Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUSRE34656 E
Publication typeGrant
Application numberUS 07/878,172
Publication dateJul 5, 1994
Filing dateMay 4, 1992
Priority dateDec 29, 1983
Publication number07878172, 878172, US RE34656 E, US RE34656E, US-E-RE34656, USRE34656 E, USRE34656E
InventorsLorne M. Golub, Thomas F. McNamara, Nungavaram S. Ramamurthy
Original AssigneeThe Research Foundation Of State University Of New York
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Use of tetracycline to enhance bone protein synthesis and/or treatment of bone deficiency
US RE34656 E
Abstract
Tetracyclines, antibacterial and non-antibacterial tetracyclines, have been found to be useful in the treatment of osteoporosis in humans by administering to the human suffering from osteoporosis an effective amount of a tetracycline to enhance bone protein synthesis. Tetracyclines which have been found to be effective in the treatment of osteoporosis in humans include minocycline, doxycycline and dedimethylaminotetracyline.
Images(1)
Previous page
Next page
Claims(19)
What is claimed is:
1. .[.A.]. .Iadd.The .Iaddend.method of .[.enhancing bone protein synthesis in a human which comprises administering to the human an effective amount of a tetracycline.]..Iadd.claim 20 wherein said disease is osteoporosis .Iaddend..
2. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is an antibacterial tetracycline.
3. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is non-antibacterial tetracycline.
4. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is minocycline.
5. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is doxycycline.
6. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 7-chlorotetracycline.
7. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 5-hydroxytetracycline.
8. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 6-demethyl-7-chlorotetracycline.
9. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 6-demethyl-6-deoxy-5-bydroxy-6-methylenetetracycline.
10. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is dedimethylamimotetracycline.
11. A method in accoredance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 6-alpha-benzylthiomethylenetetracycline.
12. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is a nitrile analog of tetracycline.
13. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is a mono-N-alkylated amide of tetracycline.
14. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 6-fluorodemethyltetracycline.
15. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 11-alpha-chlorotetracycline.
16. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 2-acetyl-8-hydroxyl-1-tetracycline.
17. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is 6-demethyl-6-deoxytetracycline.
18. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is administered systemically.
19. A method in accordance with claim .[.1.]. .Iadd.20 .Iaddend.wherein said tetracycline is administered orally. .Iadd.20. A method of treating mammal with bone deficiency disease by enhancing bone protein synthesis in said mammal which comprises administering to the mammal an effective amount of a tetracycline. .Iaddend.
Description

This application is a continuation-in-part application of copending, coassigned patent application Ser. No. 699,048 filed Feb. 7, 1985, now U.S. Pat. No. 4,704,383 which in turn, is a continuation-in-part of copending, coassigned patent application Ser. No. 566,517 filed Dec. 29, 1983, now U.S. Pat. No. 4,666,897.

The disclosures of the above-identified applications are herein incorporated and made part of this disclosure.

BACKGROUND OF THE INVENTION

In pending U.S. patent application Ser. No. 566,517, now U.S. Pat. No. 4,666,897, it is disclosed that tetracyclines, such as the antibiotic tetracyclines, e.g. tetracycline, are useful as anti-collagenolytic agents or as inhibitors of collagenase. These tetracyclines and compositions containing the same are disclosed therein as being useful in the treatment of periodontal diseases, corneal ulcers, rheumatoid arthritis and the like characterized by excessive collagen destruction.

In pending U.S. patent application Ser. No. 699,048, now U.S. Pat. No. 4,704,383, it is disclosed that the non-antibiotic or non-antibacterial tetracyclines also possess anti-collagenolytic properties and are useful as inhibitors of collagenase. Additionally, these non-antibiotic or non-antibacterial tetracyclines have also been found to be useful in the treatment of periodontal diseases, corneal ulcers, bone deficiency disorders due to excess collagenase production or excessivde collagen destruction, rheeumatoid arthristis and the like. A particularly useful non-antibiotic tetracycline in the practices of this invention is the tetracycline dedimethylaminotetracycline.

Tetracyclines are useful as broad spectrum antibiotics because they have the ability to inhibit 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 th ability to inhibit collagen-destructive enzymes, such as collagenase, responsiple for the breakdown of connective tissue in a number of diseases, such as periodontal disease, corneal ulcers and rheumatoid arthritis.

SUMMARY OF THE INVENTION

It has been discovered that inhibitors of collagen-destructive enzymes, such as collagenase, are useful in the treatment of mammals, such as humans, to prevent the development of osteoporosis and/or to stimulate bone protein synthesis. In the practices of this invention an effective amount of a physiologically acceptable collagenase inhibitor is systemically administered to the mammal or human to bring about the stimulation of bone protein synthesis or to treat bone deficiency disease or osteoporosis. The amount of the inhibitor administered to the mammal or human can be at a therapeutic level, i.e. substantially the same dosage as would be employed in the treatment of barterial infections and the like, or at a reduced, subtherapeutic level, in the range about 5-60% of the therapeutic dosage. The amount administered in accordance with the practices of this invention would be effective to inhibit the collagen-destructive enzymes, such as collagenase, in the mammal, e.g. subject to which the inhibitor is administered.

More particularly, it has been discovered that tetracyclines, antibacterial and non-antibacterial tetracyclines, which are inhibitors of collagenase, enhance or stimulate bone protein synthesis and have been found to be useful in the treatment of osteoporosis in humans. In the light of the discovery of this invention that tetracyclines stimulate and enhance bone protein synthesis, tetracyclines have been found to be useful in the treatment of osteoporosis.

DETAILED DESCRIPTION OF THE INVENTION

The following disclosures of examples are illustrative of the practices of this invention.

EXAMPLE NO. 1

In this experiment 4 groups of adult male rats were set up, viz, a group of normal rats which served as controls, a group of rats that were rendered diabetic by streptozotocin administration and two additional groups of diabetic rats, one of which was administered by oral intubation 20 mg per day of a chemically modified non-antibiotic tetracycline (CMT), and the other of which was orally administered 5 mg per day of minocycline, a semi-synthetic commercially available antibiotic tetracycline. Each of the 4 groups of rats contained 4 rats each. Three weeks after beginning the experiment, but 2 hours before sacrifice, each rat was injected with 1 mCi of H3 -proline to radioactively label the newly synthesized protein in the skeletal and other tissues. After the rats were killed, the long bones were removed, cleaned free of soft tissue, the mid-shaft of the cleaned bone collected and hydrolyzed in 6N HCI (24 h, 105 C.), and an aliquot measured in a liquid scinitillation spectrometer after evaporating the acid. The data on bone protein synthesis is shown in Table 1.

              TABLE I______________________________________The administration of minocycline or chemically-modifiednon-antibiotic tetracycline (CMT) to diabetic rats:effect on bone protein systhesis in vivo          Bone Protein synthesisExperimental Group          (DPM H3 -Pro/mg bone tissue)______________________________________Controls       886  155Diabetics (D)  588  89D + minocycline          852  145D + CMT        828  248______________________________________

Inducing diabetes in the rat suppressed protein synthesis in the skeletal tissue; after months of this metabolic dysfunction in the bones, they developed physically and chemically-detectable bone-deficiency disease. When either of the two tetracyclines was orally administered to the diabetics, bone protein synthesis was increased to essentially normal values, and this metabolic alteration was associated with the prevention of the devleopment of osteoporosis.

EXAMPLE NO. 2

In this experiment 3 groups of animals were established: a group of non-diabetic controls, a group of untreated diabetics, and a group of diabetic rats that were administered, by the oral route, 1.5 mg doxycycline, an antibiotic tetracycline, per day for the entire 31/2 month experimental period. After 3.5 months, the rats were killed, the bones (femur and tibia) were removed, defleshed, and radiographs taken. Physical and biochemical parameters were also measured. Other bones (mandible) were processed for light microscopy. Diabetes significantly reduced the dry weight, density, ash, matrix, calcium and hydroxyproline content of the skeletal tissue (the unchanged Ca/Hyp ratio indicated the bone was normally calcified even through osteopenic). Long-term doxycycline therapy retarded the loss of organic and inorganic bone constituents in the diabetics even though the severity of hyperglycemia was unaffected. Radiographic changes were consistent with the above findings. In short-term studies, treatment of diabetic rats with a different tetracycline (minocycline) showed a similar pattern of results. Tetracycline therapy in rats retarded osteoporotic changes in bone induced by diabetes.

It was observed that untreated diabetic rats developed bone deficiency disease, or osteoporosis, based on physical, radiologic, chemical and histologic assessments. However, the tetracycline, doxycycline, therapy prevented the development of diabetes-induced osteoporosis even though the drug had no effect on the severity of the diabetic state, presumably because the drug increased the depressed protein synthesis in the skeletal tissues.

EXAMPLE NO. 3

              TABLE II______________________________________Effects of CMT Administration (20 mg per day) on UrinaryCalcium Excretion in Streptozotocum-Diabetic RatsExperimental   Number of Rats                       μg Ca mGroup          per Group    urine per 24 h*______________________________________Control        4             33  5Diabetes       4            691  35Diabetes + CMT 4            398  33______________________________________ Each value represents the mean  S.E.M. of 12 volumes: a 24 h determination was made for each rat (a = 4 per group), on days 18, 19 and 20 after reducing diabetes

The results shown above in Table II summarizes the reduction in calcium excretion in the diabetic animals treated with CMT as compared with the untreated diabetic animals. Diabetes dramatically increases the urinary excretion of calcium compared with control values and an elevated urinary excretion of calcium is associated with the development of osteoporosis. Administration of CMT to the diabetic animals reduced the pathologically excessive excretion of calcium by 42%; this is biochemical evidence of the amelioration of the condition resulting from the administration of CMT.

EXAMPLE NO. 4

Tetracycline can inhibit tissue degradation by anticollagenase action and has reduced pathological bone resorption through this mechanism (Golub et al. 1983, 84). A study was undertaken to evaluate whether tetracycline could have any discernible effect upon morphologic characteristics of bone undergoing nomral remodeling. Four squirrel monkeys received a daily dose of tetracycline at 100 mg/kg/day given by oral intubation in 3 equal doses. After 17 days of tetracycline administration the animals were sacrificed and the jaws processed for histologic sectioning. Bucco-lingual sections were prepared from bicuspid and cuspid teeth. A defined coronal buccal alveolar bone region was analyzed histologically and histometrically using step-serial sections. Corresponding regions were analyzed from bicuspids and cuspids from 4 animals which had not received tetracycline administration. Morphologic characteristics of the bone were analyzed using a Bioquant computerized digitization system, and comparisons made between the groups. Within the defined region, the total area of alveolar bone and the number of marrow spaces, did not differ between the two groups. However, the area of the narrow spaces was significantly less in tetracycline-receiving animals. The marrow spaces occupied 0.50.09(SE)% of the bone in tetracycline-receiving animals, in contrast to the 7.91.2(SE)% (t=3.49, p<0.01) present in control animals. In the tetracycline-receiving animals, the marrow spaces appeared to be lined by new bone, as were the periodontal ligament surfaces of the alveolar bone. The increased bone density may have been due to inhibition of resorption without affecting the deposition phase of bone remodeling.

Although in the practices of this invention many compounds, particularly physiologically acceptable collagenase inhibitors, are useful, it is preferred to employ a tetracycline antibiotic or non-antibiotic. Tetracyclines, broadly, can be characterized as containing four fused carbcyclic groups. This arrangement appears to be characteristic of compounds which are collagenase inhibitors and which are also useful in the practices of this invention. Related compounds, compounds which are related as analogs or homologs of tetracycline, are also useful as well as compounds which are characterized as having three fused carbocyclic groups. Suitable such compounds are disclosed herein and include 7-chlorotetracycline, 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, 6-fluorodemethyltetracycline, 11-alpha-chlorotetracycline, 2-acetyl-8-hydroxy-1-tetracycline and 6-demethyl-6-deoxytetracycline.

As mentioned hereinabove, the compounds employed in the practices of this invention are employed in an effective amount for the treatment of osteoporosis, such as an amount effective to enhance the synthesis of bone protein and/or correct to treat any deficiency disease. The amount employed depends to some extent upon the body weight of the mammal or human being treated. With respect to humans, the amount employed, particularly in the case of compounds which are collagenase inhibitors and/or characterized as being a tetracycline, on a daily dosage, it is usually less than about 400 milligrams and usually below about 200 milligrams. A suitable daily dosage for a human would be in the range 10 milligrams to about 50 milligrams for the treatment of osteoporosis or other bone deficiency disease and for the enhancement of the synthesis of bone protein.

As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations, substitutions and modifications are possible in the practices of this invention without departing from the spirit or scope thereof.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2895880 *May 13, 1955Jul 21, 1959Smith Kline French LabSustained release pharmaceutical product
US3304227 *Jul 15, 1965Feb 14, 1967Loveless Loyal EAntibiotic-containing animal feed
US3636202 *Feb 12, 1968Jan 18, 1972Lewis A KleinTreatment of rheumatoid arthritis and related diseases
US3914299 *Feb 2, 1973Oct 21, 1975Research CorpTetracyclines
US4248892 *Jun 7, 1979Feb 3, 1981Takeda Chemical Industries, Ltd.Protocatechuic acid, homoprotocatechuic acid
US4276284 *Dec 10, 1975Jun 30, 1981Brown Stuart ICorneal and stomach ulcers, rheumatoid arthritis
US4371465 *Oct 7, 1981Feb 1, 1983American Home Products CorporationMammalian collagenase inhibitors
US4454110 *Aug 1, 1983Jun 12, 1984Forsyth Dental Infirmary For ChildrenSelf-gelling liquid composition for topical application in the oral cavity
US4457936 *Apr 7, 1982Jul 3, 1984Hoechst AktiengesellschaftUse of hydroxyphenyl-thiazole-, -thiazoline- and -thiazolidine-carboxylic acids, for influencing the collagen metabolism
US4666897 *Dec 29, 1983May 19, 1987Research Foundation Of State UniversityInhibition of mammalian collagenolytic enzymes by tetracyclines
US4704383 *Feb 7, 1985Nov 3, 1987The Research Foundation Of State University Of New YorkAntiarthritic
US4925833 *Dec 29, 1986May 15, 1990The Research Foundation Of State University Of New YorkUse of tetracycline to enhance bone protein synthesis and/or treatment of osteoporosis
US4935411 *Oct 28, 1987Jun 19, 1990The Research Foundation Of State University Of New YorkCollagenase inhibitor, animal feed aditive
US4935412 *Jul 13, 1987Jun 19, 1990The Research Foundation Of State University Of New YorkNon-antibacterial tetracycline compositions possessing anti-collagenolytic properties and methods of preparing and using same
GB787882A * Title not available
GB925282A * Title not available
Non-Patent Citations
Reference
1"Anti-Plaque Agents", Pharmacy Times, 97 (Jul. 1985).
2"British Bio-Technology Group's Collagenase Inhibitor Adjunctive", F-D-C Reports, Inc., 13 (1983).
3"Periodontal Disease Research, Guide to Dental Health", Journal of the American Dental Association, 70-74 (1985).
4"Zyderm Collagen Treatments", Collagen Corporation, Advertisement, (Dec. 1981).
5Addy, et al., "Comparison of the Immediate Effects on the Subgingival Microflora of Acrylic Strips Containing 40% Chlorhexdine, Metronidazole or Tetracycline", Journal of Clinical Periodontology, 11:379-386, (1984).
6Addy, et al., "The Development and in Vitro Evaluation of Acrylic Strips and Dialysis Tubing for Local Drug Delivery", J. Periodonal, 693-699, (Nov. 1982).
7 *Addy, et al., Comparison of the Immediate Effects on the Subgingival Microflora of Acrylic Strips Containing 40% Chlorhexdine, Metronidazole or Tetracycline , Journal of Clinical Periodontology , 11:379 386, (1984).
8 *Addy, et al., The Development and in Vitro Evaluation of Acrylic Strips and Dialysis Tubing for Local Drug Delivery , J. Periodonal , 693 699, (Nov. 1982).
9 *ALZA/P&G Periodontal Disease Partnership:Actisite, F D C Reports , Inc., 8 9 (1990).
10ALZA/P&G Periodontal Disease Partnership:Actisite, F-D-C Reports, Inc., 8-9 (1990).
11 *Anti Plaque Agents , Pharmacy Times , 97 (Jul. 1985).
12Berman, M. B., "Collagenase and Corneal Ulceration", 8:141-174, (1980).
13 *Berman, M. B., Collagenase and Corneal Ulceration , 8:141 174, (1980).
14 *Bitha, et al., Chemical Abstracts , 72:43253P, (1970).
15Bitha, et al., Chemical Abstracts, 72:43253P, (1970).
16 *Brandt, et al., Chemical Abstracts , 92:163746m, (1979).
17Brandt, et al., Chemical Abstracts, 92:163746m, (1979).
18 *British Bio Technology Group s Collagenase Inhibitor Adjunctive , F D C Reports , Inc., 13 (1983).
19Brown et al., "Rheumatoid Artritis in the Gorilla:A Study of Mycoplasma-Host Interaction in Pathogenesis and Treatment", Comarative Pathology of Zoo Animals, 259-266, (1980).
20 *Brown et al., Rheumatoid Artritis in the Gorilla:A Study of Mycoplasma Host Interaction in Pathogenesis and Treatment , Comarative Pathology of Zoo Animals , 259 266, (1980).
21Dreisbach, et al., "Induction of Collagenase Production in Vibrio B--30", J. Bacteriology, vol. 135, No. 2, pp. 521-527, (1978).
22 *Dreisbach, et al., Induction of Collagenase Production in Vibrio B 30 , J. Bacteriology , vol. 135, No. 2, pp. 521 527, (1978).
23 *Engesaeter, et al., Chemical Abstracts , 93:142977t, (1980).
24Engesaeter, et al., Chemical Abstracts, 93:142977t, (1980).
25 *Glantz, et al., Chemical Abstracts , 91:20178w, (1979).
26Glantz, et al., Chemical Abstracts, 91:20178w, (1979).
27Golub, et al., "Minocycline Reduces Gingival Collagenolytic Activity During Diabetes", Journal of Periodontal Research, 18: 516-526 (1983).
28Golub, et al., "Minocycline Therapy Inhibits the Abnormal Gingival Collagenolytic Activity During Experimental Diabetes", Journal of Dental Research, 62:290, Abstract 1085, (1983).
29Golub, et al., "Minocycline Therapy Reduces Gingival Collagenolytic Enzyme Activity During Diabetes: A Proposed New Mechanism of Action, J. Of Periodontal Research", 18: 516-526, Abstract, (1983).
30 *Golub, et al., Chemical Abstracts , 100:96203a, (1984).
31Golub, et al., Chemical Abstracts, 100:96203a, (1984).
32 *Golub, et al., Minocycline Reduces Gingival Collagenolytic Activity During Diabetes , Journal of Periodontal Research , 18: 516 526 (1983).
33 *Golub, et al., Minocycline Therapy Inhibits the Abnormal Gingival Collagenolytic Activity During Experimental Diabetes , Journal of Dental Research , 62:290, Abstract 1085, (1983).
34 *Golub, et al., Minocycline Therapy Reduces Gingival Collagenolytic Enzyme Activity During Diabetes: A Proposed New Mechanism of Action, J. Of Periodontal Research , 18: 516 526, Abstract, (1983).
35Gomes, et al., "Tetracyclines Inhibit Parathyroid Hormone-Induced Bone Resorption in Organ Culture", School of Dental Medicine Study, SUNY, (Mar. 19, 1984).
36 *Gomes, et al., Tetracyclines Inhibit Parathyroid Hormone Induced Bone Resorption in Organ Culture , School of Dental Medicine Study, SUNY, (Mar. 19, 1984).
37 *Goodman and Gilman, The Pharmacological Basis of Therapeutics , 6th edition, p. 961 2, (1980).
38Goodman and Gilman, The Pharmacological Basis of Therapeutics, 6th edition, p. 961-2, (1980).
39Goodson, et al., "Monolithic Tetracycline-containing Fibers for Controlled Delivery to Periodontal Pockets", J. Periodontol. 54 575-579 (Jan. 1983).
40 *Goodson, et al., Monolithic Tetracycline containing Fibers for Controlled Delivery to Periodontal Pockets , J. Periodontol. 54 575 579 (Jan. 1983).
41Katz, S. E., "Is Today's Meat Fit to Eat?", Chemical and Engineering News, 80-81 (Mar. 11, 1985).
42 *Katz, S. E., Is Today s Meat Fit to Eat , Chemical and Engineering News , 80 81 (Mar. 11, 1985).
43 *Muxfeldt, Chemical Abstracts , 76:140344j, (1972).
44Muxfeldt, Chemical Abstracts, 76:140344j, (1972).
45 *Myl nikova, Chemical Abstracts , 86:66138h, (1976).
46Myl'nikova, Chemical Abstracts, 86:66138h, (1976).
47 *O Donovan, J. P., A Chick Screen to Evaluate Chemical Compounds from Janssen Pharmaceutical for Growth Promotion , Chick Growth Promotion Screen Report (1987).
48O'Donovan, J. P., "A Chick Screen to Evaluate Chemical Compounds from Janssen Pharmaceutical for Growth Promotion", Chick Growth Promotion Screen Report (1987).
49 *Periodontal Disease Research, Guide to Dental Health , Journal of the American Dental Association , 70 74 (1985).
50Perry, et al., "Systemic Tetracycline in the Treatment of Non-Infected Corneal Ulcers and Persistent Epithelial Defects", J. Period Res. 83:20, 185-195 (Abstract and Artide) (1984).
51 *Perry, et al., Systemic Tetracycline in the Treatment of Non Infected Corneal Ulcers and Persistent Epithelial Defects , J. Period Res. 83:20, 185 195 (Abstract and Artide) (1984).
52 *Plakunov, Chemical Abstracts , 80:104410b, (1973).
53Plakunov, Chemical Abstracts, 80:104410b, (1973).
54Sheridan, P., "Tetracyclines Block Collagenase Activity", JAMA, 252, 1989-1990 (Oct. 19, 1984).
55 *Sheridan, P., Tetracyclines Block Collagenase Activity , JAMA , 252, 1989 1990 (Oct. 19, 1984).
56 *Smirnov, I. V., Chemical Abstracts , 76:30596, (1969).
57Smirnov, I. V., Chemical Abstracts, 76:30596, (1969).
58 *Valcavi, et al., Chemical Abstracts , 95:6899h, (1981).
59Valcavi, et al., Chemical Abstracts, 95:6899h, (1981).
60Williams et al., "Tetracycline Treatment of Periodontal Disease in the Beagle Dog:", Journal of Periodontal Research, 16:555-674, (1981).
61 *Williams et al., Tetracycline Treatment of Periodontal Disease in the Beagle Dog: , Journal of Periodontal Research , 16:555 674, (1981).
62 *Zyderm Collagen Treatments , Collagen Corporation, Advertisement, (Dec. 1981).
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5773430 *Mar 13, 1997Jun 30, 1998Research Foundation Of State University Of New YorkReduces tissue destruction during inflammation resulting from the activity of human leukocyte elastase
US6610274Dec 18, 2001Aug 26, 2003Wallace J. GardnerAnti-inflammatory composition comprising tetracycline
US7214669Oct 4, 2002May 8, 2007Tetragenex Pharmaceuticals, Inc.Tetracycline derivatives and methods of use thereof
US7749532Apr 7, 2004Jul 6, 2010Supernus Pharmaceuticals, Inc.doxycycline; dosage forms have immediate release and delayed release portions; antiinflammatory, antiarthritic, and antidiabetic agents, periodontal disease, rosacea, acne, dry eyes, hyperparathyroidism
US7786099Jan 18, 2005Aug 31, 2010Paratek Pharmaceuticals, Inc.such as A-ring aromatized Minocycline, having antibacterial activity; antibiotics
US8206740Jun 6, 2008Jun 26, 2012Supernus Pharmaceuticals, Inc.Once daily formulations of tetracyclines
US8318706Dec 21, 2007Nov 27, 2012Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
US8383610May 26, 2009Feb 26, 2013Paratek Pharmaceuticals, Inc.Salts and polymorphs of 9-(2,2-dimethylpropyl-aminomethyl) minocycline
US8394405Dec 17, 2010Mar 12, 2013Supernus Pharmaceuticals, Inc.Once daily formulations of tetracyclines
US8394406Dec 17, 2010Mar 12, 2013Supernus Pharmaceuticals, Inc.Once daily formulations of tetracyclines
US8470364Dec 17, 2010Jun 25, 2013Supernus Pharmaceuticals, Inc.Once daily formulations of tetracyclines
US8513223Dec 21, 2007Aug 20, 2013Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds for treatment of inflammatory skin disorders
US8709478Jun 18, 2013Apr 29, 2014Supernus Pharmaceuticals, Inc.Once daily formulations of tetracyclines
EP2213655A1Apr 28, 2008Aug 4, 2010Paratek Pharmaceuticals, Inc.Methods For Purifying Aminoalkyl Tetracycline Compounds
EP2269978A2Oct 25, 2005Jan 5, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2269985A2Oct 25, 2005Jan 5, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2269991A2Oct 25, 2005Jan 5, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284150A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284151A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284152A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284153A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284155A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284156A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2284164A2Oct 25, 2005Feb 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2287140A2Oct 25, 2005Feb 23, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2287148A2Oct 25, 2005Feb 23, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2287150A2Oct 25, 2005Feb 23, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2292590A2Jun 25, 2004Mar 9, 2011Paratek Pharmaceuticals, Inc.Prodrugs of 9-aminomethyl tetracycline compounds
EP2295404A2Jun 25, 2004Mar 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2295419A2Oct 25, 2005Mar 16, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2298322A2Jun 25, 2004Mar 23, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2298323A2Jun 25, 2004Mar 23, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2301534A1Mar 10, 2003Mar 30, 2011Paratek Pharmaceuticals, Inc.Amino-methyl substituted tetracycline compounds
EP2301550A1Jul 15, 2002Mar 30, 2011Paratek Pharmaceuticals, Inc.Tetracycline compounds having target therapeutic activities
EP2301912A2Oct 25, 2005Mar 30, 2011Paratek Pharmaceuticals, Inc.4-aminotetracyclines and methods of use thereof
EP2301915A1Jul 15, 2002Mar 30, 2011Paratek Pharmaceuticals, Inc.7-(diethylamino)methyl substituted tetracycline having target therapeutic activities
EP2301916A2Oct 25, 2005Mar 30, 2011Paratek Pharmaceuticals, Inc.4-aminotetracyclines and methods of use thereof
EP2305637A2Oct 25, 2005Apr 6, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2311440A1Apr 5, 2002Apr 20, 2011Collagenex Pharmaceuticals, Inc.Controlled delivery of tetracycline compounds and tetracycline derivatives
EP2311451A1Mar 10, 2003Apr 20, 2011Paratek Pharmaceuticals, Inc.Amino-methyl substituted tetracycline compounds
EP2311796A1Jan 6, 2003Apr 20, 2011Paratek Pharmaceuticals, Inc.4-dedimethylamino tetracycline compounds
EP2311797A1Jan 6, 2003Apr 20, 2011Paratek Pharmaceuticals, Inc.4-dedimethylamino tetracycline compounds
EP2311798A1Jan 6, 2003Apr 20, 2011Paratek Pharmaceuticals, Inc.4-dedimethylamino tetracycline compounds
EP2311799A1Jan 6, 2003Apr 20, 2011Paratek Pharmaceuticals, Inc.4-dedimethylamino tetracycline compounds
EP2316450A1Mar 10, 2003May 4, 2011Paratek Pharmaceuticals, Inc.Amino-methyl substituted tetracycline compounds
EP2319828A2Jun 25, 2004May 11, 2011Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2319829A1Jun 25, 2004May 11, 2011Paratek Pharmaceuticals, Inc.9-substituted tetracycline compounds
EP2322501A1Jan 6, 2003May 18, 2011Paratek Pharmaceuticals, Inc.4-dedimethylamino tetracycline compounds
EP2327409A1Jul 15, 2002Jun 1, 2011Paratek Pharmaceuticals, Inc.Tetracycline compound having target therapeutic activities
EP2329826A1Jul 15, 2002Jun 8, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of multiple sclerosis
EP2329828A1Jul 15, 2002Jun 8, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of ischaemia
EP2332546A1Jul 15, 2002Jun 15, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of stroke
EP2332547A1Jul 15, 2002Jun 15, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of inflammatory bowel disease
EP2332548A1Jul 15, 2002Jun 15, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of stroke
EP2332549A1Jul 15, 2002Jun 15, 2011Paratek Pharmaceuticals, Inc.Novel tetracyclines and their use in medicine
EP2332550A1Jul 15, 2002Jun 15, 2011Paratek Pharmaceuticals, Inc.Tetracyclines for the treatment of neurodegenerative diseases
EP2332904A2Jan 18, 2005Jun 15, 2011Paratek Pharmaceuticals, Inc.Derivatives of tetracycline compounds
EP2345637A2Jul 14, 2003Jul 20, 2011Paratek Pharmaceuticals, Inc.3, 10, and 12a substituted tetracycline compounds
EP2450347A1Dec 21, 2007May 9, 2012Paratek Pharmaceuticals, Inc.Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections
EP2452935A2Dec 21, 2007May 16, 2012Paratek Pharmaceuticals, Inc.Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections
EP2455367A1Dec 21, 2007May 23, 2012Paratek Pharmaceuticals, Inc.Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections
EP2481723A2Mar 18, 2003Aug 1, 2012Paratek Pharmaceuticals, Inc.Substituted tetracycline compounds
EP2682387A2Aug 7, 2009Jan 8, 2014Tetraphase Pharmaceuticals, Inc.C7-fluoro substituted tetracycline compounds
WO2003005971A2Jul 15, 2002Jan 23, 2003Paratek Pharm InncTetracycline compounds having target therapeutic activities
WO2005009943A2Jun 25, 2004Feb 3, 2005Paratek Pharm InncSubstituted tetracycline compounds
WO2009143509A1May 26, 2009Nov 26, 2009Paratek Pharmaceuticals, Inc.Salts and polymorphs of a tetracycline compound
WO2010129057A2May 7, 2010Nov 11, 2010Tetraphase Pharmaceuticals, Inc.Tetracycline compounds
WO2011025982A2Aug 27, 2010Mar 3, 2011Tetraphase Pharmaceuticals, Inc.Tetracycline compounds
WO2011123536A1Mar 30, 2011Oct 6, 2011Tetraphase Pharmaceuticals, Inc.Polycyclic tetracycline compounds
Classifications
U.S. Classification514/152, 514/899
International ClassificationA61K31/65
Cooperative ClassificationA61K31/65
European ClassificationA61K31/65
Legal Events
DateCodeEventDescription
Oct 7, 2003RRRequest for reexamination filed
Effective date: 20030819