Methods for inducing atrial and ventricular rhythms using ultrasound and microbubbles

• US 6,439,236 B1
• Filed: 10/25/1999
• Issued: 08/27/2002
• Est. Priority Date: 10/25/1999
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Nebraska
• Original Assignee: Board of Regents of the University of Nebraska
• Inventors: Xie, Feng, Porter, Thomas R.
• Primary Examiner(s): Isabella, David J.
• Assistant Examiner(s): Chattopadhyay, Urmi
• Application Number:
  US09/426,378
• Time in Patent Office: 1,037 Days
• Field of Search: 601/2, 607/152, 424/9.52, 424/94.63, 424/94.64, 424/9.5, 604/23, 604/24, 604/26, 604/27, 604/28, 604/290, 604/20, 604/500, 604/506, 604/507, 604/511, 600/431, 600/508-528, 600/437-461, 600/9-17, 128/898, 530/363, 530/427
• US Class Current: 128/898
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents

Abstract

A new and improved method for inducing or pacing atrial and ventricular arrhythmias in animals Embodiments of the invention involve using microbubbles enhanced with an insoluble gas in combination with low frequency ultrasound for its pacing activity. The methods and compositions can be used to pace patients, convert patients out of atrial fibrillation, and as a diagnostic to assess a patient'"'"'s risk for arrhythmias.

Claims

1. A method of inducing or pacing atrial and/or ventricular rhythms in animals comprising the steps of:

introducing a microbubble composition to said animal by intravenous injection so that the heart of said animal becomes perfused with said microbubble composition, said microbubble composition comprising a plurality of gas filled microbubbles with a diameter of from about 0.1 to about 10 microns and a pharmaceutically acceptable carrier, and in combination;

applying a low frequency, high mechanical index ultrasound to said animal so that an ultrasound field is directed to the heart, or a portion thereof to induce paced beats.

2. The method of claim 1 wherein said ultrasound is applied at a frequency of 2.5 Mhz or less.

3. The method of claim 1 wherein said ultrasound is applied at a frequency of 1 Mhz.

4. The method of claim 1 wherein said ultrasound is applied at a mechanical index of 0.7.

5. The method of claim 1 wherein said ultrasound is applied in continuous wave mode.

6. The method of claim 1 wherein said ultrasound is directed to the ventricle of said heart.

7. The method of claim 1 wherein said ultrasound is directed to the atrium of said heart.

8. The method of claim 1 wherein said gas is an insoluble gas.

9. The method of claim 8 wherein said insoluble gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

10. The method of claim 9 wherein said insoluble gas is perfluorobutane.

11. The method of claim 9 wherein said insoluble gas is perfluoropropane.

12. The method of claim 1 wherein said microbubbles are protein coated.

13. The method of claim 12 wherein said protein coated microspheres are albumin coated microbubbles.

14. The method of claim 1 wherein said carrier is a 5% solution of dextrose.

15. The method of claim 1 further comprising the following steps:

mixing an aqueous solution comprising from about 2% to about 10% by weight of human serum albumin diluted about two fold to about eight fold with from about 5% to about 50% by weight dextrose; and

exposing said solution to a sonication horn to generate stable microbubbles from about 0.1 to bout 10 microns in diameter, to create said microbubble composition.

16. The method of claim 15 wherein said dilution of albumin with dextrose is a 3-fold dilution.

17. The method of claim 15 wherein said human serum albumin is a 5% by weight solution.

18. The method of claim 15 wherein said dextrose is a 5% by weight solution.

19. The method of treatment for use in inducing or pacing arrhythmias in animals comprising:

(a) obtaining a pharmaceutical composition which consists essentially of;

a solution of stable microbubbles approximately 0.1 to about 10 microns in

diameter, and a pharmaceutically acceptable carrier;

(b) introducing said microbubble composition to the heart of said animal; and

(c) exposing said microbubble composition and said heart to a transthoracic ultrasound field for a time sufficient to stimulate arrhythmia.

20. The method of claim 19 wherein said ultrasound is applied at a frequency of 2.5 Mhz or less.

21. The method of claim 19 wherein said ultrasound is applied at a frequency of 1 Mhz.

22. The method of claim 19 wherein said ultrasound is applied at a mechanical index of 0.7.

23. The method of claim 19 wherein said ultrasound is applied in continuous wave mode.

24. The method of claim 19 wherein said ultrasound is directed to the ventricle of said heart.

25. The method of claim 19 wherein said ultrasound is directed to the atrium of said heart.

26. The method of claim 19 wherein said step of introducing said agent to said heart is by intravenous injection.

27. The method of claim 19 wherein said dextrose is a 5% solution.

28. The method of claim 19 wherein said protein coated microbubbles are albumin coated microbubbles.

29. The method of claim 19 further comprising the following steps:

mixing aqueous solution comprising from about 2% to about 10% by weight of human serum albumin diluted about two fold to about eight fold with from about 5% to about 50% by weight dextrose; and

exposing said solution to a sonication horn to create cavitation at particulate sites in said solution generating stable microspheres from about 0.1 to about 10 microns in diameter, to form said pharmaceutical composition.

30. The method of claim 29 wherein said dilution of albumin with dextrose is a 3-fold dilution.

31. The method of claim 29 wherein said human serum albumin is a 5% by weight solution.

32. The method of claim 29 wherein said dextrose is a 5% by weight solution.

33. The method of claim 19 wherein said microbubble composition comprises:

microbubbles enhanced with an insoluble gas wherein said gas is encapsulated in a protein-coated shell.

34. The method of claim 33 wherein said insoluble gas is a perfluorocarbon gas.

35. The method of claim 34 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

36. The method of claim 35 wherein said perfluorocarbon gas is perfluorobutane.

37. The method of claim 35 wherein said perfluorocarbon gas is perfluoropropane.

38. A method for converting animals out of fibrillation comprising:

introducing a microbubble composition to said animal by intravenous injection so that said composition will perfuse the heart, a pharmaceutical composition comprising a microbubble ultrasound contrast agent, and thereafter;

applying transthoracic high mechanical index ultrasound to said heart of a portion thereof.