compounds may reduce the level of free radicals in mammalian cells by preventing the formation of the most damaging radical species. The subject compounds are believed to bind to iron such that iron ~5 cannot participate in the formation of the above mentioned radical species.
The subject compounds, which act as iron chelators, are unexpectedly effective against both environmentally induced radical production as well as the endogenous radical production arising from metabolism.
As used herein, "alkyl" means a substituted or unsubstituted carbon-containing chain 2o which may be straight or branched; saturated, monounsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (i.e., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain).
As used herein, "topical application" means directly laying on or spreading on outer 25 skin.
As used herein, "pharmaceutically-acceptable" means that salts, drugs, medicaments or inert ingredients which the term describes are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
30 As used herein, "safe and effective amount" means an amount of compound or composition suflrcient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and 35 physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
As used herein, "free radical" means an atom or group of atoms that have one or more unpaired electrons. Such atoms or groups of atoms are highly reactive and unstable species. Also included among "free radicals" are other oxygen species which are highly reactive toward biological systems. Some "free radicals" are produced by the catalytic action of metals (e.g., iron or copper) or are more reactive toward biological systems in the presence of metals (e.g., iron or copper). Specific non-limiting examples of "free radicals" as defined above are:
superoxide 02-hydroperoxyl radical H02 1o peroxide ion 022-hydroperoxyl anion H02-hydroxyl radical HO~
singlet oxygen 102 hydrogen peroxide H202 ferryl iron Fep2+
perferryl iron Fe043-As used herein, "free radical damage" means the alteration in structure, firnction, composition, or other properties of biological tissues, organs, cells, or constituents that result from the effect of a free radical on them. Since free radicals are highly reactive and 2o unstable species, they will in general react with a wide variety of biological targets to damage them. For example, the oxidation of lipids (lipid peroxidation), especially of cell membrane lipid, is a well-known damaging effect of radicals in biological systems.
As used herein, "controlling the onset of AIDS" means delaying, retarding, and/or preventing the activation of HIV types, especially HIV (1). The activation of HN is often manifested by symptoms associated with AmS. While not limited to any particular mechanism of action, the subject chelators are believed to control the onset of AIDS by reducing systemic levels of and/or preventing the formation of free radicals which play a role in the activation of the subject virus types.
Active Agent 3o The subject invention involves a method for protecting mammalian cells from free radical damage by reducing the level of free radicals in mammalian cells by administering to the mammal a safe and effective amount of an iron chelator selected from the group consisting of:
2-furildioxime having the structure:
OH OH
I I
N N
superoxide 02-hydroperoxyl radical H02 1o peroxide ion 022-hydroperoxyl anion H02-hydroxyl radical HO~
singlet oxygen 102 hydrogen peroxide H202 ferryl iron Fep2+
perferryl iron Fe043-As used herein, "free radical damage" means the alteration in structure, firnction, composition, or other properties of biological tissues, organs, cells, or constituents that result from the effect of a free radical on them. Since free radicals are highly reactive and 2o unstable species, they will in general react with a wide variety of biological targets to damage them. For example, the oxidation of lipids (lipid peroxidation), especially of cell membrane lipid, is a well-known damaging effect of radicals in biological systems.
As used herein, "controlling the onset of AIDS" means delaying, retarding, and/or preventing the activation of HIV types, especially HIV (1). The activation of HN is often manifested by symptoms associated with AmS. While not limited to any particular mechanism of action, the subject chelators are believed to control the onset of AIDS by reducing systemic levels of and/or preventing the formation of free radicals which play a role in the activation of the subject virus types.
Active Agent 3o The subject invention involves a method for protecting mammalian cells from free radical damage by reducing the level of free radicals in mammalian cells by administering to the mammal a safe and effective amount of an iron chelator selected from the group consisting of:
2-furildioxime having the structure:
OH OH
I I
N N
2-furilmonoxime, having the structure:
OH
I
N O
O ~-C O
1-phenyl-1,2-propanedione-2-oxime, having the structure:
OH
I
O N
1-phenyl-1,3-butanedione (benzoylacetone), having the structure:
/ \/ \
1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone (piroctone), having the structure:
OH
~\
to diethyldithiocarbamic acid, having the structure:
S
-C-SH .
deferoxamine, having the structure:
I II II I
NH2(CH2)SN-C (CH2)2CNH(CHZ)5 I
H3CC-N(CHZ)SHNC(CH2)2C
O HO 0 O ; and 1,2-dimethyl-3-hydroxy-pyrid-4-one, (chelator L1), having the structure:
OH
I
N O
O ~-C O
1-phenyl-1,2-propanedione-2-oxime, having the structure:
OH
I
O N
1-phenyl-1,3-butanedione (benzoylacetone), having the structure:
/ \/ \
1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridinone (piroctone), having the structure:
OH
~\
to diethyldithiocarbamic acid, having the structure:
S
-C-SH .
deferoxamine, having the structure:
I II II I
NH2(CH2)SN-C (CH2)2CNH(CHZ)5 I
H3CC-N(CHZ)SHNC(CH2)2C
O HO 0 O ; and 1,2-dimethyl-3-hydroxy-pyrid-4-one, (chelator L1), having the structure:
O
OH
N CHs or a pharmaceutically-acceptable salt thereof; or mixtures of the subject compounds and/or their salts.
Preferred active compounds of the subject invention include 2-furildioxime, 2-s furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime (PPDO), piroctone and diethyl-dithio-carbamic acid. More preferred compounds include 2-furildioxime, 2-furilmonoxime, piroctone and diethyldithiocarbamic acid. Even more preferred compounds include 2-furildioxime and 2-furilmonoxime. The most preferred compound of the subject invention is 2-furildioxime.
o Preferred actives useful in controlling the onset of AIDS include 2-furildioxime, 2-furilmonoxime, PPDO, benzoylacetone, piroctone, and 1,2-dimethyl-3-hydroxy-pyrid-4-one.
More preferred actives useful in controlling the onset of AIDS include 2-furildioxime, 2-furilmonoxime, PPDO and piroctone. Even more preferred actives include 2-furildioxime and 2-furilmonoxime. The most preferred active is 2-furildioxime.
~s A particularly preferred piroctone salt is its ethanolamine salt, octopirox.
A particularly preferred salt of diethyldithiocarbamic acid is its sodium salt.
A particularly preferred salt of deferoxamine is its methanesulfonate salt, desferol.
Pharmaceuticall -Y Acceptable Carrier In addition to the active agent as described hereinbefore, the pharmaceutical 2o compositions of the present invention essentially comprise a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharmaceutical compositions are capable of 25 being commingled with the compound of the present invention, and with each other, in a manner such that there is no interaction , which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations.
Pharmaceutically-acceptable carriers must, of course, be of sufficiently high .purity and sufficiently low toxicity to render them suitable for administration to the human or lower 3o animal being treated.
Some examples of substances which can serve as pharmaceutically-acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc;
stearic acid;
magnesium stearate; calcium sulfate; vegetable oils such a peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; sugar; alginic acid;
pyrogen-free water; isotonic saline; phosphate buffer solutions; cocoa butter (suppository base); emulsi-fiers, such as the Tweens~; as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. .
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the compounds of the present invention is basically determined by the way the compound is to be administered. The preferred modes of administering the compounds of the present invention are orally, topically and by injection. Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in creams, gels, tapes and the like; and for oral administration include those suited for tablets and capsules.
The pharmaceutically-acceptable carrier employed in conjunction with the compounds of the present invention is used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.99% by weight of the pharmaceutical 2o compositions of the present invention, preferably from about 80% to about 99.9%, more preferably from about 90% to about 99.0%, even more preferably from about 92%
to about 97%, also preferably from about 94% to about 96%.
Pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration and injection, and dosage forms for topical application are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and/or shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.
Pharmaceutically-acceptable carriers useful in the compositions of the subject invention are described more fully hereinafter.
3o A. Oral Dose Forms:
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules, bulk powders and microcapsules of the drug. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 10% to about 50% of the compound of the subject invention. Tablets can be compressed, enteric-coated, sugar-coated or filmcoated containing suitable binders, lubricants, surfactants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted .m. '~ _ ~ 2 1 8 6 8 6 7'~~
OH
N CHs or a pharmaceutically-acceptable salt thereof; or mixtures of the subject compounds and/or their salts.
Preferred active compounds of the subject invention include 2-furildioxime, 2-s furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime (PPDO), piroctone and diethyl-dithio-carbamic acid. More preferred compounds include 2-furildioxime, 2-furilmonoxime, piroctone and diethyldithiocarbamic acid. Even more preferred compounds include 2-furildioxime and 2-furilmonoxime. The most preferred compound of the subject invention is 2-furildioxime.
o Preferred actives useful in controlling the onset of AIDS include 2-furildioxime, 2-furilmonoxime, PPDO, benzoylacetone, piroctone, and 1,2-dimethyl-3-hydroxy-pyrid-4-one.
More preferred actives useful in controlling the onset of AIDS include 2-furildioxime, 2-furilmonoxime, PPDO and piroctone. Even more preferred actives include 2-furildioxime and 2-furilmonoxime. The most preferred active is 2-furildioxime.
~s A particularly preferred piroctone salt is its ethanolamine salt, octopirox.
A particularly preferred salt of diethyldithiocarbamic acid is its sodium salt.
A particularly preferred salt of deferoxamine is its methanesulfonate salt, desferol.
Pharmaceuticall -Y Acceptable Carrier In addition to the active agent as described hereinbefore, the pharmaceutical 2o compositions of the present invention essentially comprise a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the pharmaceutical compositions are capable of 25 being commingled with the compound of the present invention, and with each other, in a manner such that there is no interaction , which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations.
Pharmaceutically-acceptable carriers must, of course, be of sufficiently high .purity and sufficiently low toxicity to render them suitable for administration to the human or lower 3o animal being treated.
Some examples of substances which can serve as pharmaceutically-acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc;
stearic acid;
magnesium stearate; calcium sulfate; vegetable oils such a peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; sugar; alginic acid;
pyrogen-free water; isotonic saline; phosphate buffer solutions; cocoa butter (suppository base); emulsi-fiers, such as the Tweens~; as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, tableting agents, stabilizers, antioxidants, and preservatives, can also be present. .
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the compounds of the present invention is basically determined by the way the compound is to be administered. The preferred modes of administering the compounds of the present invention are orally, topically and by injection. Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in creams, gels, tapes and the like; and for oral administration include those suited for tablets and capsules.
The pharmaceutically-acceptable carrier employed in conjunction with the compounds of the present invention is used at a concentration sufficient to provide a practical size to dosage relationship. The pharmaceutically-acceptable carriers, in total, may comprise from about 0.1% to about 99.99% by weight of the pharmaceutical 2o compositions of the present invention, preferably from about 80% to about 99.9%, more preferably from about 90% to about 99.0%, even more preferably from about 92%
to about 97%, also preferably from about 94% to about 96%.
Pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration and injection, and dosage forms for topical application are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and/or shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.
Pharmaceutically-acceptable carriers useful in the compositions of the subject invention are described more fully hereinafter.
3o A. Oral Dose Forms:
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules, bulk powders and microcapsules of the drug. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 10% to about 50% of the compound of the subject invention. Tablets can be compressed, enteric-coated, sugar-coated or filmcoated containing suitable binders, lubricants, surfactants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted .m. '~ _ ~ 2 1 8 6 8 6 7'~~
from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents, and flavoring agents. Preferred carriers for oral administration include gelatin and propylene glycol. Specific examples of pharmaceutically-acceptable carriers and excipients that may be used in formulating oral dosage forms containing compounds of the subject invention are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975.
Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol.
77, (Banker and Rhodes, editors), 359-427 (1979).
1o Techniques and compositions for making tablets (compressed, formulas and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980).
The preferred unit dosage form for oral administration is tablets, capsules and the like, comprising a safe and effective amount of a compound of the subject invention.
~5 Preferably oral dose forms comprise from about 0.001 g to about Sg of a compound of the subject invention, more preferably from about 0.01 g to about 2g and most preferably from about O.lg to about lg, for a 50-70 kg person.
B. Topical Dose Forms:
The compositions of the subject invention can also be administered topically to a 2o biological subject, i.e., by the direct laying on or spreading of the composition on the skin.
The topical compositions useful in the subject invention involve .
compositions suitable for topical application to mammalian skin, the composition comprising a safe and effective amount of an active agent or mixture of such actives as described hereinabove, and a pharmaceutically-acceptable topical carrier. The subject compositions preferably 25 contain from about 0.001% to about 20%, preferably from about 0.01% to about 10%, more preferably from about 0.1% to about 5%.
The topical compositions useful in the subject invention may be made into a wide variety of product types. These include, but are not limited to lotions, creams, beach oils, gels, sticks, spr~c~s, ointments, pastes, mousses, cosmetics, shampoos, cream rinses, hair 3o tonics and hair conditioners. These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels, solids, and liposomes.
The topical compositions useful in the subject invention may include a safe and effective amount of penetration enhancing agent. A preferred amount of penetration enhancing agent, is from about 1% to about 5% of the composition. Examples of useful 35 penetration enhancers, among others, are disclosed in U.S. Patents 4,537,776, Cooper, issued August 27, 1985; 4,552,872, Cooper et al., issued November 12, 1985;
4,557,934, Cooper, issued December 10, 1985; 4,130,667, Smith, issued December 19, 1978;
- 3,989,816, Rhaadhyaksha, issued November 2, 1976; 4,017,641, DiGiulio, issued April _ ... __ _. , z _ _ ~ _ _ _ _ _ .... WO 95/27485 _ . 2 ~ 8 6 g 6 ~ PCT/US95/02872 , 12, 1977; and 4,954,487, Cooper, Loomans & Wickett, issued September 4, 1990.
Other conventional skin care product additives may also be included in the compositions useful in the subject invention. For example, collagen, hyaluronic acid, elastin, hydrolysates, primrose oil, jojoba oil, epidermal growth factor, soybean saponins, mucopolysaccharides, and mixtures thereof may be used.
Various vitamins may also be included in the compositions useful in the subject invention. For example, Vitamin A, and derivatives thereof, Vitamin B2, biotin, pantothenic, Vitamin D, and mixtures thereof may be used.
C. Ini~ectable Dose Forms io The compounds of the subject invention are also useful when injected. The dosage of the compound of the subject invention which is both safe and effective will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the specific compound employed and its usage concentration, and like factors within the specific knowledge and expertise of the attending physician and commensurate i5 with a reasonable benefit/risk ratio associated with the use of any drug compound. The injectable dosages and dosage ranges given herein are based on delivery of the compound of the subject invention to a 70 kg human and can be adjusted to provide equivalent dosages for patients of different body weights.
Methods and materials for manufacturing injectables can be found in Remingtgm's 2o Pharmaceutical Sciences, l7ed., 1985, Chapter 85, p. 1518.
The injectable dosage forms typically .
contain from about 0.001 mg/ml to about 100 mg/ml, preferably from about 0.01 mg/m1 to about 10 mg/ml, more preferably from about 0.1 mg/ml to about 3.0 mg/ml, of the compound of the subject invention. The injectable dosage forms are typically administered 25 from about once a week to about four times daily, more preferably from about twice a week to about three times daily, more preferably still, about three times a week to about twice daily, also preferably about once daily. Typically, from about 1 ml to about 100 mls of the composition are injected, preferably from about 10 mls to about 50 mls, more preferaLl~r about 25 mls.
3o Combination Actives A. ~~nscreens and Sunblocks Reduction of the level of free radicals in mammalian cells can be achieved by using combinations.of the active agents together with sunscreens or sunblocks.
A known inducer of free radicals is ultraviolet radiation. Thus, in topical compositions, the inclusion 35 of sunscreens/sunblocks would increase protection against radical production and subsequent damage. Useful sunblocks include, for example, zinc oxide and titanium dioxide. The combination of an active agent, with a UVA and/or UVB sunscreen is desirable. The inclusion of sunscreens in compositions useful in the subject invention at B
Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol.
77, (Banker and Rhodes, editors), 359-427 (1979).
1o Techniques and compositions for making tablets (compressed, formulas and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980).
The preferred unit dosage form for oral administration is tablets, capsules and the like, comprising a safe and effective amount of a compound of the subject invention.
~5 Preferably oral dose forms comprise from about 0.001 g to about Sg of a compound of the subject invention, more preferably from about 0.01 g to about 2g and most preferably from about O.lg to about lg, for a 50-70 kg person.
B. Topical Dose Forms:
The compositions of the subject invention can also be administered topically to a 2o biological subject, i.e., by the direct laying on or spreading of the composition on the skin.
The topical compositions useful in the subject invention involve .
compositions suitable for topical application to mammalian skin, the composition comprising a safe and effective amount of an active agent or mixture of such actives as described hereinabove, and a pharmaceutically-acceptable topical carrier. The subject compositions preferably 25 contain from about 0.001% to about 20%, preferably from about 0.01% to about 10%, more preferably from about 0.1% to about 5%.
The topical compositions useful in the subject invention may be made into a wide variety of product types. These include, but are not limited to lotions, creams, beach oils, gels, sticks, spr~c~s, ointments, pastes, mousses, cosmetics, shampoos, cream rinses, hair 3o tonics and hair conditioners. These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels, solids, and liposomes.
The topical compositions useful in the subject invention may include a safe and effective amount of penetration enhancing agent. A preferred amount of penetration enhancing agent, is from about 1% to about 5% of the composition. Examples of useful 35 penetration enhancers, among others, are disclosed in U.S. Patents 4,537,776, Cooper, issued August 27, 1985; 4,552,872, Cooper et al., issued November 12, 1985;
4,557,934, Cooper, issued December 10, 1985; 4,130,667, Smith, issued December 19, 1978;
- 3,989,816, Rhaadhyaksha, issued November 2, 1976; 4,017,641, DiGiulio, issued April _ ... __ _. , z _ _ ~ _ _ _ _ _ .... WO 95/27485 _ . 2 ~ 8 6 g 6 ~ PCT/US95/02872 , 12, 1977; and 4,954,487, Cooper, Loomans & Wickett, issued September 4, 1990.
Other conventional skin care product additives may also be included in the compositions useful in the subject invention. For example, collagen, hyaluronic acid, elastin, hydrolysates, primrose oil, jojoba oil, epidermal growth factor, soybean saponins, mucopolysaccharides, and mixtures thereof may be used.
Various vitamins may also be included in the compositions useful in the subject invention. For example, Vitamin A, and derivatives thereof, Vitamin B2, biotin, pantothenic, Vitamin D, and mixtures thereof may be used.
C. Ini~ectable Dose Forms io The compounds of the subject invention are also useful when injected. The dosage of the compound of the subject invention which is both safe and effective will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the specific compound employed and its usage concentration, and like factors within the specific knowledge and expertise of the attending physician and commensurate i5 with a reasonable benefit/risk ratio associated with the use of any drug compound. The injectable dosages and dosage ranges given herein are based on delivery of the compound of the subject invention to a 70 kg human and can be adjusted to provide equivalent dosages for patients of different body weights.
Methods and materials for manufacturing injectables can be found in Remingtgm's 2o Pharmaceutical Sciences, l7ed., 1985, Chapter 85, p. 1518.
The injectable dosage forms typically .
contain from about 0.001 mg/ml to about 100 mg/ml, preferably from about 0.01 mg/m1 to about 10 mg/ml, more preferably from about 0.1 mg/ml to about 3.0 mg/ml, of the compound of the subject invention. The injectable dosage forms are typically administered 25 from about once a week to about four times daily, more preferably from about twice a week to about three times daily, more preferably still, about three times a week to about twice daily, also preferably about once daily. Typically, from about 1 ml to about 100 mls of the composition are injected, preferably from about 10 mls to about 50 mls, more preferaLl~r about 25 mls.
3o Combination Actives A. ~~nscreens and Sunblocks Reduction of the level of free radicals in mammalian cells can be achieved by using combinations.of the active agents together with sunscreens or sunblocks.
A known inducer of free radicals is ultraviolet radiation. Thus, in topical compositions, the inclusion 35 of sunscreens/sunblocks would increase protection against radical production and subsequent damage. Useful sunblocks include, for example, zinc oxide and titanium dioxide. The combination of an active agent, with a UVA and/or UVB sunscreen is desirable. The inclusion of sunscreens in compositions useful in the subject invention at B
low levels does not greatly reduce the tanning response of the user but enhances the effectiveness of the subject compositions. A wide variety of conventional sunscreening agents are suitable for use in combination with a subject active agent.
Sagarin, et al., at Chapter VIII, pages 189 et seq., of Cosmetics Science and Technolostv, disclose numerous suitable agents.
A safe and effective amount of sunscreen may be used in the compositions useful in the subject invention. The sunscreening agent must be compatible with the active agent. The composition preferably comprises from about 1% to about 20%, more preferably from about 2% to about 10% of a sunscreening agent. Exact amounts will vary 1o depending upon the sunscreen chosen and the desired Sun Protection Factor.
B. Anti-Inflammatory Agents In a preferred composition useful in the subject invention, an anti-inflammatory agent is included as an active along with the active agent. The inclusion of an anti-inflammatory agent enhances the benefits of the compositions because the mammalian body will respond to radical damage by mounting an inflammation response which can lead to additional cell damage. The anti-inflammatory agent also protects strongly in the UVA
radiation range (though it also provides some UVB protection as well). (See U.S. Patent 4,847,071, Bissett, Bush, and Chatterjee, issued July 11, 1989;
and U.S. Patent~4,847,069, Bissett and Chatterjee, issued July 11, 1989.).
A safe and effective amount of an anti-inflammatory agent may be added to the compositions useful in the subject invention, preferably from about 0.1 % to about 10%, more preferably from about 0.5% to about 5%, of the composition. The exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.
C. Anti-Oxidants/Radical Scavengers In a preferred composition useful in the subject invention, an anti-oxidant/radical scavenger is included as an active along with a subject active agent. The inclusion of an anti-oxidant/ radical scavenger increases the benefits of the composition because an anti-oxidant/radcial scavenger can neutralize any free radicals that are produced in spite of the subject actives' chelating action.
A safe and effective amount of an anti-oxidant/radical scavenger may be added to the compositions useful in the subject invention, preferably from about 0.1%
to about 10%, more preferably from about 1% to about 5%, of the composition.
Anti-oxidants/radicaI scavengers such as ascorbic acid (vitamin C) and its salts, tocopherol (vitamin E), tocopherol sorbate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename Trolox~), gallic acid and its alkyl esters, B
-- ~ . . , WO 95/27485 ~ ~ a 6 a 6 ~
especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, the ascorbyl esters of fatty acids, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), and dihydroxy fumaric acid and its salts may be used.
5 In a preferred composition useful in the subject invention, compositions comprise one, any two, or all three of a sunscreening agent, anti-inflammatory agent, and/or an anti-oxidant/radical scavenging agent included as actives along with a subject active agent.
The inclusion of two or all three of these agents with the subject active increases the benefits of the composition.
to D. helators In a preferred composition useful in the subject invention, an additional chelating agent is included as an active along with a subject active agent. As used herein, "chelating agent" means an active agent capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions.
is The inclusion of an additional chelating agent increases the benefits of the composition.
A safe and effective amount of a chelating agent may be added to the compositions useful in the subject invention, preferably fr.~m about 0.1% to about 10%, more preferably fi-om about 1 % to about 5%, of the composition. Chelators useful in compositions are disclosed in U.S. Patent 5,487,884, Bissett, Bush & Chatterjee; AU 94-77471, Bush & Bissett;
2o and U.S. Patent 5,364,617, Bush, Bissett & Chatterjee. The additional chelators preferred include:
kojic acid 2,3-bis-(2-pyridyt)-pyrazine 3-(4-phenyl-2-pyridyt)-S-phenyl-1,2,4-triazine 2,3-bis-(2-pyridyl)-5, 6-dihydropyrazine 2,4, 6-tri-(2-pyridyl~ 1,3,5-triazine I-pyrroIidine carbodithioic acid di-2-pyridyl ketone phenyl 2-pyridyl ketoxime 30 2,3-dihydroxy naphthalene 2,3-dihydroxy pyrridine 3-hydroxy-2-methyl-4-pyrone 2,3-dihydroxy benzoic acid ethylenediamine-N,N-bis-(2-hydroxy-phenylacetic acid) dimethyl ester B
WO 95/27485 ~ ~ ~ ~ 8 6 7 pCT~S95/02872 In a preferred composition useful in the subject invention, compositions comprise one, any two, any three, or all four of a sunscreening agent, anti-inflammatory agent, anti-oxidant/radical scavenging agent, and/or chelating agent included as actives along with the subject active agent. The inclusion of two, three, or all four of these agents with the active agent increases the benefits of the composition.
Methods for Reducing Free Radical Damage in Mammalian Cells The subject invention relates to methods for reducing the level of free radicals in mammalian cells. The reduction of the level of free radicals in mammlian cells reduces the level of free radical aging in the cells. Reduced levels of free radicals also prolongs the to interval between infection by HIV in certain mammals, and the activation of the HIV (and the accompanying symptoms of AIDS exhibited by the HIV positive mammal).
The subject methods comprise topical application of a safe and effective amount of an active agent. The amount of treatment and frequency of application will vary widely depending upon the conditions of the cells already in existence in the subject and the level of treatment desired.
A safe and effective amount of active agent, in a topical composition, is applied, generally from about 0.001 mg to about 2 mg per cm2 skin per application, preferably from about .005 mg to about 1 mg per cm2 skin per application, more preferably from about 0.01 mg to about 0.5 mg/cm2, also preferably from about 0.02 mg to about 0.2 2o mg/cm2. Application preferably ranges from about weekly to about 5 times daily, more preferably from about twice a week to about four times daily, more preferably still from about every other day to about 3 times daily, also preferably from about once a day to about twice a day. The subject compositions are preferably applied to an area of from about 10 cm2 to about 10,000 cm2 skin for each application, more preferably from about 100 cm2 to about 5,000 cm2 skin, also preferably from about 500 cm2 to about 1000 cm2 skin. Treatment is continued for at least 7 days, more preferably 6 months, even more preferably 1 year, more preferably still 5 years, also preferably 10 years.
A preferred method of the subject invention involves applying both a safe and effective amount of the active and a safe and effective amount of one or more of a 3o sunscreening agent, an anti-inflammatory agent, an anti-oxidant/radical scavenging agent, and/or a chelating agent, to the skin simultaneously. As used herein, "simultaneous application" or "simultaneously" means applying the agents to the skin at the same situs on the body at about the same time: Though this can be accomplished by applying the agents separately to the skin, preferably a composition comprising all the desired agents commingled is applied to the skin. The amount of sunscreening agent applied is preferably from about O.OS mg to about 0.5 mg per cm2 skin. The amount of anti-inflammatory agent applied is preferably from about 0.005 mg to about 0.5 mg, more preferably from about 0.01 mg to about 0.1 mg per cm2 skin. The amount of anti-oxidantlradical WO 95/27485 ~ ~ -8 6 8 6 ~ PCT/US95/02872 scavenging agent preferably applied is from about 0.01 mg to about 1.0 mg, more preferably from about 0.05 mg to about 0.5 mg per cm2 skin. The amount of chelating agent preferably applied is from about .001 mg to about 1.0 mg, more preferably from about 0.01 mg to about 0.5 mg, still more preferably from about 0.05 mg to about 0.1 mg per cm2 skin. The amount of the active compound of the subject invention applied is preferably from about 0.001 mg to about 2 m~per cm2 skin per application, more prefer-ably from about 0.01 mg to about 1 mg per cm skin per application.
The preferred modes of administration are orally, topically, and parenterally (for example, by subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection and the like). Thus, specific modes of administration include, without limitation, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal, and subcutaneous administration, as well as topical application.
Oral administration can be used to reduce the level of free radicals through oral dosing of a pharmaceutical composition comprised of a safe and effective amount of the compound of the subject invention in a suitable oral pharmaceutical carrier.
The com pound is absorbed by the gastrointestinal tract. The pharmaceutical composition may consist of solid dosage forms such as tablets, hard gelatin capsules, soft gelatin capsules, bulk powders, and microcapsules of the drug. Alternately, it may consist of a liquid dosage form such as an aqueous or nonaqueous solution, emulsion, or suspension.
2o The amount of the compound ingested depends upon the bioavailability of the compound from the oral pharmaceutical composition. Typically, however, the compounds of the subject invention are dosed in an amount of from about 0.001 mg/kg of body weight to about 100 mg/kg, preferably from about 0.01 to about 50 mg/kg of body weight, more preferably from about 0.1 to about 20 mg/kg of body weight, also preferably from about 1 2s mg to about 10 mg/kg of body weight. The amount of the pharmaceutical composition depends upon the percent of compound within its formula, which is a function of the amount of the compound required per dose, its stability, release characteristics and other pharmaceutical parameters. Generally, the oral pharmaceutical composition should com-prise from about 5% to about 50% of the compound of the subject invention.
3o Oral application preferably ranges from about weekly to about 5 times daily, more preferably from about twice a week to about four times daily, more preferably still from about every other day to about 3 times daily, also preferably from about once a day to about twice a day. Treatment is continued for at least 7 days, more preferably 6 months, even more preferably 1 year, more preferably still 5 years, also preferably 10 years.
35 For controlling the onset of AmS, the compounds of the subject invention are preferably dosed in an oral form in an amount of from about 10 mg to about 1000 mg per m2 of body surface area of the subject infected with HIV, more preferably from about 100 to about 800 mg per m2, also preferably from about 300 to about 500 mg per m2, most 21886'7 preferably about 400 mg per m2. Application preferably ranges from about once a month to about twice daily, more preferably about once every two weeks to about once a day, more preferably still about once every 10 days to about once every other day, also preferably about once a week.
The preferred method of injectable administration depends upon the solubility and a the stability of the particular active being used.
EXAMPLES
The following examples further describe and demonstrate embodiments within the scope of the subject invention. The examples are given solely for the purpose of to illustration and are not to be construed as limitations of the subject invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
ORAL DOSE FORMS
EXAMPLE I
A composition for oral administration is prepared by combining the following Component:
2-furildioxime (FDO) 1 kg Sesame oil to 4 liters The FDO is suspended in the sesame oil with the aid of sonication and is packaged in soft gelatin capsules using methods known in the art. Two of the resulting capsules, 2o each containing 250 mg of the active, are administered to a 60 kg human, daily for a period of 4 years.
EXAMPLE II
A composition for oral administration is prepared by combining the following Component 2-furilmonoxime (FMO) 250 g Propylene glycol 1800 ml Ethyl alcohol 175 ml Distilled water 75 ml Artificial Cherry flavor 10 ml 3o FD&C Red #40 0.2 g The above ingredients are combined to produce a syrup and are packaged under sterile conditions~in 6 oz. bottles. One teaspoon ofthis formulation is administered to a 70 kg human, weekly for a period of one year.
EXAMPLE III
Tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows:
Component mg per tablet piroctone 500 Microcrystalline cellulose 400 Sodium Starch glycolate 60 Magnesium stearates 10 One tablet is administered orally to a human infected with HIV, once a week for a period of one year or more.
TOPICAL DOSE FORMS
to EXAMPLE IV
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol:propylene glycol:water (1:1:2) 98.7 Diethyldithiocarbamic acid(DEDCA), 1.3 sodium salt In a suitable vessel, the Na-DEDCA is dissolved in the ethanol:propylene glycol:water with stirring. Use of an amount of the composition to deposit about 0.02 mg/cm2 of the active agent to about 200 cm2 of skin is appropriate. The composition is 2o applied twice daily, for a period of five years.
EXAMPLE V
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol 99.87 PPDO 0.13 In a suitable vessel, the PPDO is dissolved in the ethanol with stirring. Use of an amount of the composition to deposit about 0.001 mg/cm2 of the active agent to the skin ~is appropriate. The composition is applied four times daily over a 1000 cm2 area of skin for a period of six months.
EXAMPLE VI
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol ~ 49.00 Wo 95/27485 ~ ~ ~ pCT/US95/02872 Propylene glycol 25.00 Deionized water 25.00 Octopirox 1.00 In a suitable vessel, the octopirox is dissolved in the ethanol with stirring.
Propylene 5 glycol and deionized water are added with stirring. Use of an amount of the composition to deposit about 0.02 mg/cm2 of the active agent to 2000 cm2 of skin is appropriate. The composition is applied once a week for one year.
EXAMPLE VII
A nonionic oil-in-water emulsion is prepared by combining the following components 1o utilizing conventional mixing techniques:
Component % We~ht Deionized Water 79.73 Propylene Glycol 3.00 Octyl Methoxycinnamate 7.50 15 Cetyl Alcohol 2.50 Stearyl Alcohol 2.50 Laureth 23 2.00 C12-15 ~cohols Benzoate 2.00 EDTA 0.37 2o Methylparaben 0.20 Propylparaben 0.10 Deferoxamine 0.10 Use of an amount of the composition sufficient to deposit about 0.004 mg/cm2 skin of the active agent is appropriate. The composition is applied twice a week to about 500 cm2 of skin for two years.
EXAMPLE VIII
A nonionic oil-in-water emulsion is prepared by combining the following components utilizing conventional mixing techniques:
3o Component % Weightht Deionized Water 78.73 Propylene Glycol 3.00 Octyl Methoxycinnamate 7.50 Cetyl Alcohol 2.50 Stearyl Alcohol 2.50 Laureth 23 2.00 C12-15 ~cohols Benzoate 2.00 WO 95/27485 ~ ~ ~ PCT/LJS95/02872 EDTA 0.37 Methylparaben 0.20 Propylparaben 0.10 Benzoylacetone 1.10 Use of an amount of the composition sufficient to deposit about 0.05 mg/cm2 of the active agent to about 100 cm2 of skin is appropriate. The composition is applied once daily, for three years.
EXAMPLE IX
An ion pair oil-in-water emulsion is prepared by combining the following com-1o ponents utilizing conventional mixing techniques.
Component % Weight Deionized Water 78.05 Permulon TR-2 (C10-C30 Acrylate Copolymer,0.30 B.F. Goodrich) Distearyl Dimethyl Ammonium Chloride 0.15 1, 2-dimethyl-3 -hydroxy-pyrid-4-one 1. 00 4-N,N-(2-ethylhexyl)methylaminobenzoic acid 4-ester of 2-hydroxy-4-(2-hydroxyethoxy)-benzophenone 4.00 4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of 4-(2-hydroxyethoxy)dibenzoylmethane2.00 Dimethyl Isosorbide 6.00 Dioctyl Malate 6.00 Cetyl Alcohol 1.00 Stearyl Alcohol 1.00 99% Triethanolamine 0.50 Use of an amount of the composition sufficient to deposit about 0.1 mg/cm2 of the active agent to about 1000 cm2 of skin is appropriate. The composition is applied twice daily, for one year.
EXAMPLE X
A sunscreen composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Polypropylene Glycol 15 Stearyl Ether 15.00 Sorbitan Oleate 2.00 Octyl Methoxy Cinnamate 7.50 0.50 WO 95127d85 ~ ~ 8 6 8 6 7 PCT/IJS95/02872 Propyl Paraben 0.15 Butylated Hydroxy Toluene 0.05 Cyclomethicone 20.00 Sesame Oil 5.00 Mineral Oil (Blandol) 49.80 Use of an amount of the composition is sufficient to deposit about 0.1 mg/cm2 of the active agent to the skin is appropriate. This composition is applied three times daily, for six months.
While particular embodiments of the subject invention have been described, it will be to obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of the invention.
Sagarin, et al., at Chapter VIII, pages 189 et seq., of Cosmetics Science and Technolostv, disclose numerous suitable agents.
A safe and effective amount of sunscreen may be used in the compositions useful in the subject invention. The sunscreening agent must be compatible with the active agent. The composition preferably comprises from about 1% to about 20%, more preferably from about 2% to about 10% of a sunscreening agent. Exact amounts will vary 1o depending upon the sunscreen chosen and the desired Sun Protection Factor.
B. Anti-Inflammatory Agents In a preferred composition useful in the subject invention, an anti-inflammatory agent is included as an active along with the active agent. The inclusion of an anti-inflammatory agent enhances the benefits of the compositions because the mammalian body will respond to radical damage by mounting an inflammation response which can lead to additional cell damage. The anti-inflammatory agent also protects strongly in the UVA
radiation range (though it also provides some UVB protection as well). (See U.S. Patent 4,847,071, Bissett, Bush, and Chatterjee, issued July 11, 1989;
and U.S. Patent~4,847,069, Bissett and Chatterjee, issued July 11, 1989.).
A safe and effective amount of an anti-inflammatory agent may be added to the compositions useful in the subject invention, preferably from about 0.1 % to about 10%, more preferably from about 0.5% to about 5%, of the composition. The exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.
C. Anti-Oxidants/Radical Scavengers In a preferred composition useful in the subject invention, an anti-oxidant/radical scavenger is included as an active along with a subject active agent. The inclusion of an anti-oxidant/ radical scavenger increases the benefits of the composition because an anti-oxidant/radcial scavenger can neutralize any free radicals that are produced in spite of the subject actives' chelating action.
A safe and effective amount of an anti-oxidant/radical scavenger may be added to the compositions useful in the subject invention, preferably from about 0.1%
to about 10%, more preferably from about 1% to about 5%, of the composition.
Anti-oxidants/radicaI scavengers such as ascorbic acid (vitamin C) and its salts, tocopherol (vitamin E), tocopherol sorbate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename Trolox~), gallic acid and its alkyl esters, B
-- ~ . . , WO 95/27485 ~ ~ a 6 a 6 ~
especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, the ascorbyl esters of fatty acids, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), and dihydroxy fumaric acid and its salts may be used.
5 In a preferred composition useful in the subject invention, compositions comprise one, any two, or all three of a sunscreening agent, anti-inflammatory agent, and/or an anti-oxidant/radical scavenging agent included as actives along with a subject active agent.
The inclusion of two or all three of these agents with the subject active increases the benefits of the composition.
to D. helators In a preferred composition useful in the subject invention, an additional chelating agent is included as an active along with a subject active agent. As used herein, "chelating agent" means an active agent capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions.
is The inclusion of an additional chelating agent increases the benefits of the composition.
A safe and effective amount of a chelating agent may be added to the compositions useful in the subject invention, preferably fr.~m about 0.1% to about 10%, more preferably fi-om about 1 % to about 5%, of the composition. Chelators useful in compositions are disclosed in U.S. Patent 5,487,884, Bissett, Bush & Chatterjee; AU 94-77471, Bush & Bissett;
2o and U.S. Patent 5,364,617, Bush, Bissett & Chatterjee. The additional chelators preferred include:
kojic acid 2,3-bis-(2-pyridyt)-pyrazine 3-(4-phenyl-2-pyridyt)-S-phenyl-1,2,4-triazine 2,3-bis-(2-pyridyl)-5, 6-dihydropyrazine 2,4, 6-tri-(2-pyridyl~ 1,3,5-triazine I-pyrroIidine carbodithioic acid di-2-pyridyl ketone phenyl 2-pyridyl ketoxime 30 2,3-dihydroxy naphthalene 2,3-dihydroxy pyrridine 3-hydroxy-2-methyl-4-pyrone 2,3-dihydroxy benzoic acid ethylenediamine-N,N-bis-(2-hydroxy-phenylacetic acid) dimethyl ester B
WO 95/27485 ~ ~ ~ ~ 8 6 7 pCT~S95/02872 In a preferred composition useful in the subject invention, compositions comprise one, any two, any three, or all four of a sunscreening agent, anti-inflammatory agent, anti-oxidant/radical scavenging agent, and/or chelating agent included as actives along with the subject active agent. The inclusion of two, three, or all four of these agents with the active agent increases the benefits of the composition.
Methods for Reducing Free Radical Damage in Mammalian Cells The subject invention relates to methods for reducing the level of free radicals in mammalian cells. The reduction of the level of free radicals in mammlian cells reduces the level of free radical aging in the cells. Reduced levels of free radicals also prolongs the to interval between infection by HIV in certain mammals, and the activation of the HIV (and the accompanying symptoms of AIDS exhibited by the HIV positive mammal).
The subject methods comprise topical application of a safe and effective amount of an active agent. The amount of treatment and frequency of application will vary widely depending upon the conditions of the cells already in existence in the subject and the level of treatment desired.
A safe and effective amount of active agent, in a topical composition, is applied, generally from about 0.001 mg to about 2 mg per cm2 skin per application, preferably from about .005 mg to about 1 mg per cm2 skin per application, more preferably from about 0.01 mg to about 0.5 mg/cm2, also preferably from about 0.02 mg to about 0.2 2o mg/cm2. Application preferably ranges from about weekly to about 5 times daily, more preferably from about twice a week to about four times daily, more preferably still from about every other day to about 3 times daily, also preferably from about once a day to about twice a day. The subject compositions are preferably applied to an area of from about 10 cm2 to about 10,000 cm2 skin for each application, more preferably from about 100 cm2 to about 5,000 cm2 skin, also preferably from about 500 cm2 to about 1000 cm2 skin. Treatment is continued for at least 7 days, more preferably 6 months, even more preferably 1 year, more preferably still 5 years, also preferably 10 years.
A preferred method of the subject invention involves applying both a safe and effective amount of the active and a safe and effective amount of one or more of a 3o sunscreening agent, an anti-inflammatory agent, an anti-oxidant/radical scavenging agent, and/or a chelating agent, to the skin simultaneously. As used herein, "simultaneous application" or "simultaneously" means applying the agents to the skin at the same situs on the body at about the same time: Though this can be accomplished by applying the agents separately to the skin, preferably a composition comprising all the desired agents commingled is applied to the skin. The amount of sunscreening agent applied is preferably from about O.OS mg to about 0.5 mg per cm2 skin. The amount of anti-inflammatory agent applied is preferably from about 0.005 mg to about 0.5 mg, more preferably from about 0.01 mg to about 0.1 mg per cm2 skin. The amount of anti-oxidantlradical WO 95/27485 ~ ~ -8 6 8 6 ~ PCT/US95/02872 scavenging agent preferably applied is from about 0.01 mg to about 1.0 mg, more preferably from about 0.05 mg to about 0.5 mg per cm2 skin. The amount of chelating agent preferably applied is from about .001 mg to about 1.0 mg, more preferably from about 0.01 mg to about 0.5 mg, still more preferably from about 0.05 mg to about 0.1 mg per cm2 skin. The amount of the active compound of the subject invention applied is preferably from about 0.001 mg to about 2 m~per cm2 skin per application, more prefer-ably from about 0.01 mg to about 1 mg per cm skin per application.
The preferred modes of administration are orally, topically, and parenterally (for example, by subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection and the like). Thus, specific modes of administration include, without limitation, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal, and subcutaneous administration, as well as topical application.
Oral administration can be used to reduce the level of free radicals through oral dosing of a pharmaceutical composition comprised of a safe and effective amount of the compound of the subject invention in a suitable oral pharmaceutical carrier.
The com pound is absorbed by the gastrointestinal tract. The pharmaceutical composition may consist of solid dosage forms such as tablets, hard gelatin capsules, soft gelatin capsules, bulk powders, and microcapsules of the drug. Alternately, it may consist of a liquid dosage form such as an aqueous or nonaqueous solution, emulsion, or suspension.
2o The amount of the compound ingested depends upon the bioavailability of the compound from the oral pharmaceutical composition. Typically, however, the compounds of the subject invention are dosed in an amount of from about 0.001 mg/kg of body weight to about 100 mg/kg, preferably from about 0.01 to about 50 mg/kg of body weight, more preferably from about 0.1 to about 20 mg/kg of body weight, also preferably from about 1 2s mg to about 10 mg/kg of body weight. The amount of the pharmaceutical composition depends upon the percent of compound within its formula, which is a function of the amount of the compound required per dose, its stability, release characteristics and other pharmaceutical parameters. Generally, the oral pharmaceutical composition should com-prise from about 5% to about 50% of the compound of the subject invention.
3o Oral application preferably ranges from about weekly to about 5 times daily, more preferably from about twice a week to about four times daily, more preferably still from about every other day to about 3 times daily, also preferably from about once a day to about twice a day. Treatment is continued for at least 7 days, more preferably 6 months, even more preferably 1 year, more preferably still 5 years, also preferably 10 years.
35 For controlling the onset of AmS, the compounds of the subject invention are preferably dosed in an oral form in an amount of from about 10 mg to about 1000 mg per m2 of body surface area of the subject infected with HIV, more preferably from about 100 to about 800 mg per m2, also preferably from about 300 to about 500 mg per m2, most 21886'7 preferably about 400 mg per m2. Application preferably ranges from about once a month to about twice daily, more preferably about once every two weeks to about once a day, more preferably still about once every 10 days to about once every other day, also preferably about once a week.
The preferred method of injectable administration depends upon the solubility and a the stability of the particular active being used.
EXAMPLES
The following examples further describe and demonstrate embodiments within the scope of the subject invention. The examples are given solely for the purpose of to illustration and are not to be construed as limitations of the subject invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
ORAL DOSE FORMS
EXAMPLE I
A composition for oral administration is prepared by combining the following Component:
2-furildioxime (FDO) 1 kg Sesame oil to 4 liters The FDO is suspended in the sesame oil with the aid of sonication and is packaged in soft gelatin capsules using methods known in the art. Two of the resulting capsules, 2o each containing 250 mg of the active, are administered to a 60 kg human, daily for a period of 4 years.
EXAMPLE II
A composition for oral administration is prepared by combining the following Component 2-furilmonoxime (FMO) 250 g Propylene glycol 1800 ml Ethyl alcohol 175 ml Distilled water 75 ml Artificial Cherry flavor 10 ml 3o FD&C Red #40 0.2 g The above ingredients are combined to produce a syrup and are packaged under sterile conditions~in 6 oz. bottles. One teaspoon ofthis formulation is administered to a 70 kg human, weekly for a period of one year.
EXAMPLE III
Tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows:
Component mg per tablet piroctone 500 Microcrystalline cellulose 400 Sodium Starch glycolate 60 Magnesium stearates 10 One tablet is administered orally to a human infected with HIV, once a week for a period of one year or more.
TOPICAL DOSE FORMS
to EXAMPLE IV
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol:propylene glycol:water (1:1:2) 98.7 Diethyldithiocarbamic acid(DEDCA), 1.3 sodium salt In a suitable vessel, the Na-DEDCA is dissolved in the ethanol:propylene glycol:water with stirring. Use of an amount of the composition to deposit about 0.02 mg/cm2 of the active agent to about 200 cm2 of skin is appropriate. The composition is 2o applied twice daily, for a period of five years.
EXAMPLE V
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol 99.87 PPDO 0.13 In a suitable vessel, the PPDO is dissolved in the ethanol with stirring. Use of an amount of the composition to deposit about 0.001 mg/cm2 of the active agent to the skin ~is appropriate. The composition is applied four times daily over a 1000 cm2 area of skin for a period of six months.
EXAMPLE VI
A topical composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Ethanol ~ 49.00 Wo 95/27485 ~ ~ ~ pCT/US95/02872 Propylene glycol 25.00 Deionized water 25.00 Octopirox 1.00 In a suitable vessel, the octopirox is dissolved in the ethanol with stirring.
Propylene 5 glycol and deionized water are added with stirring. Use of an amount of the composition to deposit about 0.02 mg/cm2 of the active agent to 2000 cm2 of skin is appropriate. The composition is applied once a week for one year.
EXAMPLE VII
A nonionic oil-in-water emulsion is prepared by combining the following components 1o utilizing conventional mixing techniques:
Component % We~ht Deionized Water 79.73 Propylene Glycol 3.00 Octyl Methoxycinnamate 7.50 15 Cetyl Alcohol 2.50 Stearyl Alcohol 2.50 Laureth 23 2.00 C12-15 ~cohols Benzoate 2.00 EDTA 0.37 2o Methylparaben 0.20 Propylparaben 0.10 Deferoxamine 0.10 Use of an amount of the composition sufficient to deposit about 0.004 mg/cm2 skin of the active agent is appropriate. The composition is applied twice a week to about 500 cm2 of skin for two years.
EXAMPLE VIII
A nonionic oil-in-water emulsion is prepared by combining the following components utilizing conventional mixing techniques:
3o Component % Weightht Deionized Water 78.73 Propylene Glycol 3.00 Octyl Methoxycinnamate 7.50 Cetyl Alcohol 2.50 Stearyl Alcohol 2.50 Laureth 23 2.00 C12-15 ~cohols Benzoate 2.00 WO 95/27485 ~ ~ ~ PCT/LJS95/02872 EDTA 0.37 Methylparaben 0.20 Propylparaben 0.10 Benzoylacetone 1.10 Use of an amount of the composition sufficient to deposit about 0.05 mg/cm2 of the active agent to about 100 cm2 of skin is appropriate. The composition is applied once daily, for three years.
EXAMPLE IX
An ion pair oil-in-water emulsion is prepared by combining the following com-1o ponents utilizing conventional mixing techniques.
Component % Weight Deionized Water 78.05 Permulon TR-2 (C10-C30 Acrylate Copolymer,0.30 B.F. Goodrich) Distearyl Dimethyl Ammonium Chloride 0.15 1, 2-dimethyl-3 -hydroxy-pyrid-4-one 1. 00 4-N,N-(2-ethylhexyl)methylaminobenzoic acid 4-ester of 2-hydroxy-4-(2-hydroxyethoxy)-benzophenone 4.00 4-N,N-(2-ethylhexyl)methylaminobenzoic acid ester of 4-(2-hydroxyethoxy)dibenzoylmethane2.00 Dimethyl Isosorbide 6.00 Dioctyl Malate 6.00 Cetyl Alcohol 1.00 Stearyl Alcohol 1.00 99% Triethanolamine 0.50 Use of an amount of the composition sufficient to deposit about 0.1 mg/cm2 of the active agent to about 1000 cm2 of skin is appropriate. The composition is applied twice daily, for one year.
EXAMPLE X
A sunscreen composition is prepared by combining the following components utilizing conventional mixing techniques.
Component % Weight Polypropylene Glycol 15 Stearyl Ether 15.00 Sorbitan Oleate 2.00 Octyl Methoxy Cinnamate 7.50 0.50 WO 95127d85 ~ ~ 8 6 8 6 7 PCT/IJS95/02872 Propyl Paraben 0.15 Butylated Hydroxy Toluene 0.05 Cyclomethicone 20.00 Sesame Oil 5.00 Mineral Oil (Blandol) 49.80 Use of an amount of the composition is sufficient to deposit about 0.1 mg/cm2 of the active agent to the skin is appropriate. This composition is applied three times daily, for six months.
While particular embodiments of the subject invention have been described, it will be to obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of the invention.
Claims (9)
1. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof, for reducing free radical damage in cells of living mammals.
2. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof, for the production of a medicament for reducing free radical damage in cells of living mammals.
3. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof, for reducing the level of free radicals in mammalian cells.
4. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof, for the production of a medicament for reducing the level of free radicals in mammalian cells.
5. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocaxbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof, for controlling the onset of AIDS in a mammal infected by HIV.
6. A use of a safe and effective amount of an iron chelator selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, benzoylacetone, piroctone, diethyldithiocarbamic acid, deferoxamine and 1,2-dimethyl-3-hydroxy-pyrid-4-one; or a pharmaceutically-acceptable salt thereof for the production of a medicament for controlling the onset of AIDS in a mammal infected by HIV.
7. The use of claim 1 or 2 wherein the iron chelator is selected from the group consisting of 2-furildioxime, 2-furilmonoxime, 1-phenyl-1,2-propanedione-2-oxime, piroctone and diethyldithiocarbamic acid.
8. The use of claim 1 or 2 wherein the iron chelator is selected from the group consisting of 2-fuildioxime, 2-furilmonoxime, piroctone and diethyldithiocarbamic acid.
9. The use of claim 1 or 2 wherein the iron chelator is 2-furildioxime or 2-furilmonoxime.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22494994A | 1994-04-08 | 1994-04-08 | |
| US08/224,949 | 1994-04-08 | ||
| PCT/US1995/002872 WO1995027485A1 (en) | 1994-04-08 | 1995-03-06 | Methods of using iron chelating compounds to reduce free radical damage in mammals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2186867A1 CA2186867A1 (en) | 1995-10-19 |
| CA2186867C true CA2186867C (en) | 2000-12-12 |
Family
ID=22842898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002186867A Expired - Fee Related CA2186867C (en) | 1994-04-08 | 1995-03-06 | Methods of using iron chelating compounds to reduce free radical damage in mammals |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0754039A4 (en) |
| JP (1) | JP2001508755A (en) |
| CA (1) | CA2186867C (en) |
| WO (1) | WO1995027485A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2746015B1 (en) * | 1996-03-18 | 1998-04-24 | USE OF OCTOPIROX AS A DEPIGMENTANT AGENT | |
| US5922761A (en) * | 1996-09-06 | 1999-07-13 | Medinox, Inc. | Methods for in vivo reduction of iron levels and compositions useful therefor |
| TWI234467B (en) | 1997-06-04 | 2005-06-21 | Univ Michigan | Composition for inhibiting photoaging of skin |
| EP1013272A1 (en) * | 1998-12-23 | 2000-06-28 | Biomedical Primate Research Centre (BPRC) | Manipulation of the activity of a nitric oxide radical production pathway for the treatment of diseases associated with the presence of oxygen free radicals |
| NL1012825C2 (en) * | 1999-08-13 | 2001-02-23 | Faculteit Geneeskunde Universi | Pharmaceutical for the treatment of viral infections, in particular of the human immunodeficiency virus (HIV). |
| JP2003528031A (en) * | 1999-08-24 | 2003-09-24 | ザ、プロクター、エンド、ギャンブル、カンパニー | Method for lightening keratin tissue by topical application of oxime compound-containing composition |
| ITMI20022447A1 (en) * | 2002-11-19 | 2004-05-20 | Carlo Ghisalberti | USE OF PYRIDINONS IN THE TREATMENT OF CAPILLARY PURPURE AND RELATED SKIN DISEASES. |
| WO2005055931A2 (en) * | 2003-12-03 | 2005-06-23 | University Of Medicine And Dentistry Of New Jersey | Method of preventing survival of retrovirally cells and of inhibiting formation of infectious retroviruses |
| CA2627529A1 (en) | 2007-03-28 | 2008-09-28 | Apotex Technologies Inc. | Fluorinated derivatives of deferiprone |
| ES2539414T3 (en) * | 2008-04-25 | 2015-06-30 | Apotex Technologies Inc. | Liquid formulation for deferiprone with appetizing flavor |
| SG177462A1 (en) | 2009-07-03 | 2012-02-28 | Apotex Technologies Inc | Fluorinated derivatives of 3-hydroxypyridin-4-ones |
| AU2017307566B2 (en) * | 2016-08-05 | 2023-06-15 | Abfero Pharmaceuticals, Inc. | Dosing regimens for treating metal-mediated conditions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0496434B1 (en) * | 1987-10-22 | 1999-02-03 | The Procter & Gamble Company | Photoprotection compositions comprising chelating agents |
| AU662101B2 (en) * | 1990-04-26 | 1995-08-24 | Procter & Gamble Company, The | Chelator compositions comprising oxime compounds |
| AU1672692A (en) * | 1991-03-20 | 1992-10-21 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | The use of hydroxamic acid derivatives to inhibit viral replication |
-
1995
- 1995-03-06 WO PCT/US1995/002872 patent/WO1995027485A1/en not_active Application Discontinuation
- 1995-03-06 JP JP52632995A patent/JP2001508755A/en active Pending
- 1995-03-06 CA CA002186867A patent/CA2186867C/en not_active Expired - Fee Related
- 1995-03-06 EP EP95912791A patent/EP0754039A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995027485A1 (en) | 1995-10-19 |
| EP0754039A4 (en) | 2002-07-17 |
| EP0754039A1 (en) | 1997-01-22 |
| CA2186867A1 (en) | 1995-10-19 |
| JP2001508755A (en) | 2001-07-03 |
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