Combinations and methods for the treatment and/or prevention of fungal infections
Provided are combinations comprising terbinafine or a pharmaceutically acceptable salt thereof and a NO source. The combination may be a synergistic combination. Also provided are methods of treating and/or preventing a fungal infection in a subject comprising administering terbinafine or a pharmaceutically acceptable salt thereof to the subject; and administering a NO source to the subject, thereby treating and/or preventing the fungal infection in the subject. The dose of terbinafine or a pharmaceutically acceptable salt thereof and the dose of the NO source administered to the subject may achieve a synergistic effect.
1. A method of treating and/or preventing a fungal infection in a subject, the method comprising:
administering terbinafine or a pharmaceutically acceptable salt thereof to the subject; and
administering a NO source to the subject, thereby treating and/or preventing the fungal infection in the subject,
wherein the NO source is a N-diazeniumdiolate-functionalized macromolecule, and
wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are each administered to the subject at a dose that achieves a synergistic effect.
2. The method of claim 1 , wherein administering the NO source to the subject comprises increasing a level of nitric oxide at a given site on and/or in a subject.
3. The method of claim 2 , wherein the given site comprises skin and/or a nail of the subject where the fungal infection is present.
4. The method of claim 1 , wherein the N-diazeniumdiolate-functionalized macromolecule is a N-diazeniumdiolate co-condensed polysiloxane macromolecule.
5. The method of claim 1 , wherein administering the NO source to the subject further comprises releasing nitric oxide from the NO source by exposure to light and/or an electrical current.
6. The method of claim 1 , wherein administering terbinafine or the pharmaceutically acceptable salt thereof to the subject comprises administering terbinafine or the pharmaceutically acceptable salt thereof at a dose of less than 250 mg per day.
7. The method of claim 1 , wherein the NO source delivers a dose of nitric oxide to the subject that is at least 20% less than the concentration effective to inhibit fungi growth and/or kill fungi for the NO source alone.
8. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof is administered at a concentration that is less than a concentration for terbinafine or the pharmaceutically acceptable salt thereof alone that provides a 3 log microbial kill for the fungi in 4 hours or 24 hours and the NO source is administered at a concentration that is less than a concentration for the NO source alone that provides a 3 log microbial kill for the fungi in 4 hours or 24 hours.
9. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are each administered at a concentration that provides a greater than or equal to 2 log i c (CFU/mL) decrease in fungi compared to administration of terbinafine or a pharmaceutically acceptable salt thereof or the NO source alone.
10. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are each administered at a sub-microbial bactericidal concentration for the fungi.
11. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof is administered at a concentration that is less than a concentration for terbinafine or the pharmaceutically acceptable salt thereof alone that provides a 3 log microbial kill for the fungi in 4 hours or 24 hours.
12. The method of claim 1 , wherein the NO source is administered at a concentration that is less than a concentration for the NO source alone that provides a 3 log microbial kill for the fungi in 4 hours or 24 hours.
13. The method of claim 1 , wherein administering terbinafine or the pharmaceutically acceptable salt thereof to the subject comprises administering terbinafine or the pharmaceutically acceptable salt thereof at a dose of less than 200 mg per day.
14. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are simultaneously administered to the subject.
15. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are sequentially administered to the subject in any order.
16. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are separately administered to the subject.
17. The method of claim 1 , wherein terbinafine or a pharmaceutically acceptable salt thereof and the NO source are in a fixed combination that is administered to the subject.