Pulmonary hypertension treatment
Disclosed herein is a therapeutically active agent usable in the treatment of pulmonary arterial hypertension (PAH), for use in the treatment of pulmonary arterial hypertension, as well as methods of treating PAH, said treatment and methods comprising administering such an active agent and effecting pulmonary artery denervation in the subject. In some aspects, a sub-therapeutically effective amount of the active agent is administered. In some aspects, the method is devoid of administering such an active agent for at least one month subsequent to the denervation. Further disclosed is a method of treating PAH comprising determining a responsiveness of the subject to at least one therapeutically active agent usable in treating PAH; and effecting pulmonary artery denervation in a subject responsive to the active agent(s).
1. A method of treating pulmonary arterial hypertension in a subject in need thereof, the method comprising:
a) determining a responsiveness of the subject to at least one therapeutically active agent usable in treating pulmonary arterial hypertension; and
b) effecting pulmonary artery denervation in a subject which has been determined according to (a) as being responsive to said at least one therapeutically active agent,
thereby treating the pulmonary arterial hypertension.
2. The method of claim 1 , wherein said at least one therapeutically active agent is selected from the group consisting of an anticoagulant, a prostacyclin receptor agonist, an endothelin inhibitor, and a guanylate cyclase activity enhancer.
3. The method of claim 1 , wherein effecting said pulmonary artery denervation comprises thermally damaging nerve tissue associated with a main pulmonary artery.
4. The method according to claim 3 , wherein said thermally damaging nerve tissue comprises selectively damaging nerves that are not coated by myelin, by emitting energy at a frequency, intensity and duration sufficient to damage only nerves that are not coated by myelin, by producing a predetermined temperature profile in the treated tissue, said temperature profile ranging between 47-57° C.
5. The method according to claim 3 , wherein said thermally damaging nerve tissue is effected by cryotherapy and/or by emitting energy from at least one energy-emitting device introduced into the body.
6. The method according to claim 5 , wherein said energy is selected from the group consisting of ultrasound energy and monopolar or bipolar radiofrequency energy.
7. The method according to claim 6 , wherein said energy comprises unfocused ultrasound energy.
8. The method according to claim 5 , wherein effecting said pulmonary artery denervation comprises introducing a catheter device comprising said at least one energy-emitting device into a main pulmonary artery lumen.
9. The method according to claim 5 , wherein said energy-emitting device is a transceiver, and effecting said pulmonary artery denervation further comprises:
receiving, using said at least one energy-emitting transceiver, echo signals reflected from non-targeted tissue following emission of energy by said at least one transceiver;
analyzing said received echo signals to identify at least one of a type and location of said non-targeted tissue relative to said at least one transceiver; and
emitting energy from said at least one transceiver in accordance with said analyzing, to modify nerve activity without substantially damaging said identified non-targeted tissue.
10. The method according to claim 5 , wherein effecting said pulmonary artery denervation further comprises:
positioning said at least one energy-emitting device within the left pulmonary artery, right pulmonary artery and/or pulmonary artery trunk at a location which is in between the first bifurcation of the left pulmonary artery and the first bifurcation of the right pulmonary artery,
wherein said thermally damaging nerve tissue comprises emitting energy having parameters selected to damage nerves only within a distance window of between 0.2 mm and 10 mm from the intimal aspect of the pulmonary artery wall when said at least one device is positioned at said location.
11. The method of claim 1 , further comprising:
administering to the subject at least one therapeutically active agent usable in treating pulmonary arterial hypertension,
wherein said administering is at a sub-therapeutically effective amount,
thereby treating the pulmonary arterial hypertension.
12. The method of claim 11 , wherein said administering said sub-therapeutically effective amount comprises administering, subsequently to said denervation, a dosage of at least one therapeutically active agent which is lower than a dosage of said agent administered to the subject prior to said denervation.
13. The method of claim 11 , wherein said administering said sub-therapeutically effective amount comprises administering, subsequently to said denervation, fewer therapeutically active agents than are administered to the subject prior to said denervation, wherein at least two therapeutically active agent usable in treating pulmonary arterial hypertension are administered to the subject prior to said denervation.
14. The method of claim 11 , wherein said at least one therapeutically active agent is selected from the group consisting of an anticoagulant, a prostacyclin receptor agonist, an endothelin inhibitor, and a guanylate cyclase activity enhancer.
15. The method of claim 11 , wherein effecting said pulmonary artery denervation comprises thermally damaging nerve tissue associated with a main pulmonary artery.
16. The method according to claim 15 , wherein said thermally damaging nerve tissue comprises selectively damaging nerves that are not coated by myelin, by emitting energy at a frequency, intensity and duration sufficient to damage only nerves that are not coated by myelin, by producing a predetermined temperature profile in the treated tissue, said temperature profile ranging between 47-57° C.
17. The method according to claim 15 , wherein said thermally damaging nerve tissue is effected by cryotherapy and/or by emitting energy from at least one energy-emitting device introduced into the body.
18. The method according to claim 17 , wherein said energy is selected from the group consisting of ultrasound energy and monopolar or bipolar radiofrequency energy.
19. The method according to claim 18 , wherein said energy comprises unfocused ultrasound energy.
20. The method according to claim 15 , wherein effecting said pulmonary artery denervation comprises introducing a catheter device comprising said at least one energy-emitting device into a main pulmonary artery lumen.
21. The method according to claim 15 , wherein said energy-emitting device is a transceiver, and effecting said pulmonary artery denervation further comprises:
receiving, using said at least one energy-emitting transceiver, echo signals reflected from non-targeted tissue following emission of energy by said at least one transceiver;
analyzing said received echo signals to identify at least one of a type and location of said non-targeted tissue relative to said at least one transceiver; and
emitting energy from said at least one transceiver in accordance with said analyzing, to modify nerve activity without substantially damaging said identified non-targeted tissue.
22. The method according to claim 15 , wherein effecting said pulmonary artery denervation further comprises:
positioning said at least one energy-emitting device within the left pulmonary artery, right pulmonary artery and/or pulmonary artery trunk at a location which is in between the first bifurcation of the left pulmonary artery and the first bifurcation of the right pulmonary artery,
wherein said thermally damaging nerve tissue comprises emitting energy having parameters selected to damage nerves only within a distance window of between 0.2 mm and 10 mm from the intimal aspect of the pulmonary artery wall when said at least one device is positioned at said location.
23. The method of claim 1 ,
the method being devoid of administering to the subject a therapeutically active agent usable in the treatment of pulmonary arterial hypertension for a time period of at least one month subsequent to said denervation,
thereby treating the pulmonary arterial hypertension.
24. The method of claim 23 , wherein the method is devoid of administering to the subject said therapeutically active agent usable in the treatment of pulmonary arterial hypertension for a time period of at least one year subsequent to said denervation.
25. The method of claim 24 , wherein said at least one therapeutically active agent is selected from the group consisting of an anticoagulant, a prostacyclin receptor agonist, an endothelin inhibitor, and a guanylate cyclase activity enhancer.
26. The method of claim 23 , wherein effecting said pulmonary artery denervation comprises thermally damaging nerve tissue associated with a main pulmonary artery.
27. The method according to claim 26 , wherein said thermally damaging nerve tissue comprises selectively damaging nerves that are not coated by myelin, by emitting energy at a frequency, intensity and duration sufficient to damage only nerves that are not coated by myelin, by producing a predetermined temperature profile in the treated tissue, said temperature profile ranging between 47-57° C.
28. The method according to claim 26 , wherein said thermally damaging nerve tissue is effected by cryotherapy and/or by emitting energy from at least one energy-emitting device introduced into the body.
29. The method according to claim 28 , wherein said energy is selected from the group consisting of ultrasound energy and monopolar or bipolar radiofrequency energy.
30. The method according to claim 29 , wherein said energy comprises unfocused ultrasound energy.
31. The method according to claim 26 , wherein effecting said pulmonary artery denervation comprises introducing a catheter device comprising said at least one energy-emitting device into a main pulmonary artery lumen.
32. The method according to claim 26 , wherein said energy-emitting device is a transceiver, and effecting said pulmonary artery denervation further comprises:
receiving, using said at least one energy-emitting transceiver, echo signals reflected from non-targeted tissue following emission of energy by said at least one transceiver;
analyzing said received echo signals to identify at least one of a type and location of said non-targeted tissue relative to said at least one transceiver; and
emitting energy from said at least one transceiver in accordance with said analyzing, to modify nerve activity without substantially damaging said identified non-targeted tissue.
33. The method according to claim 26 , wherein effecting said pulmonary artery denervation further comprises:
positioning said at least one energy-emitting device within the left pulmonary artery, right pulmonary artery and/or pulmonary artery trunk at a location which is in between the first bifurcation of the left pulmonary artery and the first bifurcation of the right pulmonary artery,
wherein said thermally damaging nerve tissue comprises emitting energy having parameters selected to damage nerves only within a distance window of between 0.2 mm and 10 mm from the intimal aspect of the pulmonary artery wall when said at least one device is positioned at said location.
34. The method according to claim 1 , wherein said at least one therapeutically active agent comprises guanylate cyclase activity enhancer.
35. The method accoridng to claim 34 , wherein said guanylate cyclase activity enhancer is selected from a group consisting of sildenafil, tadalafil, vardenafil and riociguat.
36. The method according to claim 34 , wherein said guanylate cyclase activity enhancer is an an inhibitor of phosphodiesterase 5.
37. The method according to claim 36 , wherein said guanylate cyclase activity enhancer is selected from a group consisting of, avanafil, benzamidenafil, dasantafil, lodenafil, mirodenafil, udenafil, and zaprinast.
38. The method of claim 34 , wherein said determining comprises determining a responsiveness of the subject to said guanylate cyclase activity enhancer and to at least one additional active agent used in combination in treating pulmonary arterial hypertension.
39. The method of claim 38 , wherein said at least one additional active agent comprises at least one of, an anticoagulant, a prostacyclin receptor agonist and/or an endothelin inhibitor.
40. The method of claim 1 , comprising:
c) administering a sub-therapeutically effective amount of said at least one therapeutically active agent following said effecting.