Methods for diagnostic imaging by regulating the administration rate of a contrast agent

• US 6,033,645 A
• Filed: 06/19/1996
• Issued: 03/07/2000
• Est. Priority Date: 06/19/1996
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: DuPont Displays Incorporated (Corteva, Inc.)
• Inventors: Matsunaga, Terry, Fritz, Thomas A., Unger, Evan C., Ramaswami, Varadarajan
• Primary Examiner(s): RICHTER, JOHANN R
• Assistant Examiner(s): Delaney, Patrick R.
• Application Number:
  US08/666,129
• Time in Patent Office: 1,357 Days
• Field of Search: 424/9.5, 424/450, 424/9.51, 424/9.52
• US Class Current: 424/9.5
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: Y10S 977/801 Drug
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/928 X-ray agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent
• CPC Class Codes: Y10S 977/93 MRI contrast agent

Abstract

Methods for providing an image of an internal region of a patient. Embodiments of the methods involve administering to the patient a contrast agent which comprises a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids, proteins or polymers. The patient is scanned using diagnostic imaging, such as ultrasound, to obtain a visible image of the region. The contrast agent is administered to the patient at a rate to substantially eliminate diagnostic artifacts in the image. The methods are particularly useful for diagnosing the presence of any diseased tissue in the patient.

Claims

1. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said vesicle composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in the image, wherein said administration rate comprises continuos infusion.

14. A method according to claim 1 wherein said gas comprises a fluorinated gas.

15. A method according to claim 14 wherein said fluorinated gas is selected from the group consisting of a perfluorocarbon, sulfur hexafluoride and heptafluoropropane.

16. A method according to claim 15 wherein said fluorinated gas comprises a perfluorocarbon.

17. A method according to claim 16 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

18. A method according to claim 1 wherein said gaseous precursor has a boiling point of greater than about 37°

C.

19. A method according to claim 18 wherein said gaseous precursor comprises a fluorinated compound.

20. A method according to claim 19 wherein said fluorinated compound comprises a perfluorocarbon.

21. A method according to claim 20 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

22. A method according to claim 1 wherein said internal region comprises the heart region.

23. A method according to claim 1 wherein said vesicle composition is administered to the patient at a rate of from about 1×

10⁶ to less than about 8×

10⁶ vesicles/Kg-sec.

24. A method according to claim 23 wherein said vesicle composition is administered at a rate of from about 1×

10⁶ to about 7×

10⁶ vesicles/Kg-sec.

25. A method according to claim 24 wherein said vesicle composition is administered at a rate of from about 1.5×

10⁶ to about 6×

10⁶ vesicles/Kg-sec.

26. A method according to claim 25 wherein said vesicle composition is administered at a rate of from about 2×

10⁶ to about 5.5×

10⁶ vesicles/Kg-sec.

27. A method according to claim 26 wherein said vesicle composition is administered at a rate of from about 2.5×

10⁶ to about 5×

10⁶ vesicles/Kg-sec.

28. A method according to claim 27 wherein said vesicle composition is administered at a rate of from about 3×

10⁶ to about 4.5×

10⁶ vesicles/Kg-sec.

29. A method according to claim 1 wherein said vesicle composition is administered to the patient at a rate of from about 1×

10^-7 to about 3×

10^-3 cc gas/Kg-sec.

30. A method according to claim 29 wherein said vesicle composition is administered at a rate of from about 3×

10^-6 to about 3×

10^-3 cc gas/Kg-sec.

31. A method according to claim 30 wherein said vesicle composition is administered at a rate of from about 4×

10^-6 to about 2×

10^-3 cc gas/Kg-sec.

32. A method according to claim 31 wherein said vesicle composition is administered at a rate of from about 8×

10⁶ to about 2×

10^-3 cc gas/Kg-sec.

33. A method according to claim 32 wherein said vesicle composition is administered at a rate of from about 1×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

34. A method according to claim 33 wherein said vesicle composition is administered at a rate of from about 4×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

35. A method according to claim 33 wherein said vesicle composition is administered at a rate of from about 8×

10^-5 to less than about 1×

10^-3 CC gas/Kg-sec.

36. A method according to claim 35 wherein said vesicle composition is administered at a rate of from about 1×

10^-4 to about 9×

10^-4 cc gas/Kg-sec.

178. A method according to claim 1 wherein said composition is reconstructed from a lyophilized composition.

2. A method according to claim I wherein said vesicles comprise lipids.

3. A method according to claim 2 wherein said vesicle composition comprises vesicles selected from the group consisting of micelles and liposomes.

4. A method according to claim 2 wherein said lipids comprise phospholipids.

5. A method according to claim 4 wherein said phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

6. A method according to claim 5 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidycholine.

7. A method according to claim 6 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

8. A method according to claim 5 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

9. A method according to claim 8 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

10. A method according to claim 5 wherein said phosphatidic acid comprises dipalmitolylphosphatidic acid.

11. A method according to claim 2 wherein said lipid further comprises a polymer.

12. A contrast agent according to claim 11 wherein said polymer comprises a hydrophilic polymer.

13. A method according to claim 11 wherein said hydrophilic polymer comprises polyethylene glycol.

127. A method according to claim 2 wherein said vesicles comprise lipid-coated bubbles.

128. A method according to claim 127 wherein said vesicles are selected from the group consisting of unilamellar vesicles, oligolamellar vesicles and multilamellar vesicles.

129. A method according to claim 128 wherein said vesicles comprise unilamellar vesicles.

130. A method according to claim 129 wherein said vesicles comprise one monolayer.

131. A method according to claim 130 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

132. A method according to claim 129 wherein said vesicles comprise one bilayer.

133. A method according to claim 132 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

134. A method according to claim 128 wherein said vesicles are selected from the group consisting of oligolamellar vesicles and multilamellar vesicles.

135. A method according to claim 134 wherein said vesicles comprise one monolayer.

136. A method according to claim 135 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

137. A method according to claim 134 wherein said vesicles comprise one bilayer.

138. A method according to claim 137 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

163. A method according to claim 127 wherein said vesicles further comprise polyethylene glycol.

165. A method according to claim 127 wherein said lipid is a phospholipid.

166. A method according to claim 130 wherein said lipid is a phospholipid.

167. A method according to claim 132 wherein said lipid is a phospholipid.

168. A method according to claim 135 wherein said lipid is a phospholipid.

169. A method according to claim 137 wherein said lipid is a phospholipid.

179. A method according to claim 2 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

180. A method according to claim 179 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

37. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a lipid composition comprising, in an aqueous carrier, a lipid and a gas or gaseous precursor, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said lipid composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in the image, wherein said administration rate comprises continuous infusion.

38. A method according to claim 37 wherein said lipid comprises a phospholipid.

39. A method according to claim 38 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

40. A method according to claim 39 wherein said lipid composition comprises a vesicle composition.

41. A method according to claim 40 wherein said vesicle composition comprises vesicles selected from the group consisting of micelles and liposomes.

42. A method according to claim 37 wherein said lipid composition is administered to the patient at a rate of from about 1×

10^-7 to about 3×

10^-3 cc gas/Kg-sec.

43. A method according to claim 42 wherein said lipid composition is administered at a rate of from about 3×

10^-6 to about 3×

10^-3 cc gas/Kg-sec.

44. A method according to claim 43 wherein said lipid composition is administered at a rate of from about 4×

10^-6 to about 2×

10^-3 cc gas/Kg-sec.

45. A method according to claim 44 wherein said lipid composition is administered at a rate of from about 8×

10^-6 to about 2×

10^-3 cc gas/Kg-sec.

46. A method according to claim 45 wherein said lipid composition is administered at a rate of from about 1×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

47. A method according to claim 46 wherein said lipid composition is administered at a rate of from about 4×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

48. A method according to claim 47 wherein said lipid composition is administered at a rate of from about 8×

10^-5 to less than about 1×

10^-3 cc gas/Kg-sec.

49. A method according to claim 48 wherein said lipid composition is administered at a rate of from about 1×

10^-4 to about 9×

10^-4 cc gas/Kg-sec.

139. A method according to claim 37 wherein said lipid is selected from the group consisting of unilamellar lipids, oligolamellar lipids or multilamellar lipids.

140. A method according to claim 139 wherein said lipid is a unilamellar lipid.

141. A method according to claim 140 wherein said unilamellar lipid comprises one monolayer.

142. A method according to claim 141 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

143. A method according to claim 141 wherein said lipid comprises one bilayer.

144. A method according to claim 143 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

145. A method according to claim 139 wherein said lipid is selected from the group consisting of oligolamellar lipids and multilamellar lipids.

146. A method according to claim 145 wherein said lipid comprises one monolayer.

147. A method according to claim 146 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

148. A method according to claim 145 wherein said lipid comprises one bilayer.

149. A method according to claim 148 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

170. A method according to claim 141 wherein said lipid is a phospholipid.

171. A method according to claim 143 wherein said lipid is a phospholipid.

172. A method according to claim 146 wherein said lipid is a phospholipid.

173. A method according to claim 148 wherein said lipid is a phospholipid.

181. A method according to claim 37 wherein said composition is reconstituted from a lyophilized composition.

182. A method according to claim 37 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

183. A method according to claim 182 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

50. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

51. A method accroding to claim 50 wherien said vesicles comprise lipids.

52. A method according to claim 50 wherein said lipids comprise phospholipids.

53. A method according to claim 52 wherein said phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

54. A method according to claim 53 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

55. A method according to claim 54 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

56. A method according to claim 53 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

57. A method according to claim 56 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

58. A method according to claim 53 wherein said phosphatidic acid comprises dipalmitolylphosphatidic acid.

59. A method according to claim 50 wherein said vesicle composition is flushed with a saline solution.

60. A method according to claim 50 wherein said gas comprises a fluorinated gas.

61. A method according to claim 60 wherein said fluorinated gas is elected from the group consisting of a perfluorocarbon gas, sulfur hexafluoride and eptafluoropropane.

62. A method according to claim 61 wherein said fluorinated gas comprises a perfluorocarbon.

63. A method according to claim 62 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

64. A method according to claim 50 wherein said gaseous precursor has a boiling point of greater than about 37°

C.

65. A method according to claim 64 wherein said gaseous precursor comprises a fluorinated compound.

66. A method according to claim 65 wherein said fluorinated compound comprises a perfluorocarbon.

67. A method according to claim 66 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

68. A method according to claim 61 wherein said vesicle composition comprises vesicles selected from the group consisting of micelles and liposomes.

69. A method according to claim 50 wherein said internal region omprises the heart region.

70. A method according to claim 50 wherein said vesicle composition is flushed at a rate of from about 0.01 to about 2.4 mL/sec.

71. A method according to claim 70 wherein said vesicle composition is flushed at a rate of from about 0.05 to about 2 mL/sec.

72. A method according to claims 71 wherein said vesicle composition is flushed at a rate of from about 0.07 to about 1.8 mL/sec.

73. A method according to claim 72 wherein said vesicle composition is flushed at a rate of from about 0.09 to about 1.6 mL/sec.

74. A method according to claim 73 wherein said vesicle composition is flushed at a rate of from about 0.1 to about 1.5 mL/sec.

75. A method according to claim 74 wherein said vesicle composition is flushed at a rate of from about 0.3 to about 1.3 mL/sec.

150. A method according to claim 50 wherein said vesicles comprise lipid-coated bubbles.

151. A method according to claim 150 wherein said vesicles are selected from the group consisting of unilamellar vesicles, oligolamellar vesicles and multilamellar vesicles.

152. A method according to claim 151 wherein said lipids comprise a phospholipid.

153. A method according to claim 151 wherein said vesicles comprise unilamellar vesicles.

154. A method according to claim 153 wherein said vesicles comprise one monolayer.

155. A method according to claim 153 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

156. A method according to claim 153 wherein said vesicles comprise one bilayer.

157. A method according to claim 156 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

158. A method according to claim 157 wherein said vesicles are selected from the group consisting of oligolamellar vesicles and multilamellar vesicles.

159. A method according to claim 158 wherein said vesicles comprise one monolayer.

160. A method according to claim 159 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

161. A method according to claim 158 wherein said vesicles comprise one bilayer.

162. A method according to claim 161 wherein said lipid is a phospholipid and said gas or gaseous precursor is perfluoropropane.

164. A method according to claim 150 wherein said vesicles further comprise polyethylene glycol.

174. A method according to claim 154 wherein said lipid is a phospholipid.

175. A method according to claim 156 wherein said lipid is a phospholipid.

176. A method according to claim 159 wherein said lipid is a phospholipid.

177. A method according to claim 161 wherein said lipid is a phospholipid.

184. A method according to claim 50 wherein said composition is reconstituted from a lyophilized composition.

185. A method according to claim 51 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

186. A method according to claim 185 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

76. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a lipid composition comprising, in an aqueous carrier, a lipid and a gas or gaseous precursor, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises contiguous infusion.

77. A method according to claim 76 wherein said lipid comprises a phospholipid.

78. A method according to claim 77 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

79. A method according to claim 78 wherein said lipid composition comprises a vesicle composition.

80. A method according to claim 76 wherein said vesicle composition comprises vesicles selected from the group consisting of micelles and liposomes.

81. A method according to claim 76 wherein said internal region comprises the heart region.

82. A method according to claim 76 wherein said composition is flushed at a rate of from about 0.01 to about 2.4 mL/sec.

83. A method according to claim 82 wherein said lipid composition is flushed at a rate of from about 0.05 to about 2 mL/sec.

84. A method according to claim 83 wherein said lipid composition is flushed at a rate of from about 0.07 to about 1.8 mL/sec.

85. A method according to claim 84 wherein said lipid composition is flushed at a rate of from about 0.09 to about 1.6 mL/sec.

86. A method according to claim 85 wherein said lipid composition is flushed at a rate of from about 0.1 to about 1.5 mL/sec.

87. A method according to claim 86 wherein said lipid composition is flushed at a rate of from about 0.3 to about 1.3 mL/sec.

187. A method according to claim 76 wherein said composition is reconstituted from a lyophilized composition.

188. A method according to claim 76 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

189. A method according to claim 188 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

88. A method for substantially eliminating ultrasound artifacts in an ultrasound image of an internal region of a patient comprising regulating the rate at which a contrast agent is administered to the patient, wherein said administration rate comprises continuous infusion.

89. A method according to claim 88 wherein said contrast agent comprises a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids.

90. A method according to claim 89 wherein said vesicle composition comprises vesicles selected from the group consisting of micelles and liposomes.

91. A method according to claim 89 wherein said lipids comprise phospholipids.

92. A method according to claim 91 wherein said phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

93. A method according to claim 92 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

94. A method according to claim 93 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

95. A method according to claim 92 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

96. A method according to claim 95 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

97. A method according to claim 92 wherein said phosphatidic acid comprises dipalmitolylphosphatidic acid.

98. A method according to claim 89 wherein said lipid further comprises a polymer.

99. A contrast agent according to claim 98 wherein said polymer comprises a hydrophilic polymer.

100. A method according to claim 99 wherein said hydrophilic polymer comprises polyethylene glycol.

101. A method according to claim 89 wherein said vesicle composition is administered to the patient at a rate of from about 1×

10⁶ to less than about 8×

10⁶ vesicles/Kg-sec.

102. A method according to claim 101 wherein said vesicle composition is administered at a rate of from about 1×

10⁶ to about 7×

10⁶ vesicles/Kg-sec.

103. A method according to claim 102 wherein said vesicle composition is administered at a rate of from about 1.5×

10⁶ to about 6×

10⁶ vesicles/Kg-sec.

104. A method according to claim 103 wherein said vesicle composition is administered at a rate of from about 2×

10⁶ to about 5.5×

10⁶ vesicles/Kg-sec.

105. A method according to claim 104 wherein said vesicle composition is administered at a rate of from about 2.5×

10⁶ to about 5×

10⁶ vesicles/Kg-sec.

106. A method according to claim 105 wherein said vesicle composition is administered at a rate of from about 3×

10⁶ to about 4.5×

10⁶ vesicles/Kg-sec.

107. A method according to claim 89 wherein said vesicle composition is administered to the patient at a rate of from about 1×

10^-7 to about 3×

10^-3 cc gas/Kg-sec.

108. A method according to claim 107 wherein said vesicle composition is administered at a rate of from about 3×

10^-6 to about 3×

10^-3 cc gas/Kg-sec.

109. A method according to claim 108 wherein said vesicle composition is administered at a rate of from about 4×

10^-6 to about 2×

10^-3 cc gas/Kg-sec.

110. A method according to claim 108 wherein said vesicle composition is administered at a rate of from about 8×

10^-6 to about 2×

10^-3 cc gas/Kg-sec.

111. A method according to claim 110 wherein said vesicle composition is administered at a rate of from about 1×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

112. A method according to claim 111 wherein said vesicle composition is administered at a rate of from about 4×

10^-5 to about 1×

10^-3 cc gas/Kg-sec.

113. A method according to claim 112 wherein said vesicle composition is administered at a rate of from about 8×

10^-5 to less than about 1×

10^-3 cc gas/Kg-sec.

114. A method according to claim 113 wherein said vesicle composition is administered at a rate of from about 1×

10^-4 to about 9×

10^-4 cc gas/Kg-sec.

115. A method according to claim 88 wherein said administration also comprises flushing said contrast agent.

116. A method according to claim 115 wherein said contrast agent is flushed at a rate of from about 1×

10^-7 to about 3×

10^-3 cc gas/Kg-sec.

117. A method according to claim 116 wherein said contrast agent is flushed at a rate of from about 0.05 to about 2 mL/sec.

118. A method according to claim 117 wherein said contrast agent is flushed at a rate of from about 0.07 to about 1.8 mL/sec.

119. A method according to claim 118 wherein said contrast agent is flushed at a rate of from about 0.09 to about 1.6 mL/sec.

120. A method according to claim 119 wherein said contrast agent is flushed at a rate of from about 0.1 to about 1.5 mL/sec.

121. A method according to claim 120 wherein said contrast agent is flushed at a rate of from about 0.3 to about 1.3 mL/sec.

122. A method according to claim 88 wherein the region comprises the heart region.

190. A method according to claim 89 wherein said composition is reconstituted from a lyophilized composition.

191. A method according to claim 89 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

192. A method according to claim 191 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

221. A method according to claim 88 wherein said contrast agent comprises a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising surfactants.

222. A method according to claim 221 wherein said composition is reconstituted from a lyophilized composition.

223. A method according to claim 221 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

224. A method according to claim 223 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

123. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said vesicle composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in said image, wherein said administration rate comprises continuous infusion.

193. A method according to claim 123 wherein said composition is reconstituted from a lyophilized composition.

194. A method according to claim 123 wherein said vesicles comprise lipids and wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

195. A method according to claim 194 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

124. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a lipid composition comprising, in an aqueous carrier, a lipid and a gas or gaseous precursor, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said lipid composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in said image, wherein said administration rate comprises continuous infusion.

196. A method according to claim 124 wherein said composition is reconstituted from a lyophilized composition.

197. A method according to claim 124 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

198. A method according to claim 197 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

125. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising lipids, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said vesicle composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

199. A method according to claim 125 wherein said composition is reconstituted from a lyophilized composition.

200. A method according to claim 125 wherein said vesicles comprise lipids and wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

201. A method according to claim 200 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

126. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a lipid composition comprising, in an aqueous carrier, a lipid and a gas or gaseous precursor, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said lipid composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

202. A method according to claim 126 wherein said composition is reconstituted from a lyophilized composition.

203. A method according to claim 126 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

204. A method according to claim 203 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

205. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising surfactants, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said vesicle composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in the image, wherein said administration rate comprises continuous infusion.

206. A method according to claim 205 wherein said composition is reconstituted from a lyophilized composition.

207. A method according to claim 205 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononanc.

208. A method according to claim 207 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

209. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a composition comprising, in an aqueous carrier, a surfactant and a gas or gaseous precursor, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in the image, wherein said administration rate comprises continuous infusion.

210. A method according to claim 209 wherein said composition is reconstituted from a lyophilized composition.

211. A method according to claim 209 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

212. A method according to claim 211 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

213. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising surfactants, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

214. A method according to claim 213 wherein said composition is reconstituted from a lyophilized composition.

215. A method according to claim 213 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

216. A method according to claim 215 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

217. A method for providing an image of an internal region of a patient comprising (i) administering to the patient a composition comprising, in an aqueous carrier, a surfactant and a gas or gaseous precursor, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of the region, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

218. A method according to claim 217 wherein said composition is reconstituted from a lyophilized composition.

219. A method according to claim 217 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

220. A method according to claim 219 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

225. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising surfactants, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said vesicle composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in said image, wherein said administration rate comprises continuous infusion.

226. A method according to claim 225 wherein said composition is reconstituted from a lyophilized composition.

227. A method according to claim 225 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

228. A method according to claim 225 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

229. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a composition comprising, in an aqueous carrier, a surfactant and a gas or gaseous precursor, and (ii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said composition is administered to the patient at a rate which substantially eliminates ultrasound artifacts in said image, wherein said administration rate comprises continuous infusion.

230. A method according to claim 229 wherein said composition is reconstituted from a lyophilized composition.

231. A method according to claim 229 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

232. A method according to claim 231 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

233. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a vesicle composition comprising, in an aqueous carrier, a gas or gaseous precursor and vesicles comprising surfactants, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

234. A method according to claim 233 wherein said composition is reconstituted from a lyophilized composition.

235. A method according to claim 233 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

236. A method according to claim 235 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.

237. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a composition comprising, in an aqueous carrier, a surfactant and a gas or gaseous precursor, (ii) flushing said composition, and (iii) scanning the patient using ultrasound imaging to obtain a visible image of any diseased tissue in the patient, wherein said composition is flushed at a rate which substantially eliminates ultrasound artifacts in the image, wherein said flushing rate comprises continuous infusion.

238. A method according to claim 237 wherein said composition is reconstituted from a lyophilized composition.

239. A method according to claim 237 wherein said gas or gaseous precursor is selected from the group consisting of nitrogen, sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, perfluoroheptane, perfluorooctane and perfluorononane.

240. A method according to claim 239 wherein said gas or gaseous precursor is a combination of nitrogen and perfluoropropane.