Methods and formulations for minimizing spasticity in blood vessel grafts

• US 20030087878A1
• Filed: 10/31/2002
• Published: 05/08/2003
• Est. Priority Date: 10/31/2001
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Vinten-Johansen, Jakob, Velez, Daniel A.
• Granted Patent: US 6,900,008 B2
• Time in Patent Office: Days
• US Class Current: 514/56
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications

Abstract

The present invention relates to me methods for minimizing spasticity in blood vessels during transplantation and more particularly for minimizing spasticity in arterial transplants, for both ex-vivo and in-vivo procedures. The invention also relates to formulations, which can be used in these methods.

Claims

1. A pharmaceutical formulation for minimizing spasticity in blood vessel grafts during and after implantation, comprising a spasticity minimizing agent, an anti-coagulating agent and at least one vasodilator agent.

2. The formulation of claim 1 wherein said spasticity minimizing agent is selected from the group consisting of haloalkylamine alpha adrenergic blocking agents.

3. The formulation of claim 1 wherein said spasticity minimizing agent is selected from the group consisting of phenoxybenzamine, isomers of phenoxybenzamine and tertiary amines of phenoxybenzamine.

4. The formulation of claim 2 wherein said haloalkylamine alpha-adrenergic blocking agent is selected from the group consisting of phenoxybenzamine, isomers of phenoxybenzamine and tertiary amines of phenoxybenzamine.

5. The formulation of claim 1 wherein the spasticity minimizing agent is present in solution in a concentration of about 10⁻

6M to about 10<sup>−

1</sup>M, the anti-coagulating agent is present in a concentration sufficient to make activated clotting time greater than about 200 seconds, and the at least one vasodilator agent is present in a concentration of about 5 to about 60 mg.

6. The formulation of claim 5 wherein the anti-coagulating agent is present in a dosage of about 10 to about 1000 IU.

7. The formulation of claim 1, wherein the anti-coagulating agent is selected from the group consisting of heparin, coumadin, ETDA, citrate, EGTA and other anti-coagulating agents that increase activated clotting time greater than about 200 seconds.

8. The formulation of claim 1 wherein the at least one vasodilator agent is selected from the group consisting of lidocaine, xylocaine, tetracaine, procaine and other short-term vasodilators such as papaverine, adenosine, nitric oxide donor agents, calcium channel blocker agents, sodium channel blocker agents and related adenosine regulating agents.

9. The formulation of claim 1 wherein the at least one vasodilator agent is selected from the group consisting of papaverine, adenosine, nitric oxide donor agents, calcium channel blocker agents, sodium channel blocker agents and related adenosine regulating agents.

10. The formulation of claim 1 wherein the at least one vasodilator agent is selected from the group at lidocaine and papaverine.

11. A method for the pretreatment and implantation of blood vessel grafts in a patient undergoing vascular surgery, which comprises:

(a) harvesting a blood vessel for use as an arterial graft;

(b) forming a solution including a spasticity minimizing agent;

(c) combining the solution of the spasticity minimizing agent with at least one vasodilator agent and an anti-coagulating agent to form the spasticity minimizing agent pretreatment solution;

(d) soaking the harvested blood vessel in the spasticity minimizing agent pretreatment solution for a period of time; and

(e) removing the harvested blood vessel from the spasticity minimizing agent pretreatment solution and implanting the harvested blood vessel as an arterial graft into the patient.

12. The method of claim 11, wherein an amount of the patient'"'"'s blood is added to combination step (c).

13. The method of claim 12, wherein a physiologic crystalloid buffer solution is added to combination step (c).

14. A method for the pretreatment and implantation of arterial grafts in patients undergoing vascular surgery, which comprises:

(a) harvesting an artery for use as an arterial graft;

(b) forming a solution including a diluent and phenoxybenzamine;

(c) combining the solution including phenoxybenzamine with an amount of a patient'"'"'s blood, at least one vasodilator agent, and an anti-coagulating agent to form a phenoxybenzamine pretreatment solution;

(d) soaking the harvested artery in the phenoxybenzamine pretreatment solution for a period of time; and

(e) removing the harvested artery from the phenoxybenzamine pretreatment solution and implanting the harvested artery as an arterial graft into the patient.

15. The method of claim 14, wherein the diluent is selected from the group consisting of normal saline and related physiological solutions and buffer solutions.

16. The method of claim 14, wherein the harvesting of the artery includes the artery and the surrounding pedicle of the artery.

17. The method of claim 16, wherein the pedicle has been modified to increase exposure of the arterial graft to the phenoxybenzamine pretreatment solution.

18. The method of claim 17, wherein the pedicle is modified by a fasciotomy.

19. The method of claim 14, wherein the harvesting of the artery includes only the skeletonized portion of the artery.

20. The method of claim 14, wherein the harvested artery is selected from the group consisting of internal mammary arteries, gastroepiploic arteries, inferior epigastric arteries. radial arteries and any other artery designated for a vascular conduit.

21. The method of claim 20, wherein the harvested artery is a radial artery.

22. The method of claim 14, wherein the concentration of phenoxybenzamine in the phenoxybenzamine pretreatment solution ranges from about 10⁻

6M to about 10<sup>−

1</sup>M.

23. The method of claim 16, wherein the concentration of phenoxybenzamine in the phenoxybenzamine pretreatment solution ranges from about 10⁻

6M to about 10<sup>−

1</sup>M.

24. The method of claim 14, wherein the time period in which the harvested artery is soaked in the phenoxybenzamine pretreatment solution ranges from about 5 to about 60 minutes.

25. The method of claim 14, wherein the harvested artery and the phenoxybenzamine pretreatment solution are placed into an enclosure capable of being sealed and pressurized, the enclosure is then sealed, and the enclosure is then pressurized to a pressure of 0.01 to 100 mm Hg for a period of time to assist the penetration of the phenoxybenzamine pretreatment solution into the harvested artery.

26. The method of claim 25, wherein the time period in which the harvested artery is soaked in the phenoxybenzamine pretreatment solution ranges from about 5 to about 60 minutes.

27. The method of claim 14, wherein the soaking step additionally comprises an intralumenal injection of the phenoxybenzamine pretreatment solution into the harvested artery or a companion vein that may empty into the harvested artery.

28. The method of claim 27, wherein the harvested artery, after the intralumenal injection of the phenoxybenzamine pretreatment solution into the harvested artery or companion vein that may empty into the harvested artery, is pressurized to a pressure of 0.01 to 100 mm Hg for a period of time to assist the penetration of the phenoxybenzamine pretreatment solution into the harvested artery.

29. The method of claim 28, wherein the harvested artery, after the intralumenal injection of the phenoxybenzamine pretreatment solution into the harvested artery or companion vein that may empty into the harvested artery, is clamped or otherwise closed at least one end prior to being pressurized.

30. A method for the in-vivo pretreatment and implantation of an internal thoracic artery conduit in patients undergoing coronary bypass surgery, which comprises:

a) harvesting the internal thoracic artery for use as one end of the conduit;

b) soaking the one end of the harvested artery conduit in a phenoxybenzamine solution for a period of time; and

c) removing the one end of the harvested artery conduit from the phenoxybenzamine solution and implanting the harvested artery conduit as an arterial graft into the patient.