Details for Patent: 7,014,858

Title:	Use methods of treating acne and telangiectasia
Abstract:	A method of treating telangiectasia in a human in need thereof comprising administering to said human a tetracycline compound in an amount that is effective to treat telangiectasia, but has substantially no antibiotic activity.
Inventor(s):	Ashley; Robert A. (Newtown, PA)
Assignee:	CollaGenex Pharmaceuticals, Inc. (Newton, PA)
Filing Date:	Oct 15, 2002
Application Number:	10/272,499
Claims:	1. A method for treating telangiectasia in a human in need thereof comprising administering orally or intravenously to said human a tetracycline compound in a sub-antibacterial amount that reduces telangiectasia, said amount being 10 80% of the antibacterial effective amount, wherein the tetracycline compound is administered long term, wherein the tetracycline compound is administered without a bisphosphonate compound. 2. A method according to claim 1, wherein said telangiectasia is associated with age, acne rosacea, sun exposure, alcohol use, scleroderma, hereditary hemorrhagic telangiectasia, Ataxia-Telangiectasia, spider angioma, cutis marmorata telangiectasia congenita, Bloom syndrome, Klippel-Trenaunay-Weber syndrome, Sturge-Weber disease, Xeroderma pigmentosa or Nevus flammeus, or any combination thereof. 3. A method according to claim 1 wherein said tetracycline compound is minocycline administered once a day in a dose of 38 mg. 4. A method according to claim 1, wherein said tetracycline compound is minocycline administered twice a day in a dose of 38 mg. 5. A method according to claim 1, wherein said tetracycline compound is minocycline administered three times a day in a dose of 38 mg. 6. A method according to claim 1, wherein said tetracycline compound is minocycline administered four times a day in a dose of 38 mg. 7. A method according to claim 1, wherein said tetracycline compound is tetracycline administered once a day in a dose of 60 mg/day. 8. A method according to claim 1, wherein said tetracycline compound is tetracycline administered twice a day in a dose of 60 mg/day. 9. A method according to claim 1, wherein said tetracycline compound is tetracycline administered three times a day in a dose of 60 mg/day. 10. A method according to claim 1, wherein said tetracycline compound is tetracycline administered four times a day in a dose of 60 mg/day. 11. A method according to claim 1, wherein said tetracycline compound is an antibiotic tetracycline compound administered in an amount which results in a serum concentration which is 10 80% of the minimum antibiotic serum concentration. 12. A method according to claim 1, wherein said tetracycline compound is doxycycline administered in an amount which results in a serum concentration which is 1.0 .mu.g/ml. 13. A method according to claim 1, wherein said tetracycline compound is minocycline administered in an amount which results in a serum concentration which is 0.8 .mu.g/ml. 14. A method according to claim 1, wherein said tetracycline compound is tetracycline administered in an amount which results in a serum concentration which is 0.5 .mu.g/ml. 15. A method according to claim 11, wherein said antibiotic tetracycline compound is doxycycline, minocycline, tetracycline, oxytetracycline, chlortetracycline, demeclocycline or pharmaceutically acceptable salts thereof. 16. A method according to claim 15, wherein said antibiotic tetracycline compound is doxycycline. 17. A method according to claim 16, wherein said doxycycline is administered in an amount which provides a serum concentration in the range of about 0.1 to about 0.8 .mu.g/ml. 18. A method according to claim 16, wherein said doxycycline is administered in an amount of 20 milligrams twice daily. 19. A method according to claim 17, wherein said doxycycline is administered by sustained release over a 24 hour period. 20. A method according to claim 19, wherein said doxcycline is administered in an amount of 40 milligrams. 21. A method according to claim 1, wherein said tetracycline compound is a non-antibiotic tetracycline compound. 22. A method according to claim 21, wherein said non-antibiotic tetracycline compound is: 4-de(dimethylamino)tetracycline (CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3), 4-de(dimethylamino)-7-chlorotetracycline (CMT-4), tetracycline pyrazole (CMT-5) 4-hydroxy-4-de(dimethylamino)tetracycline (CMT-6), 4-de(dimethylamino)-12.alpha.-deoxytetracycline (CMT-7), 6-.alpha.-deoxy-5-hydroxy-4-de(dimethylamino)tetracycline (CMT-8), 4-de(dimethylamino)-12.alpha.-deoxyanhydrotetracycline (CMT-9), or 4-de(dimethylamino)minocycline (CMT-10). 23. A method according to claim 21, wherein the non-antibiotic tetracycline compound is selected from the group consisting of: ##STR00010## wherein: R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl; R6-a is selected from the group consisting of hydrogen and methyl; R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; R8 is selected from the group consisting of hydrogen and halogen; R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH.sub.2)CO; R is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof; with the following provisos: when either R7 and R9 are hydrogen then R8 must be halogen; and when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen; and when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen; and when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen; and when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen. 24. A method according to claim 21, wherein the non-antibiotic tetracycline compound is selected from the group consisting of: ##STR00011## wherein: R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, and di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl; R6-a is selected from the group consisting of hydrogen and methyl; R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; R4 is selected from the group consisting of NOH, N--NH-A, and NH-A, where A is a lower alkyl group; R8 is selected from the group consisting of hydrogen and halogen; R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH.sub.2)CO; R is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof; with the following provisos: when R4 is NOH, N--NH-alkyl or NH-alkyl and R7, R6-a, R6, R5, and R9 are all hydrogen, then R8 must be halogen; and when R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, R5 and R9 are both hydrogen, then R8 must be halogen; and when R4 is N--NH-alkyl, R6-a is methyl, R6 is hydroxyl and R7, R5, R9 are all hydrogen, then R8 must be halogen; and when R4 is NH-alkyl, R6-a, R6, R5 and R9 are all hydrogen, R7 is hydrogen, amino, mono(lower alkyl)amino, halogen, di(lower alkyl)amino or hydroxyl, then R8 must be halogen; and when R4 is NH-alkyl, R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is mono(lower alkyl)amino or di(lower alkyl)amino, then R8 must be halogen; and when R4 is NH-alkyl, R6-a is methyl, R6 is hydroxy or hydrogen and R7, R5, and R9 are all be hydrogen, then R8 must be halogen. 25. A method according to claim 21, wherein the non-antibiotic tetracycline compound is selected from the group consisting of: ##STR00012## wherein: R7, R8, and R9 taken together in each case, have the following meanings: TABLE-US-00011 R7 R8 R9 azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen acylamino dimethylamino hydrogen diazonium dimethylamino chloro amino hydrogen chloro amino amino chloro amino acylamino chloro acylamino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino dimethylamino chloro acylamino dimethylamino chloro dimethylamino hydrogen hydrogen dimethylamino dimethylamino hydrogen hydrogen and ##STR00013## wherein: R7, R8, and R9 taken together in each case, have the following meanings: TABLE-US-00012 R7 R8 R9 azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen acylamino hydrogen hydrogen diazonium hydrogen hydrogen dimethylamino diazonium hydrogen hydrogen ethoxythiocarbonylthio hydrogen hydrogen dimethylamino chloro amino amino chloro amino acylamino chloro acylamino hydrogen chloro amino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino and ##STR00014## wherein: R8 is hydrogen or halogen and R9 is selected from the group consisting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio; and ##STR00015## wherein: R7, R8, and R9 taken together in each case, have the following meanings: TABLE-US-00013 R7 R8 R9 amino hydrogen hydrogen nitro hydrogen hydrogen azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro bromo hydrogen hydrogen dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino diethylamino hydrogen hydrogen hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen methylamino dimethylamino hydrogen acylamino dimethylamino chloro amino amino chloro amino acylamino chloro acylamino hydrogen chloro amino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino and pharmaceutically acceptable salts thereof. 26. A method according to claim 21, wherein the non-antibiotic tetracycline compound is selected from the group consisting of: ##STR00016## wherein: R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl; R6-a is selected from the group consisting of hydrogen and methyl; R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; R8 is selected from the group consisting of hydrogen and halogen; R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH.sub.2)CO; R is hydrogen or lower alkyl; R.sup.a and R.sup.b are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that R.sup.a and R.sup.b cannot both be hydrogen; R.sup.c and R.sup.d are, independently, (CH.sub.2).sub.nCHR.sup.e wherein n is 0 or 1 and R.sup.e is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C.sub.1 C.sub.3) alkoxy, amino, or nitro; and, W is selected from the group consisting of (CHR.sup.e).sub.m wherein m is 0 3 and said R.sup.e is as above, NH, N(C.sub.1 C.sub.3) straight chained or branched alkyl, O, S and N(C.sub.1 C.sub.4) straight chain or branched alkoxy; and, pharmaceutically acceptable salts thereof. 27. A method according to claim 26, wherein the non-antibiotic tetracycline compound selected from the group consisting of structures S Z has the following provisos: when either R7 and R9 are hydrogen then R8 must be halogen; and when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen; and when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen; and when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen; and when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen; and when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen. 28. A method according to claim 1, wherein said tetracycline compound has a photoirritancy factor of less than the photoirritancy factor of doxycycline. 29. A method according to claim 1, wherein said tetracycline compound has a photoirritancy factor from about one to about two. 30. A method according to claim 29, wherein said tetracycline compound has a general formula: ##STR00017## wherein R7, R8, and R9 taken together are, respectively, hydrogen, hydrogen and dimethylamino. 31. A method according to claim 1, wherein said tetracycline compound has a photoirritancy factor from about 1.0 to about 1.2. 32. A method according to claim 31, wherein said tetracycline compound is selected from the group consisting of: ##STR00018## wherein R7, R8, and R9 taken together in each case, have the following meanings: TABLE-US-00014 R7 R8 R9 hydrogen hydrogen amino hydrogen hydrogen palmitamide and ##STR00019## wherein R7, R8, and R9 taken together in each case, have the following meanings: TABLE-US-00015 R7 R8 R9 hydrogen hydrogen acetamido hydrogen hydrogen dimethylaminoacetamido hydrogen hydrogen nitro hydrogen hydrogen amino and ##STR00020## wherein R8, and R9 taken together are, respectively, hydrogen and nitro.