What is claimed is:
1. A method of reducing the concentration of oxygen in an aqueous solution, comprising adding to the aqueous solution a reducing agent and a hemoprotein having deoxygenase activity, and incubating the resulting solution under conditions suitable for deoxygenase activity.
2. A method of reducing the concentration of oxygen in an aqueous solution, comprising adding to the aqueous solution a reducing agent, a hemoprotein having deoxygenase activity and NO or a source of NO, and incubating the resulting solution under conditions suitable for deoxygenase activity.
3. A method of consuming NO in an aqueous solution, comprising adding an NO-consuming hemoprotein to the aqueous solution in the presence of O2 and a reducing agent, and incubating the resulting solution under conditions suitable for NO-consuming activity by the hemoprotein.
4. The method of claim 3 wherein the NO-consuming hemoprotein is a flavohemoglobin.
5. A method of enzymatically reducing the concentration of oxygen in a mammal, comprising administering an effective amount of a hemoprotein having deoxygenase activity to said mammal.
6. The method of claim 5 further comprising administering a reducing agent to said mammal.
7. The method of claim 5 further comprising administering NO or a source of NO to said mammal.
8. The method of claim 5 wherein said hemoprotein is a naturally occurring hemoprotein or an enzymatically active variant thereof.
9. The method of claim 8 wherein said hemoprotein is selected from the group consisting of: Ascaris hemoglobin, myoglobin, a flavohemoglobin and an enzymatically active variant of any of the foregoing.
10. A method of enzymatically reducing the concentration of nitric oxide in a mammal, comprising administering an effective amount of an NO-consuming hemoprotein to said mammal.
11. The method of claim 10 wherein said hemoprotein is selected from the group consisting of: Ascaris hemoglobin, myoglobin, a flavohemoglobin and an enzymatically active variant of any of the foregoing.
12. The method of claim 10 wherein said hemoprotein is a bacterial flavohemoglobin.
13. A method of treating a mammal having a disorder characterized by pathologically proliferating cells, comprising administering a therapeutically effective amount of a hemoprotein having deoxygenase activity to said mammal.
14. The method of claim 13 wherein the mammal has a tumor.
15. The method of claim 13 wherein the mammal has prostatic hypertrophy or restenosis.
16. The method of claim 13 further comprising administering a reducing agent to said mammal.
17. The method of claim 16 wherein said reducing agent is selected from the group consisting of NADH, NADPH and a thiol.
18. A method of deoxygenating a tumor in a mammal, comprising administering a therapeutically effective amount of a hemoprotein having deoxygenase activity to said mammal.
19. The method of claim 18 wherein said hemoprotein is selected from the group consisting of: Ascaris hemoglobin, myoglobin, a bacterial flavohemoglobin and an enzymatically active variant of any of the foregoing.
20. The method of claim 18 further comprising administering a reducing agent to said mammal.
21. The method of claim 20 wherein said reducing agent is selected from the group consisting of NADH, NADPH and a thiol.
22. A method of anti-tumor therapy, comprising administering a therapeutically effective amount of a hemoprotein having deoxygenase activity, and a therapeutically effective amount of one or more bioreductive cytotoxic agents to a mammal having a tumor.
23. The method of claim 22 wherein said hemoprotein is selected from the group consisting of: Ascaris hemoglobin, myoglobin, a bacterial flavohemoglobin and an enzymatically active variant of any of the foregoing.
24. The method of claim 22 further comprising administering a reducing agent to said mammal.
25. The method of claim 24 wherein said reducing agent is selected from the group consisting of NADH, NADPH and a thiol.
26. The method of claim 22 wherein said hemoprotein and said bioreductive cytotoxic agent are administered locally.
27. A method of potentiating the cytotoxic activity of a bioreductive cytotoxic agent, comprising administering a therapeutically effective amount of a hemoprotein having deoxygenase activity, or an enzymatically active fragment thereof, and a therapeutically effective amount of said bioreductive cytotoxic agent to a mammal.
28. The method of claim 27 wherein said hemoprotein is activated by NO.
29. The method of claim 28 wherein said hemoprotein is selected from the group consisting of Ascaris hemoglobin, myoglobin, a flavohemoglobin and an enzymatically active variant of any of the foregoing.
30. A method of enzymatically generating toxic reactive oxygen species in a mammal, comprising administering an effective amount of a hemoprotein to the mammal.
31. The method of claim 30 wherein the hemoprotein is a flavohemoglobin.
32. The method of claim 30 further comprising administering a reducing agent to said mammal.
33. The method of claim 32 wherein said reducing agent is selected from the group consisting of NADH, NADPH and a thiol.
34. The method of claim 30 wherein said reactive oxygen species is hydrogen peroxide or superoxide.
35. A composition comprising one or more hemoproteins having deoxygenase activity or NO-consuming activity, and a physiologically acceptable carrier.
36. The composition of claim 35 further comprising one or more cytotoxic agents.
37. The composition of claim 36 wherein at least one of said cytotoxic agents is a bioreductive toxic agent.
38. The composition of claim 35 wherein at least one hemoprotein is a naturally occurring hemoprotein or an enzymatically active variant thereof.
39. The composition of claim 35 wherein said hemoprotein is selected from the group consisting of Ascaris hemoglobin, a myoglobin, a flavohemoglobin and an enzymatically active variant of any of the foregoing.
40. The composition of claim 35 wherein said composition further comprises a reducing agent.
41. The composition of claim 40 wherein said reducing agent is NADH, NADPH or a thiol.
42. A method of treating a mammal infected with Ascaris sp., comprising administering to said mammal a therapeutically effective amount of an inhibitor of NO synthase.
43. The method of claim 42 wherein said inhibitor is selected from the group consisting of an L-arginine uptake inhibitor, arginase, NG-nitro-L-arginine, L-nitroarginine methyl ester, N-monomethyl-L-arginine, 2-ethyl-2-thiopseudourea, L-N6-(1-iminoetyl)lysine, aminoguanidine, and 7-nitroindazole.
44. A method of constricting blood vessels in a mammal, comprising administering to the mammal a hemoprotein.
45. A method of reducing blood flow in a tumor, comprising introducing into the tumor a hemoprotein.
46. A composition comprising a flavohemoglobin in a pharmaceutically acceptable vehicle.
47. The composition of claim 46 wherein the flavohemoglobin is a bacterial flavohemoglobin.
48. The composition of claim 46 wherein the flavohemoglobin is a yeast flavohemoglobin.
49. The composition of claim 46 wherein the flavohemoglobin is E. coli flavohemoglobin.
50. A method for treating a disease or medical disorder in a mammal, comprising administering an effective amount of a flavohemoglobin to the mammal, wherein the disease or disorder is selected from the group consisting of inflammation, stroke, septic shock, arthritis, iritis, ulcerative colitis, acute respiratory distress syndrome and heart failure.
51. The method of claim 50 wherein the flavohemoglobin is administered by local injection.
52. The method of claim 50 wherein the flavohemoglobin is administered intravenously.
53. The method of claim 50 wherein the flavohemoglobin is from Escherichia coli.
54. The method of claim 50 wherein the flavohemoglobin is from Saccharomyces cerevisiae.
55. A method for treating cancer in a mammal, comprising administering an effective amount of a flavohemoglobin to the mammal.
56. The method of claim 55 wherein the flavohemoglobin is administered locally into a tumor.
57. A method for sensitizing a tumor of a mammal to radiation or chemotherapy, comprising administering an effective amount of a flavohemoglobin to the mammal.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A cover for at least one wirebound book having a plurality of pages and a longitudinal axis, said cover comprising:
a. a front panel having planar inwardly and outwardly facing surfaces, said inwardly facing surface having an interior edge extending essentially parallel to the longitudinal axis of the book;
b. a first tab associated with and extending from said interior edge;
c. a first wire interconnected to said first tab and adapted for binding the pages of a first book, said first wire being a coiled wire;
d. a rear panel interconnected to said front panel, said rear panel including inwardly and outwardly facing surfaces, wherein a pocket is defined between said inwardly and outwardly facing surfaces of said rear panel, said pocket being open along the longitudinal edge thereof that is adjacent the front panel and closed along the other edges of said pocket, wherein said pocket receives a cover of a second book having a binding other than the first wire and not binding the first book; and
e. a middle panel interconnected to said rear panel, wherein said middle panel is folded between said front and rear panels when said cover is closed.
2. The cover according to claim 1, further comprising a binding of predetermined width interconnecting said front panel to said rear panel, each of said front and rear panels being pivotally movable relative to said binding about a second axis that is essentially parallel to the longitudinal axis.
3. The cover according to claim 1, wherein said inwardly facing surface of said rear panel includes a second tab associated therewith and extending therefrom, and a second wire interconnected to said second tab and adapted for binding the pages of a book.
4. The cover according to claim 3, wherein said second tab is integral with said inwardly facing surface.
5. The cover according to claim 3, wherein said second tab is affixed to said inwardly facing surface.
6. The cover according to claim 3, wherein said first tab is integral with said inwardly facing surface.
7. The cover according to claim 3, wherein said first tab is affixed to said inwardly facing surface.
8. A cover for at least one wirebound book having a plurality of pages and a longitudinal axis, said cover comprising:
a. a front panel having planar inwardly and outwardly facing surfaces, said inwardly facing surface having an interior edge extending essentially parallel to the longitudinal axis of the book;
b. a first tab associated with and extending from said interior edge;
c. a first wire interconnected to said first tab and adapted for binding the pages of the book, said first wire being a coiled wire;
d. a rear panel interconnected to said front panel through a binding other than the first wire and not binding the first book, said rear panel including inwardly and outwardly facing surfaces; and
e. a middle panel interconnected to said rear panel, wherein said middle panel is folded between said front and rear panels when said cover is closed.
9. The cover according to claim 8, wherein said middle panel and rear panel are pivotally moveable relative to one another about a third axis that extends essentially parallel to the longitudinal axis.
10. The cover according to claim 8, wherein said middle panel includes a pocket formed therein with an opening for said pocket formed along a fourth axis that is transverse to said longitudinal axis.
11. A cover for at least one wirebound book having a plurality of pages and a longitudinal axis, said cover comprising:
a. a front panel comprising at least first and second plies of material, said first ply defining a planar inwardly facing surface and said second ply defining an outwardly facing surface, said inwardly facing surface having an interior edge extending essentially parallel to the longitudinal axis of the book;
b. a first wire interconnected to said inwardly facing surface and separated from said outwardly facing surface, said first wire adapted for binding the pages of a first book, said first wire being a coiled wire;
c. a rear panel interconnected to said front panel, said rear panel including inwardly and outwardly facing surfaces, wherein a pocket is defined between said inwardly and outwardly facing surfaces of said rear panel, said pocket being open along the longitudinal edge thereof that is adjacent the front panel and closed along the other edges of said pocket, wherein said pocket receives a cover of a second book having a binding other than the first wire and not binding the first book, and
d. a middle panel interconnected to said rear panel, wherein said middle panel is folded between said front and rear panels when said cover is closed.
12. The cover according to claim 11, further comprising a
binding of predetermined width interconnecting said front panel to said rear panel, each of said front and rear panels being pivotally movable relative to said binding about a second axis that is essentially parallel to the longitudinal axis.
13. The cover according to claim 11, wherein said middle panel and rear panel are pivotally moveable relative to one another about a third axis that extends essentially parallel to the longitudinal axis.
14. The cover according to claim 11, wherein said middle panel includes a pocket formed therein with an opening for said pocket formed along a fourth axis that is transverse to said longitudinal axis.
15. A cover for at least one wirebound book having a plurality of pages and a longitudinal axis, said cover comprising:
a. a front panel comprising at least first and second plies of material, said first ply defining a planar inwardly facing surface and said second ply defining an outwardly facing surface, said inwardly facing surface having an interior edge extending essentially parallel to the longitudinal axis of the book;
b. a first wire interconnected to said inwardly facing surface and separated from said outwardly facing surface, said first wire adapted for binding the pages of the book, said first wire being a coiled wire;
c. a rear panel interconnected to said front panel, said rear panel including inwardly and outwardly facing surfaces, wherein said inwardly facing surface of said rear panel includes a second wire interconnected thereto that is adapted for binding the pages of a second book and not binding the first book, and
d. a middle panel interconnected to said rear panel, wherein said middle panel is folded between said front and rear panels when said cover is closed.
16. The cover according to claim 15, wherein said second wire is a coiled wire.