U.S. patent application number 10/614713 was filed with the patent office on 2004-01-08 for methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase.
Invention is credited to Hebert, Rolland F..
Application Number | 20040006045 10/614713 |
Document ID | / |
Family ID | 26916774 |
Filed Date | 2004-01-08 |
United States Patent
Application |
20040006045 |
Kind Code |
A1 |
Hebert, Rolland F. |
January 8, 2004 |
Methods for the treatment or prophylaxis of disease by inhibition
of ornithine decarboxylase
Abstract
Methods to prevent or treat conditions or diseases treatable by
inhibition of ornithine decarboxylase are disclosed.
Inventors: |
Hebert, Rolland F.;
(Seattle, WA) |
Correspondence
Address: |
ROLLAND HEBERT
427 BELLEVUE AVE E. SUITE 301
SEATTLE
WA
98102
US
|
Family ID: |
26916774 |
Appl. No.: |
10/614713 |
Filed: |
July 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10614713 |
Jul 7, 2003 |
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09919692 |
Jul 31, 2001 |
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6630511 |
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60222420 |
Aug 1, 2000 |
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Current U.S.
Class: |
514/55 ;
514/564 |
Current CPC
Class: |
A61Q 7/02 20130101; A61Q
7/00 20130101; A61K 47/61 20170801; A61K 8/44 20130101 |
Class at
Publication: |
514/55 ;
514/564 |
International
Class: |
A61K 031/722; A61K
031/198 |
Claims
I claim:
1. A method for the treatment of a disease or a condition which is
treatable by inhibition of ornithine decarboxylase, which comprises
administration of a therapeutically active or nithine
decarboxylase-inhibiting amount of a salt of
2-difluoromethyl-2,5-diamino- pentanoic acid with chitosan.
2. A method for the prevention of a disease or a condition which is
preventable by inhibition of omithine decarboxylase, which
comprises administration of a therapeutically active omithine
decarboxylase-inhibiting amount of a salt of
2-difluoromethyl-2,5-diamino- pentanoic acid with chitosan.
3. The method as defined by claim 1, wherein a salt of
2-difluoromethyl-2,5-diaminopentanoic acid with chitosan is
administered to treat a disease or condition selected from the
group consisting of cancer, benign prostatic hypertrophy, protozoal
in fections, actinic keratosis, and hirsutism.
4. The method as defined by claim 2, wherein a salt of
2-difluoromethyl-2,5-diaminopentanoic acid with chitosan is
administered to prevent a condition or disease selected from the
group consisting of cancer, benign prostatic hypertrophy, HIV,
prozoal infections, actinic keratosis, and hirsutism.
5. A method wherein a salt of 2-difluoromethyl-2,5-diaminopentanoic
acid with chitosan is administered topically to prevent hair
growth.
Description
CROSS-REFERENCES TO RELATED APPLICATION
[0001] This is a divisional of U.S. patent application Ser. No.
09/919,692 filed on Jul. 31, 2001, the entire disclosure and
contents of which are incorporated by reference.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention relates to methods of treatment or
prevention of disease using salts of
2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with
chitosan.
[0004] 2. Technical Field
[0005] This patent relates to the therapeutic use of salts of
2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with chitosan.
DFMO, in vitro and in vivo, is an inhibitor of omithine
decarboxylase, an enzyme that is involved in polyamine formation in
organisms.
BACKGROUND OF THE INVENTION
[0006] In both eukaryotic and prokaryotic cells, the
decarboxylation of omithine to putrescine, a reaction catalyzed by
omithine decarboxylase (ODC), is the first step in the biosynthesis
of the polyamines known as spermidine and spermine. The polyamines,
which are found in animal tissues and microorganisms, are known to
play an important role in cell growth and proliferation. The onset
of cell growth and proliferation is associated with a marked
increase in ODC activity and an increase in the levels of
putrescine and the polyamines. Although the exact mechanism of the
role of the polyamines in cell growth and proliferation is not
known, it appears that the polyamines may facilitate macromolecular
processes such as DNA, RNA, or protein synthesis. (Tabor H, Tabor C
W, Cohn M S, Hafner E W. Streptomycin resistance produces an
absolute requirement for polyamines for growth on an Escherichia
coli strain unable to synthesize spermidine. J Bacteriolol 1981;
147: 702-4; Mamont P S, Bohelen, P, McCann P P, Bey P, Schuber R,
Tardif C. Alpha-methyl omithine, a potent competitive inhibitor of
omithine decarboxylase, blocks proliferation of rat hepatoma cells
in culture. Proc Natl Acad Sci USA 1976; 73: 1626-30.)
[0007] The association between high levels of the polyamines and
rapid proliferation was discovered more than a quarter of a century
ago. (Bachrach U and Weinstein A. Effect of aliphatic polyamines on
growth and macromolecular syntheses in bacteria. J. Gen.
Microbiol., 60: 159-165 1970.) Subsequent studies showed that
activation of the enzyme ODC was important for carcinogenesis and
subsequent tumor development in animal and tumor models. (Weeks C
E, Harmann A L, Nelson F R, Slaga T J. Alpha
difluoromethylomithine, an irreversible inhibitor of omithine
decarboxylase, inhibits tumor promoter-induced polyamine
accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci
USA 1982; 79:6028-32.)
[0008] It is currently known that increased intracellular polyamine
concentrations are related to human neoplastic conditions. (Verma,
A K Inhibition of tumor promotion by
DL-alpha-difluoromethylomithine, specific irreversible inhibitor of
ornithine decarboxylase. Basic Life Sci., 52:195-204, 1990). A
further example of this relationship between high polyamine
concentrations and neoplasms involves colonic polyps and cancers
compared to surrounding normal colon mucosa. (Hixson, L J, Garewal,
H S, McGee D., Sloan D, Fennerty, M B, Sampliner R E and Gerner E W
Omithine decarboxylase and polyamines in colorectal neoplasia and
adjacent mucosa. Cancer Epidemiol. Biomark. Prev. 2;369-374, 1993;
Rozhin J, Wilson P S, Bull A W, and Nigro, N D. Omithine
decarboxylase activity in the rat and human colon. Cancer Res. 44:
3226-3230, 1984.)
[0009] Other groups have reported that polyamine metabolism was
necessary for carcinogenesis, especially in epithelial tissues. ODC
inhibitors have been found to inhibit or suppress tumor formation
in models of bladder, breast, colon and skin carcinogenesis.
(Verma, A K Inhibition of tumor promotion by
DL-alpha-difluoromethylomithine, specific irreversible inhibitor of
omithine decarboxylase. Basic Life Sci., 52:195-204, 1990; Nigro N
D, Bull A W and Boyd, M E. Inhibition of intestinal carcinogenesis
in rats: effect of difluoromethylomithine for colon cancer
prevention. J. Natl Cancer Inst. 77: 1309-1313, 1986; Thompson H J,
and Ronan Am. Effect of DL-2-difluoromethylomrithine and endocrine
manipulation on the induction of mammary carcinogenesis by
1-methyl-1-nitrosourea. Carcinogenesis (Lond.), 7: 20032006,
1986.)
[0010] It is thought, however, that the mechanism of cancer
prevention by ODC inhibitors such as DFMO may involve more than
just inhibition of cell proliferation. Animal studies show that
DFMO may act at later stages in models of chemical carcinogenesis.
These stages involve the transition of non-invasive tumors to
invasive cancers. (Slaga, T J. Multistage skin carcinogenesis: a
useful model for the study of the chemoprevention of cancer. Acta
Pharmacol. Toxicol., 55 (Suppl. 2): 107-124, 1984.)
[0011] DFMO has been studied and continues to be studied as a
cancer prevention agent, especially in skin, cervical and colon
cancer. (Love R R, Carbone, P P Verma, A K, Gilmore D, Carey P,
Tutsch K D. Pomplun M, and Wilding G. Randomized Phase I
chemoprevention dose-seeking study of
alpha-difluoromethylornithine. J. Natl. Cancer Inst., 85:732-736,
1993; Nishioka K, Melgarejo A B, Lyon R R and Mitchell M F.
Polyamines as biomarkers of cervical intraepithelial neoplasia. J.
Cell. Biochem., 23 (Suppl.): 87-95, 1995; Mitchell M F,
Tortolero-Luna G, Lee J J, Hittelman W N, Lotan R, Wharton J T,
Hong, W K and Nishioka, K. Phase I dose de-escalation trial of
alpha-difluoromethylornithine in patients with grade 3 cervical
intraepithelial neoplasia. Clin. Cancer Res., 4:303-310, 1998;
Meyskens F I, Emerson S S, Pelot D, Meshkinpour H, Shassetz R,
Einspahr J, Alberts D S, and Gerner, E W Dose de-escalation
chemoprevention trial of alphadifluoromethylomithine in patients
with colon polyps. J. Natl. Cancer Inst., 86:1122-1130, 1994.)
[0012] While high doses of DFMO in humans can cause some problems
with hearing (reversible upon discontinuation of DFMO), at the
doses used for chemoprevention of cancer (0.50 g/m2/day) such
concerns have been found to be groundless. (Meyskens F L, Gerner E,
Emerson S, Pelot D, Durbin T, Doyle K and Lagerber W. A randomized
double-blind placebo controlled Phase IIb trial of
difluoromethylornithine for colon cancer prevention. J. Natl.
Cancer Inst., 90: 1212-1218, 1998).
[0013] DFMO has also been found useful in conditions unrelated to
cancer. ODC inhibitors have been associated with control of hair
growth. Studies in mice have suggested that the ODC gene is an
important regulatory gene for the mouse hair follicle. (Soler A P,
Gilliard G, Megosh L C, O'Brien T G. J Modulation of murine hair
follicle function by alterations in omithine decarboxylase
activity. Invest Dermatol 1996 May; 106(5):1108-13.) The FDA, to
control facial hair growth in women, has recently approved DFMO.
(Current DFMO salts, when used topically, cause burning, irritation
and inflammation.) DFMO may have use in controlling male facial
hair growth as well and may constitute a methodology to supplant or
reduce the use of razors to remove facial hair in men.
[0014] Review of Prior Art
[0015] U.S. Pat. No. 4,330,559, May 18, 1982, Bey, et al. discloses
the use of DFMO to treat benign prostatic hypertrophy. U.S. Pat.
No. 4,399,151, Aug. 16, 1983, Sjoerdsma, et al. discloses the use
of 2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) for
inhibiting the growth of protozoa. U.S. Pat. No. 4,405,530, Sep.
20, 1983, Gerhart, discloses the preparation of fluorinated
amino-nitriles. These patents do not disclose the use of salts of
DFMO with chitosan.
[0016] U.S. Pat. No. 4,413,141, Nov. 1, 1983 Bey, et al. discloses
2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) and the methods
for the preparation and use thereof U.S. Pat. No. 4,499,072, Feb.
12, 1985, Sunkara, et al. discloses the use of DFMO as an ODC
inhibitor along with interferon in treating diseases. U.S. Pat. No.
4,720,489, Jan. 19, 1988, Shander, discloses the use of DFMO as an
ornithine decarboxylase inhibitor to modify hair growth. These
patents do not disclose the use of salts of DFMO with chitosan.
[0017] U.S. Pat. No. 5,648,394 Jul. 15, 1997, Boxall, et al.
discloses the use of DFMO as a topical composition for inhibiting
hair growth but does not teach the use salts of DFMO with chitosan.
WO9814188, May 04, 1998, Love et al. teaches the use of
preparations comprising a single enantiomer or defined ratio of
enantiomers of alphadifluoromethylornithin- e (DFMO) for treating,
preventing, controlling the growth of and/or reducing the risk of
developing estrogen independent breast cancer or tumor and for
administering DFMO alone or in combination with taxol. However,
this patent does not teach the use of salts of DFMO with chitosan.
U.S. Pat. No. 5,851,537, Dec. 22, 1998, Alberts et al. discloses
the use of topical application of DFMO to prevent skin cancer but
does not teach the salts of DFMO with chitosan. WO0069434, Nov. 23,
2000, Love discloses the use of Celecoxib, a COX-2 specific
nonsteroidal antiinflammatory agent, in combination with DFMO for
the prevention and/or treatment of cancers. However, this patent
does not teach the salts of DFMO with chitosan. U.S. Pat. No.
6,166,079, Dec. 26, 2000, Follen et al. discloses the use of DFMO
for the treatment or prevention of cervical intraepithelial
neoplasia. U.S. Pat. No. 6,258,845, Jul. 10, 2001, Gerner, et al.
discloses the use of DFMO and sulindac combination in cancer
chemoprevention. These patents do not teach the use of salts of
DFMO with chitosan.
[0018] Administration of agents that inhibit ornithine
decarboxylase would have significant utility over a wide range of
disorders or conditions associated with an increase polyamine
metabolism. For example, in addition to the prevention and/or
treatment of different types of cancer or precancer conditions,
such agents would have utility in preventing and/or treating colon
polyps, benign prostatic hypertrophy (BPH), or hirsutism. Such
agents may also provide a means to decrease the need for daily
shaving of facial hair in males.
[0019] Accordingly, there is a need in the art for methods related
to the use of such ODC inhibition agents to prevent and/or treat
conditions associated with increased polyamine metabolism. The
present invention fulfills this need, and provides further related
advantages.
SUMMARY OF THE INVENTION
[0020] Briefly stated, the present invention discloses methods for
the use of salts of DFMO with chitosan. These salts of DFMO with
chitosan have utility in treating or preventing a variety of
conditions related to the aforementioned mechanisms of action of
DFMO, namely ODC inhibition. Thus in one embodiment, a salt of DFMO
with chitosan is administered to a warmblooded animal in need
thereof to inhibit ODC. In yet a further embodiment, a salt of DFMO
with chitosan is administered to a warm blooded animal to prevent
and or treat the following conditions: aging of the skin, cancer,
HIV, alopecia, solar keratosis, benign prostatic hypertrophy,
prostate cancer, breast cancer, cervical cancer, and other such
conditions in which polyamine metabolism requires modulation. Such
a salt may be administered along with any other agent to enhance
its therapeutic effectiveness. Other aspects of the present
invention will become evident upon reference to the following
detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0021] As mentioned above, this invention is generally directed to
therapeutic uses of salts of DFMO with chitosan. Such salts of DFMO
with chitosan, when administered to a warm-blooded animal in need
thereof, have utility in the prevention or treatment of conditions
enumerated above in warm-blooded animals, including humans.
[0022] The term "treat" or "treatment" means that the symptoms
associated with one or more conditions mentioned above are
alleviated or reduced in severity or frequency and the term
"prevent" means that subsequent occurrences of such symptoms are
avoided or that the frequency between such occurrences is
prolonged.
[0023] It has now surprisingly been found that salts of DFMO with
chitosan have good characteristics that are such as to render them
particularly suitable both for use in pharmaceutical formulations
and for preparative applications.
[0024] The example illustrates the complete absence of the well
known irritation side effects of DFMO when a cream containing 20%
salt of DFMO with chitosan is applied topically to the forearm of
healthy volunteers.
[0025] This example is given to illustrate the present invention,
but not by way of limitation. Accordingly, the scope of this
invention should be determined not by the embodiments illustrated,
but rather by the appended claims and their legal equivalents.
EXAMPLE 1
[0026] A cream containing 20% salt of DFMO with chitosan was
applied to the forearm of 10 healthy individuals twice daily for a
two-week period in an outpatient clinic. No patients complained of
burning, irritation, scaling or redness after the cream. Patients
returned to the clinic after having used the cream for two weeks
for a visual inspection of the forearm area. The examining
physician noted no redness, irritation or scaling in the area where
the cream had been applied.
* * * * *