U.S. patent number RE38,386 [Application Number 09/973,331] was granted by the patent office on 2004-01-13 for retardation of metalloproteinase incidental to hiv and/or aids.
Invention is credited to Charles L. Berman.
United States Patent |
RE38,386 |
Berman |
January 13, 2004 |
Retardation of metalloproteinase incidental to HIV and/or AIDS
Abstract
The instant invention provides a product of manufacture for
retarding the biochemical formation of metalloproteinase, including
gelatinase, elastase, collaginase, and the like, within the tissues
of the body of a patient who has been inflicted with the HIV virus
and/or the HIV virus which has advance to the AIDS virus, through
the administration of an effective amount of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) analog, its salts, cojugates and/or
derivatives, and combinations thereof.
Inventors: |
Berman; Charles L. (New York,
NY) |
Family
ID: |
29782738 |
Appl.
No.: |
09/973,331 |
Filed: |
October 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
848290 |
Apr 29, 1997 |
06063775 |
May 16, 2000 |
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Current U.S.
Class: |
514/152 |
Current CPC
Class: |
A61K
31/65 (20130101) |
Current International
Class: |
A61K
31/65 (20060101); A61K 031/65 () |
Field of
Search: |
;514/152 |
Other References
Lemaitre, et al., 112 CA 191459, 1990. .
Wondrok, et al., 108 CA 179643, 1988. .
Take, et al., 110 CA 147191, 1989..
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Primary Examiner: Criares; Theodore J.
Attorney, Agent or Firm: Feldman; Stephen E.
Claims
I claim:
1. A method for healing HIV viral infections, or AIDS comprising
administering to patients in need of such treatment an
anti-retroviral amount of non-antimicrobial, non-antibiotic,
non-antibacterial chemically modified tetracycline (CMT)
analogs.
2. The method of claim 1, wherein the chemically modified
tetracycline (CMT) is selected from the group consisting of:
4-dedimethylaliiinotetracycline,
4-dedimtntnhylamino-oxytetracycline,
4-dedimethylamino-7-chlortetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
5a,6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-alpha-dcoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-dernethyl-6-deoxy-4-dedimelhylaminotetracycline,
4-dedimethylamino-11-hydroxy-12a-deoxytetracyclins,
12a-deoxy-4-deoxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminodoxycycline,
12a,4a-anhydro-4-dedimethylaminotetracycline, minocycline-CMT,
7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
6a-benzylthiomethylenetetracycline, the 2-nitrilo analogs of
tetracycline (tetracyclinonitrile), the mono-N-alkylated amide of
tetracycline, 6-fluoro-6-demethyltetracycline,
11a-chlortetracycline, tetracycline pyrazole,
12a-deoxytetracycline, 4-dedimethylamino-5-oxytetracycline,
5a,6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
12a,4a-anhydro-4-dedimethylaminotetracycline, tetracyclonitrile,
7-chloro-4-dedimethylaminotetracycline,
12a-deoxy-4-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-7-chlorotetracycline,
4-dedimethylamino-7-dedimethylaminotetracycline, the 2-nitrilo
analogs of tetracycline, 4-dedimethylamino 12a-deoyotetracycline,
tetracyclines altered at the 2-carbon position to produce a
nitrile, 4-dedimethylamino-7-chlorotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
tetracyclonitrile, 6-alpha-benzylthiomethyltetracycline, the
2-nitrilo analog of tetracycline, 11-alpha-chlorotetracycline,
7-chlortetracycline, 5 hydroxytetracycline,
6-demethyl-7-chlortetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
6-alpha-benzylthiomethylenetetracycline, a nitrile analog of
tetracycline, a mono-N-alkylated amide of tetracycline,
2-acetyl-8-hydroxy-1-tetracycline, 6-demethyl-6-deoxytetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
2-acetyl-8-hydroxyl-1-tetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
5a,6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
6-deoxy-8-demethyl-4-dedimethylaminotetracycline,
6a-deoxy-5-hydroxy-4-dedimethylaminotetracycline, tetracyclines
altered at the 2-carbon position to produce a nitrile, pyrazole
derivative of tetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
11-apha-chlortetracycline, 4-dedimethylamino-7-chlortetracycline,
4-de(dimethylamino)-tetracycline,
4-de(dimethylamino)-5-oxytetracycline,
4-de(dimethylamino)-7-chlortetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
6-o-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-alpha-obenzylthiomethylenetetracycline,
4-de(dimethylamino)-5-oxytetracycline,
4-de(dimethylamino)-7-chlortetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
4-de(dimethylamino)-tetracycline,
4-de(dimethylamino)-7-chlortetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline.
dedimethylaminotetracycline
6-alpha-benzyl-thiomethylenetetracycline,
11-alpha-chlortetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
6-fluoro-demethyltetracycline, and the salts, conjugates,
derivatives and combinations thereof.
3. The method of claim 1, wherein said analog comprises a form
suitable for oral administion.
4. The method of claim 2, wherein said analog comprises a form
suitable for topical application.
5. The method of claim 1, wherein said analog comprises a form
suitable for administion by way of an injection or intravenous
perfusion.
6. The method of claim 1, wherein said analog comprises an amount
suitable for providing a dosage of from about 0.1 mg/kg/day to
about 100 mg/kg/day.
7. The method of claim 6, wherein said analog comprises an amount
suitable for providing a dosage of from about 10 mg per kg per day
to about 50 mg per kg per day.
8. The method of claim 7, wherein said analog comprises an amount
suitable for providing a dosage of from about 20 mg per kg per day
to about 25 mg per kg per day..Iadd.
9. A method for treating the biochemical formation of materials
incidental to HIV or AIDS or which promote the advancement of HIV
or AIDS or which promote the advancement of AIDS and other
opportunistic diseases to which a patient might become ill
comprising administering to patients in need of such treatment an
anti-retroviral amount of non-antimicrobial, non-antibiotic,
non-antibacterial chemically modified tetracycline (CMT)
analogs..Iaddend..Iadd.
10. The method of claim 9 wherein the chemically modified
tetracycline (CMT) is selected from the group consisting of:
4-dedimethylaliinotetracycline, 4-dedimethylamino-oxytetracycline,
4-dedimethylamino-7-chlorotetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
5-alpha-6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-dimethyl-6-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-11-hydroxy-12-alpha-deoxytetracycline,
12-alpha-deoxy-4deoxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
12-alpha,4alpha-anhydro-4-dedimethylaminotetracycline,
minocycline-CMT,
7-dimethylamino-6-dimethyl-6-deoxy-4-dedimethylaminotetracycline,
6-alpha-benzylthiomethylenetetracycline, the 2-nitrilo analogs of
tetracycline (tetracyclinonitrile), the mono-N-alkylated wide of
tetracycline, 6-fluoro-6-demethyltetracycline,
11alpha-chlorotetracycline, tetracycline pyrazole,
12-alpha-deoxytetracycline, 4-dedimethylamino-5-oxytetracycline,
5-alpha, 6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
12-alpha, 4alpha-anhydro-4-dedimethylaminotetracycline,
tetracyclonitrile, 7-chloro-4-dedimethylaminotetracycline,
12-alpha-4-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-7-chlorotetracycline,
4-dedimethylamino-7-dedimethylaminotetracycline, the 2-nitrilo
analogs of tetracycline,
4-dedimethylamino-12alpha-deoxyotetracycline, tetracyclines altered
at the 2-carbon position to produce a nitrile,
4-dedimethylamino-7-chlorotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
tetracyclonitrile, 6-alpha-benzylthiomethyltetracycline, the
2-nitrilo analog of tetracycline, 11-alpha-chlorotetracycline,
7-chlortetracycline, 5-hydroxytetracycline,
6-demethyl-7-chlorotetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
6-alpha-benzylthiomethylenetetracycline, a nitrile analog of
tetracycline, a mono-N-alkylated amide of tetracycline,
2-acetyl-8-hydroxy-1-tetracycline, 6-demethyl-6-deoxytetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
2-acetyl-8-hydroxyl-1-tetracycline,
4-hydroxy-4-dedimethylaminotetracycline, 5-alpha,
6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
6-deoxy-8-demethyl-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
tetracyclines altered at the 2-carbon position to produce a
nitrile, pyrazole derivative of tetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
11-alpha-chlorotetracycline,
4-dedimethylamino-7-chlorotetracycline,
4-de(dimethylamino)-tetracycline, 4-de(dimethyl)-5-oxytetracycline,
4-de(dimethylamino)-7-chlorotetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-alpha-obenzylthiomethylenetetracycline,
4-de(dimethylamino)-5-oxytetracycline,
4-de(dimethylamino)-7-chlorotetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
4-de(dimethylamino)-tetracycline,
4-de(dimethylamino)-7-cholorotetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
dedimethylaminotetracycline,
6-alpha-benzyl-thiomethylenetetracycline,
11-alpha-chlorotetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
6-fluoro-demethyltetracycline,
and the salts, conjugates, derivatives and combinations
thereof..Iaddend..Iadd.
11. The method of claim 9 wherein said analog comprises a form
suitable for oral administration..Iaddend..Iadd.
12. The method of claim 10 wherein said analog comprises a form
suitable for topical application..Iaddend..Iadd.
13. The method of claim 9 wherein said analog comprises a form
suitable for administration by way of an injection or intravenous
perfusion..Iaddend..Iadd.
14. The method of claim 9 wherein said analog comprises an amount
suitable for providing a dosage of from about 0.1 mg/kg/day to
about 100 mg/kg/day..Iaddend..Iadd.
15. The method of claim 14 wherein said analog comprises an amount
suitable for providing a dosage of from about 10 mg per kg per day
to about 50 mg per kg per day..Iaddend..Iadd.
16. The method of claim 15 wherein said analog comprises an amount
suitable for providing a dosage of from about 20 mg per kg per day
to about 25 mg per kg per day..Iaddend.
Description
BACKGROUND OF THE INVENTION
.Iadd.This is an application for the Reissue of U.S. Pat. No.
6,063,775, published May 16, 2000..Iaddend.
The instant invention broadly relates to retardation of the
biochemical formation of materials incidental to HIV and/or AIDS,
which promotethe advancement of HIV to AIDS; which promote the
advancement of AIDS and other opportunistic diseases to which a
patient could inevitably succumb. Specifically, the invention
retards the biochemical formation of species of metalloproteinase
which are formed as a product of conditions such HIV and/or AIDS.
Still more specifically, the invention provides for the
administration of an effective amount of a drug which retards the
biochemical formation of metalloproteinase species including
coliagenase and gelatinase, incidental to the conditions of HIV
and/or AIDS. Still even more specifically, the invention provides
for the administration of an effective amount of a chemically
modified tetracycline (CMT) analog which retards the biochemical
formation of metalloproteinase species including gelatinase,
collagenase and elastase, incidental to the conditions of HIV
and/or AIDS.
Tetracyclines are useful as broad spectrum antibiotics because they
have the ability to retard protein synthesis in a wide variety of
bacteria. As disclosed in the above-identified pending patent
applications, it has also been discovered that tetracyclines,
antibiotic tetracyclines and non-antibiotic tetracyclines, have the
ability to retard collagen-destructive enzymes, such as
collagenase, responsible for the break-down of connective tissue in
a number of diseases, such as periodontal disease, corneal ulcers
and rheumatoid arthritis.
The use of tetracycline antibiotics, while effective, may lead to
undesirable side effects. For example, the long term administration
of antibiotic tetracyclines may reduce or eliminate healthy flora,
such as intestinal flora, and may lead to the production of
antibiotic resistant organisms or the overgrowth of yeast and
fungi.
Tetracycline may be a chemically modified tetracycline (CMT) or any
tetracycline administered to a mammal in a dose that is effectively
non-antimicrobial in the mammal. Preferably, the tetracycline is
chemically modified so as to reduce its antimicrobial properties.
Methods for reducing the antimicrobial properties of a tetracycline
are disclosed in "The Chemistry of the Tetracyclines", Chapter 6,
Mitscher, (1978), at page 211. As pointed out by Mitscher,
modification a positions 1, 2, 3, 4, 10 and 12a lead to loss of
bioactivity. The use of such modified tetracyclines is preferred in
the present invention, since they can be used to higher levels than
antimicrobial tetracyclines with fewer side effects.
The tetracycline molecule is amenable to substantial modification
without losing its antibiotic properties. Examples of modifications
that may and may not be made to the basic tetracycline structure
have been reviewed by Mitscher in the Chemistry of Tetracyclines,
Chapter 6. According to Mitscher, the substituents at positions 5-9
of the tetracycline ring, may be modified without complete loss of
antibiotic properties. Changes to the basic ring system or
replacement of the substituents at positions 1-4 and 10-12,
however, generally lead to synthetic tetracyclines having
substantially less or effectively no antibacterial activity. For
example, 4-dedimethylaminotetracycline is commonly considered to be
a non-antibacterial tetracycline.
U.S. Pat. No. 5,532,227 to Golub, et al teaches a method for
treating mammals suffering from excessive extracellular protein
glycosylation which is associated with diabetes, scleroderma and
progeria by administering to the mammal a tetracycline which
effectively inhibits excessive protein glycosylation.
Inhibition of metalloproteinase activity with various species of
non-antimicrobial tetracycline, is well known in the prior art:
U.S. Pat. No. 5,321,017 to Golub, et al teaches a method for
treating mammals suffering from rheumatoid arthritis and other
tissue-destructive (chronic inflammatory or other) conditions
associated with excess metalloproteinase activity which comprises:
administering to the mammal an amount of a tetracycline that is
effectively anti-metalloproteinase, but that is not effectively
antimicrobial, and an amount of non-steroidal anti-inflammatory
agent which, when combined with the effectively
anti-metalloproteinase amount of tetracycline, results in a
significant reduction of tissue destruction and/or bone loss.
U.S. Pat. No. 5,045,538 to Schneider, et al teaches a method for
treating mammals suffering from skeletal muscle wasting and/or
intracellular protein degradation of skeletal muscle systems by
administering to the mammal an amount of tetracycline which results
in a significant reduction of the muscle wasting and protein
degradation. In addition, there is also disclosed a method of
increasing the protein content of skeletal muscle systems of
mammals by administration of tetracyclines. The tetracyclines
useful in the above methods are both antimicrobial and
non-antimicrobial. In a preferred embodiment, the method of
treatment utilizes a non-antimicrobial tetracycline such as
dedimethylaminotetracycline.
U.S. Pat. No. 5,324,634 to Zucker teaches diagnostic agents and
methods for detecting the presence of metastatic activity in
biological samples such as plasma. The agent and method preferably
immunologically detect matrix metalloproteinases in complexed form
with endogenous inhibitors of MMP's A kit for detecting the
metalloproteinases is also disclosed.
U.S. Pat. No. 5,260,059 to Acott, et al relates to a method of
treating ocular disease by modulating cellular secretion of a
family of matrix metalloproteinases and their inhibitor.
Specifically, differential stimulation of secretion of interstitial
collagenase, gelatinase or type IV collaginase, stromelysin or
proteoglycanase, and their tissue glycoprotein inhibitor is
employed to treat open-angle glaucoma, retinal degeneration and
detachment, ocular neovascularization and diabetic retinopathy.
U.S. Pat. No. 5,595,885 to Stetler-Stevenson, et al teaches an
isolated protein of 21,600 Da which binds to both latent and
activated type IV collagenase with high affinity at 1:1 molar
stoichiometry, thereby abolishing enzyme activity. The protein is
purified by affinity chromatography on solid phase
metalloproteinase, or solid phase metalloproteinase substrates
which bind the enzyme-inhibitor complex. The complete primary
structure of this protein (initially called CSC-21K), as determined
by sequencing overlapping peptides spanning the entire protein,
reveals homology with a protein called TIMP, Tissue Inhibitor of
Metalloproteinases. In addition, a cDNA for this novel inhibitor,
now designated TIMP-2, was cloned from a melanoma cell and its
sequence was compared with that of human TIMP-1. Northern blots of
melanoma cell mRNA showed two distinct transcripts of 0.9 kb and
3.5 kb which are down-regulated by transforming growth factor-beta,
and are unchanged by phorbol ester treatment. The inhibitor of the
present invention may be used for treatment of pathologic
conditions resulting from inappropriate degradation of
extracellular matrix molecules by matrix metalloproteinases, such
as metastatic neoplasia, myocardial infarction, and arthritis.
Therapeutic treatments using this inhibitor may include
formulations for inhalation and inclusion complexes adapted for
buccal or sublingual administration, or administration of a
recombinant DNA molecule which expresses a DNA segment that encodes
the matrix metalloproteinase inhibitor of this invention.
U.S. Pat. No. 5,308,839 to Golub, et al teaches a method for
treating mammals suffering from rheumatoid arthritis, other
tissue-destructive conditions, and chronic inflammatory or other
conditions associated with excess metalloproteinase activity which
comprises: administering to the mammal an amount of a tetracycline
that is effectively anti-metalloproteinase, but that is not
effectively antimicrobial, and an amount of a non-steroidal
anti-inflammatory agent which, when combined with the effectively
anti-metalloproteinase amount of tetracycline, results in a
significant reduction of tissue destruction and/or bone loss.
U.S. Pat. No. 5,532,227 to Golub, et al teaches a method for
treating mammals suffering from excessive extracellular protein
glycosylation which is associated with diabetes, scleroderma and
progeria by administering to the mammal a tetracycline which
effectively inhibits excessive protein clycosylation.
U.S. Pat. No. 5,308,839 to Golub, et al teaches a method for
treating mammals suffering from rheumatoid arthritis, other
tissue-destructive conditions, and chronic inflammatory or other
conditions associated with excess metalloproteinase activity
comprising administering to the mammal an amount of a tetracycline
that is effectively anti-metalloproteinase, but that is not
effectively antimicrobial, and an amount of a non-steroidal
anti-inflammatory agent which, when combined with the effectively
anti-metalloproteinase amount of tetracycline, results in a
significant reduction of tissue destruction and/or bone loss.
U.S. Pat. No. 5,223,248 to McNamara et al teaches a method of
inhibiting plaque formation on mammalian tooth surfaces. The method
includes contacting the tooth surfaces with an effective amount of
a non-antibacterial tetracycline. In a preferred embodiment, such
tetracyclines are included in various oral hygiene products such as
dentifrices, lozenges, chewing gums and the like to contact the
tooth surfaces and prevent plaque accumulation thereon.
U.S. Pat. No. 5,045,538 in Schneider, et al teaches a method for
treating mammals suffering from skeletal muscle wasting and/or
intercellular protein degradation of skeletal muscle systems by
administering to the mammal an amount of tetracycline which results
in a significant reduction of the muscle wasting and protein
degradation. In addition, there is also disclosed a method of
increasing the protein content of skeletal muscle systems of
mammals by administration of tetracyclines. The tetracyclines
useful in the above methods are both antimicrobial and
non-antimicrobial. In a preferred embodiment, the method of
treatment utilizes a non-antimicrobial tetracycline such as
dedimethylaminotetracycline (CMT).
Generally, tetracyclines, as has now been discovered, whether
possessing antimicrobial or antibiotic activity or not, all possess
anti-collagen-destructive enzyme activity or anti-collagenase
activity. They are known to inhibit the activity of collagen
destructive enzymes such as mammalian collagenase, macrophage
elastase and bacterial collagenase; Golub et al., J. Periodont.
Res. 20, 12-23 (1985), Golub et al., Crit. Revs. Oral Biol. Med. 2,
297-332 (1991). Collagen is a major component of connective tissue
matrices such as those in bone, synovium, eye, skin, tendons and
gingiva. Collagenase, which is naturally produced by only a few
types of bacteria and in a number of tissues and cells in mammals,
degrades collagen.
This anti-collagenase activity appears to be attributable to the
unique structure of tetracyclines, i.e. the special four
carbocyclic ring structure which is characteristic of and possessed
by the tetracyclines.
As an observation, it is believed that the carbonyl moieties in the
carbocyclic ring nucleus of the tetracycline are important to the
anti-collagenolytic activity of these compounds because they
chelate the metal ions calcium and zinc. This is an important
property since the collagenolytic enzymes mentioned are metal
dependent.
It is known that antimicrobial and non-antimicrobial tetracyclines
can bind to metal ions such as calcium.
Tetracyclines are also known retarders of collagen destructive
enzymes such as mammalian collagenase, a calcium dependent
zinc-metalloproteinase. Collagen is a major component of connective
tissue matrices such as those in the bone, synovium, eye, skin,
tendons and gingiva but not tooth surface enamel.
In the case of mammalian collagenase, degradation of collagen is a
natural part of the normal growth-degradation-regeneration process
that occurs in connective tissue. The production of collagenase,
however, may become excessive. Such excessive collagenase
production often results in the pathologic and debilitating
destruction of connective tissue.
It is well known that metalloproteinases which include collogenases
are produced as byproducts of HIV and AIDS.
It is known that HIV-infected monocytes form highly invasive
network on basement membrane matrix and secrete high levels of
92-kd metalloproteinase (MMP-9), an enzyme that degrades basement
membrane proteins. In a study, using matrigel as a model basement
membrane system, it was demonstrated that treatment of human
immunodeficiency virus HIV-infected monocytes with interferon-gamma
at 50 U/ml inhibited the ability of infected monocytes to form an
invasive network on matrigel and their invasion through the
matrigel matrix. These effects were associated with a significant
reduction in the levels of MMP-9 produced by HIV-infected monocytes
treated with interferon-gamma 1 day prior to infection with HIV as
compared with that of untreated HIV-infected monocytes. Monocytes
treated with interferon-gamma 1 day after HIV infection showed the
presence of integrated HIV sequences; however, the levels of MMP-9
were substantially lower than those produced by monocytes
inoculated with live HIV, heat-inactivated HIV, or even the control
uninfected monocytes. Exposure of monocytes to heat-inactivated HIV
did not result in increased invasiveness or high MMP-9 production,
suggesting that regulation of metalloproteinase by monocytes was
independent of CD4-gp 120 interactions and required active virus
infection. Furthermore, addition of interferon-gamma to monocytes
on day 10 after infection inhibited MMP-9 production by more than
threefold with no significant reduction of virus replication. It
was concluded that these results indicate that the mechanism of
interferon-gamma-induced down-regulation of MMP-9 levels and
reduced monocyte invasiveness may be mediated by a mechanism
independent of antiviral activity of IFN-gamma in monocytes.
Down-regulation of MMP-9 in HIV-infected monocytes by
interferon-gamma may play an important role in the control of HIV
pathogenesis.
It has further been reported that monocytes are susceptible to HIV
infection and to activation by a regulatory gene product of the HIV
genome, HIV-Tat. Recently, it was demonstrated that treatment with
HIV-Tat up-regulates monocyte adhesion to the endothelium and
increases metalloproteinase production in the present study, the
ability of the HIV-Tat protein to alter the migratory and invasive
behavior of monocytes were examined. Monocytes pre-treated for 24
hours with 10 ng/ml HIV-Tat exhibited enhanced migratory behavior
compared with untreated monocytes in chemotaxis assays, both in the
absence of a chemoattractant as well as in response to FMLP in
addition, HIV-Tat itself induced the migration of both untreated
and HIV-Tat pretreated monocytes. Checkerboard analysis showed that
monocytes migrated in response to an HIV-Tat concentration
gradient, thus confirming the chemotactic characteristics of the
HIV-Tat protein. Pretreatment of monocytes with 10 ng/ml HIV-Tat
for 24 h also increased their ability to invade reconstituted
extracellular membrane (Matrigel)-coated filters by 5-fold in the
absence of chemoattractant. The presence of FMLP or HIV-Tat further
enhanced invasion by both untreated and HIV-Tat-pretreated
monocytes by more than 10-fold. Monocyte invasion was partially
inhibited by the inclusion of anti-beta integrin Ab or tissue
inhibitor of metalloproteinase (TIMP). Thus, for the first time,
evidence was provided that HIV-Tat can enhance the chemotactic and
invasive behaviors of monocytes and propose an active role for
HIV-Tat in the recruitment of monocytes into extravascular tissues,
a process which may contribute to the destruction of tissues and
cellular architecture often seen in patients with acquired
immunodeficiency syndrome.
It was further demonstrated HIV infection of monocytes resulted in
twofold elevation of adhesion molecule LFA-1 (both alpha L/CD11a
and beta 2/CD18 subunits) and LFA-3 (CD58), with no apparent
increase in LFA-2 (CD2) or various beta 1-integrins. Homotypic
aggregation of monocytes was evident 2 hours after exposure to
virus and was inhibited by mAbs to both the alpha L- and beta
2-subunits of LFA-1. HIV-infected monocytes also showed a marked
increase in adherence to brain capillary endothelial cell
monolayers derived from brain, lung, and skin. This adherence was
inhibited by mAb to either LFA-1 subunit and by mAb to the
counter-receptor intercellular adhesion molecule-1. Cocultivation
of HIV-infected monocytes with endothelial cells increased
permeability of endothelial cell monolayers to 125I albumin in
transwell assay systems. The increased endothelial permeability
induced by HIV-infected monocytes was associated with a substantial
disruption of the endothelial cell monolayer. Morphologic
disruption was not a direct toxic effect on endothelial cells, but
appeared to be secondary to changes in endothelial cell-cell to
cell-matrix interactions. Northern blot analysis showed increased
expression of gelatinase B (92-kDa gelatinase), tissue inhibitor of
metalloproteinase TIMP-1, and TIMP-2 in the-infected monocytes.
Consistent with these Northern analyses, secretion of gelatinase
activity in culture fluids of HIV-infected monocytes was also
increased and was dependent on the staage of virus replication.
Incubation of HIV-infected monocytes with the proteinase inhibitors
TIMP-1 and TIMP-2 inhibited the increased permeability of
endothelial cell monolayers to 125I albumin. These results suggest
possible mechanisms for extravasation of HIV-infected monocytes
through vascular endothelium into tissue in early stages of HIV
disease.
SUMMARY OF THE INVENTION
The instant invention in large part solves the problems of the
prior and fulfills a long felt need by providing a drug in a dosage
sufficient for effectively retarding the biochemical formation of
metalloproteinase within the bodies of patients inflicted with HIV
and/or AIDS viruses.
Here are the more important features of the invention as broadly
outlined, in order that the detailed description that follows may
be better understood; and in order for the present contribution to
the art may be better appreciated. There are additional features of
the invention that will be described hereinafter and which form the
subject matter of the appended claims. Those of ordinary skill in
the art will appreciate that the conception upon which this
disclosure is based may readily be utilized as a basis for the
designing of other structures, methods and systems for carrying out
the several purposes of the instant invention. It is important,
therefore, that the claims be regarded as including such equivalent
constructions insofar as they do not depart from the spirit and
scope of the instant invention.
Further, the purpose of the instant abstract is to enable the U.S.
Patent and Trademark office and the public generally, and
especially the scientists, engineers and practitioners in the art
who are not familiar with parent or legal terms or phraseology, to
determine quickly from a cursory inspection of it, the technical
disclosure of the patent application. The abstract is neither
intended to define the invention of the instant patent application,
which is measured by the claims, nor is it intended in any manner
to be limiting as to the scope of the instant invention.
The instant invention in large part solves the problems of the
prior and fulfills a long felt need by providing a treatment for a
patient with HIV and/or AIDS.
The instant invention provides a drug in a dosage sufficient for
treating a patient who has been inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, drug in the
body of the patient.
The instant invention provides a drug to a dosage sufficient for
treating a patient who has been inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) analog in the body of the patient.
The instant invention provides a drug in a dosage sufficient for
treating a patient who has been inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) sufficient to retard the biochemical
formation of metalloproteinase within the body of the patient.
The instant invention provides a drug in a dosage sufficient for
treating a patient who is inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) analog effective to retard the
biochemical formation of metalloproteinase within the body of the
patient.
The instant invention provides a drug in a dosage sufficient for
treating a patient who is inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a chemically modified
tetracycline (CMT) analog sufficient to retard the biochemical
formation of gelatinase, elastase, collaginase, and the like,
within the tissues of the body of the patient.
The instant invention provides a drug to a dosage sufficient for
treating a patient who is inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) analog sufficient to retard the
biochemical formation of gelatinase, elastase, collaginase, and the
like, within the tissues of the body of the patient.
The instant invention provides a drug in a dosage sufficient for
treating a patient who is inflicted with the HIV and/or AIDS
viruses, with an effective dosage of a
non-antimicrobial/non-antibiotic/non-antibacterial, chemically
modified tetracycline (CMT) analog sufficient to retard the
biochemical formation of gelatinase, elastase, collaginase, and the
like, within the tissues of the body of the patient.
Other objects, features, and advantages of the instant invention,
in its details of construction and arrangement of parts, will be
seen from the above, from the following description of the
preferred embodiment when considered in light of the appended
claims.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides a drug in a dosage sufficient for
retarding endrogenous metalloproteinase and at least its species of
elastase, collagenase and gelatinase, characterized by that
occurring in the body of a patient who has become inflicted with
the HIV virus and/or treating a patient who has become infected
with the HIV virus which has progressed to AIDS. The instant
invention contemplates administering to the patient an effective
dosage of an analog of chemically modified tetracycline (CMT)
selected from the group consisting of:
4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline,
4-dedimethylamino-7-chlortetracycline,
4-hydroxy-4-dedimethylaminotetracycline, 5a,
6-anhydro-4hydroxy-4-dedimethylaminotetracycline,
6alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
4-dedimethyaminno-11-hydroxy-12a-deoxytetracycine,
12a-deoxy-4-deoxy-4-dedimethylaminotetracycline,
6alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
12a,4a-anhydro-4-dedimethylaminotetracycline, minocycline-CMT,
7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
6a-benzylthiomethylenetetracycline, the 2-nitrilo analogs of
tetracycline (tetracyclinonitrile), the mono-N-alkylated amide of
tetracycline; 6fluoro-6-demethyltetracycline,
11a-chloroletracycline, tetracycline pyrazole,
12a-deoxytetracycline and its derivatives,
4-dedimethylamino-5oxytetracycline, 5a,
6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
12a,4a-anhydro-4-dedimethylaminotetracycline, tetracyclinonitrile,
7-chloro-4-dedimethylaminotetracycline,
12a-deoxy-4-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-7chlorotetracycline,
4-dedimethylamino-7-dimethylamninoletracycline, the 2-nitrilo
analogs of tetracycline, 4-dedimethylamino-12a-deoxytetracycline
and its derivatives, tetracyclines altered at the 2 carbon position
to produce a nitrile, 4-de-dimethylamino-7-chlorotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
tetracyclinotrile, 6-alpha-benzylthiomethylenetetracycline, the
2-nitrilo analog of tetracycline, 11 alpha-chlorotetracycline,
7-chlorotetracycline, 5-hydroxytetracycline,
6-demethyl-7-chlorotetracycline,
6-demethyl,-6-deoxy-5-hydroxy-6-methylenetetracycline,
6-alpha-benzylthiomethylenetetracycline, a nitrite analog of
tetracycline, a mono-N-alkylated amide of tetracycline,
11-alpha-chlorotetracycline, 2-acetyl-8-hydroxy-1-tetracycline,
6-demethyl-6-deoxytetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline,
2-acetyl-8-hydroxyl-1-tetracycline,
4-hydroxy-4dedimethylaminotetracycline,
5a,6-anhydro-4-hydroxy-4dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
6-deoxy-6-demethyl-4-dedimethylaminotetracycline,
6a-deoxy-5-hydroxy-4-dedimethylaminotetracycline, Tetracyclines
altered at the 2-carbon position to produce a nitrile, pyrazole
derivative of tetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline, 11
alpha-chlortetracycline, 4-dedimethylamino-7-chlortetracycline,
4-de(dimethylamino)-tetracycline,
4-de(dimethylamino)-5-oxytetracycline,
4-de(dimethylamino)-7-chlortetracycline, 11 alpha
a-chlortetracycline,
7-chloro-6-demethyl-4-dedimethylaminotetracycline,
6-o-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-alpha-obenzylthiomethylenetetracycline,
4-de(dimethylamino-5-oxytetracycline,
4-de(dimethylamino)-7-chlorotetracycline,
4-hydroxy-4-dedimethylaminotetracycline,
6-alpha-deoxy-5-hydroxy-4-dedimethylamino-tetracycline,
4-de(dimethylamino) tetracycline, 4-de(dimethylamino)-7
chlorotetracycline,
7-chloro-6-demethyl-4-dedimethylamino-tetracycline,
dedimethylaminotetracycline, a 6-alpha-benzylthiomethylene
tetracycline, 6-alpha benzylthiomethylene tetracycline, an
11-alpha-chlortetracycline,
6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline, a 6
alpha-benzylthiomethylene tetracycline, and a 6 Fluoro
demethyltetracycline, their salts, cojugates and/or derivatives,
and combinations thereof.
The analog of the instant invention may be administered orally, or
systemically, or by way of an injection or intravenously. It may
also be administered topically in the form of an ointment, or other
storable topical delivery system, i.e., applying it with a highly
adsorptive material such as DMSO.
Dosages of the analog can range in amounts of from about 0.1
mg/kg/day to about 50 mg/kg/day, more preferably in amounts of from
about 10.0 mg/kg/day to about 30 mg/kg/day; and most preferably
amounts of about 20.0 mg/kg/day to about 25.0 mg/kg/day.
The preferred pharmaceutical composition for use in the present
invention comprises a combination of the chemically modified
tetracycline (CMT) and the anti-inflammatory agent in a suitable
pharmaceutical carrier. The means of delivery of the pharmaceutical
carrier with active may be in the form of a capsule, compressed
tablet, pill, solution or suspension suitable for oral
administration to a mammal. Other means of delivery include a gel
for topical application for corneal ulcers, periodontal disease,
etc. It is contemplated that carriers be included which are
suitable for administration orally, topically, by injection into a
joint, and by other selected means.
The non-steroidal anti-inflammatory agent may be selected from the
various classes of such compounds. Such classes include, for
example, salicylates such as acetylsalicyclic acid and diflunisal,
acetic acids such as indomethacin, sulindac, tolmetin, diclofenac,
and etodolac; propionic acids such as flurbiprofen, naproxen, and
ketoprofen; fenamates such as meclofenamate; and oxicams such as
piroxicam.
The preferred non-steroidal anti-inflammatory agents include
flurbiprofen, piroxicam, tolmetin sodium, ibuprofen, naproxen and
indomethacin. The preferred non-steroidal anti-inflammatory agents
include flurbiprofen, piroxicam, tolmetin sodium, ibuprofen,
naproxen, indomethacin and tenidap. Tenidap (CP-66,248-2) is
available from Pfizer Central Research (Groton, Conn.).
The non-steroidal anti-inflammatory agent may be selected from the
various classes of such compounds. Such classes include, for
example, salicylates such as acetylsalicyclic acid and diflunisal;
acetic acids such as indomethacin, sulindac, tolmetin, diclofenac,
and etodolac; propionic acids such as flurbiprofen, naproxen,
indomethacin, tolmetin sodium and ketoprofen; fenamates such as
meclofenamate; oxicams such as piroxicam; and oxindoles such as
tenidap.
The amount of the non-steroidal anti-inflammatory agent is an
amount which, when combined with the effectively anti-collagenase
amount of tetracycline, results in a significant reduction of bone
loss in mammals suffering from tissue-destructive conditions
associated with excess metalloproteinase activity. The amount
depends on the particular anti-inflammatory agent used, the mammal
to which the composition is administered, and the amount of the
tetracycline in the composition. Some typical doses for routine
human use include, for example, 20 mg/day for piroxicam, 150 mg/day
for indomethacin, 1600-1800 mg/day for lolmetin, 1000 mg/day for
naproxen, and 3200 mg/day for ibuprofen.
For example, a suitable amount of a CMT such as 4-dedimethylamino
tetracycline is 15 mg/kg. A suitable mount of anti-inflammatory
agent in combination with 30 mg/kg of a CMT such as
4-dedimethylamino tetracycline would be, for example, 1-8 mg/kg
flurbiprofen, 0.3 mg/kg piroxicam and 40 mg/kg ibuprofen. As a
guideline for providing the proper amount of anti-inflammatory
agents for implementing the present invention, a rule of thumb is
to administer an amount which is 20% to 80% of the conventional
anti-inflammatory dose for treating arthritis. Thus, the dosage
could be from as small as 10 mg/person/day for piroxicam, to as
great as 3200 mg/person/day for ibuprofen. In any event, the
practitioner is guided by skill and knowledge in the field and the
present invention includes without limitation dosages which arc
effective to achieve the described phenomenon. For example, the
non-steroidal anti-inflammatory agent my be administered in an
amount of from about 0.3 mg/kg per day to about 3,500 mg per person
per day.
Thus, without undue experimentation, one of ordinary skill in the
art can readily vary the dosage, form and/or method of
administration, with respect to a particularly selected CMT of the
instant invention, so as to provide a product of manufacture for
the effective treatment for a patient inflicted with HIV and/or
AIDS.
Although the invention preferably contemplates treatment of the
tissues of the body of a patient inflicted with the HIV and/or AIDS
viruses, it is equally applicable to the treatment of any disease
which causes the biochemical formation of metalloproteinase and any
of its species, elastase, gelatinase, collagenase, and the like,
within any tissue in the body of a patient.
The term "analog" and its variants as broadly used herein, is meant
to include other related species such as homologs of
tetracycline.
The terms "non-antimicrobial," "non-antibiotic," and
"non-antibacterial," are meant to have equivalent definitions as
used herein.
The term "biochemical" as used herein is intended to refer to
biotechnology.
Although the invention has been described with reference to certain
preferred embodiments, it will be appreciated that many variations
and modifications may be made within the scope of the broad
principles of the invention. Hence, it is intended that the
preferred embodiments and all of such variations and modifications
be included within the scope and spirit of the invention, as
defined by the following claims.
* * * * *