Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-03-12
2003-10-07
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C600S420000
Reexamination Certificate
active
06630126
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to magnetic resonance imaging (“MRI”) and spectroscopy methods, and more particularly to the use of hyperpolarized
129
Xe in MRI and spectroscopy.
BACKGROUND OF THE INVENTION
MRI using hyperpolarized noble gases has been demonstrated as a viable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. The contents of this patent are hereby incorporated by reference as if recited in full herein. Albert et al. proposed several techniques of introducing the hyperpolarized gas (either alone or in combination with another substance) to a subject, such as via direct injection, intravenous injection, and inhalation. See also
Biological magnetic resonance imaging using laser
-
polarized
129
Xe, 370 Nature, pp. 199-201 (Jul. 21, 1994). Other researchers have since obtained relatively high-quality images of the lung using pulmonary ventilation of the lung with both hyperpolarized
3
He and
129
Xe. See J. R. MacFall, H. C. Charles, R. D. Black, H. Middleton, J. Swartz, B. Saam, B. Driehuys, C. Erickson, W. Happer, G. Cates, G. A. Johnson, and C. E. Ravin, “
Human lung air spaces: Potential for MR imaging with hyperpolarized He
-3,” Radiology 200, 553-558 (1996); and Mugler et al.,
MR Imaging and spectroscopy using hyperpolarized
129
Xe gas:
Preliminary human results,
37 Mag. Res. Med., pp. 809-815 (1997). See also E. E. de Lange, J. P. Mugler, J. R. Brookeman, J. Knight-Scott, J. Truwit, C. D. Teates, T. M. Daniel, P. L. Bogorad, and G. D. Cates, “
Lung Airspaces: MR Imaging Evaluation with Hyperpolarized Helium
-3
Gas
, ” Radiology 210, 851-857(1999); L. F. Donnelly, J. R. MacFall, H. P. McAdams, J. M. Majure, J. Smith, D. P. Frush, P. Bogorad, H. C. Charles, and C. E. Ravin, “
Cystic Fibrosis: Combined Hyperpolarized
3
He
-
enhanced and Conventional Proton MR Imaging in the Lung—Preliminary Observations,”
Radiology 212 (September 1999), 885-889 (1999); H. P. McAdams, S. M. Palmer, L. F. Donnelly, H. C. Charles, V. F. Tapson, and J. R. MacFall, “
Hyperpolarized
3
He
-
Enhanced MR Imaging of Lung Transplant Recipients: Preliminary Results,”
AJR 173, 955-959 (1999).
In addition, due to the high solubility of
129
Xe in blood and tissues, vascular and tissue imaging using inhaled hyperpolarized
129
Xe has also been proposed. Generally described, during inhalation delivery, a quantity of hyperpolarized
129
Xe is inhaled by a subject (a subject breathes in the
129
Xe gas) and the subject then holds his or her breath for a short period of time, i.e., a “breath-hold” delivery. This inhaled
129
Xe gas volume then exits the lung space and is generally taken up by the pulmonary vessels and associated blood or pulmonary vasculature at a rate of approximately 0.3% per second. For example, for an inhaled quantity of about 1 liter of hyperpolarized
129
Xe, an estimated uptake is about 3 cubic centimeters per second or a total quantity of about 40 cubic centimeters of
129
Xe over about a 15 second breath-hold period. Accordingly, it has been noted that such uptake can be used to generate images of pulmonary vasculature or even organ systems more distant from the lungs. See co-pending and co-assigned U.S. patent application Ser. No. 09/271,476 to Driehuys et al, entitled Methods for Imaging Pulmonary and Cardiac Vasculature and Evaluating Blood Flow Using Dissolved Polarized
129
Xe. Although primarily directed to inhalation delivery, this application also proposes injection of
129
Xe to replace conventional radioactive tracers in perfusion imaging methods. The contents of this application are hereby incorporated by reference as if recited in full herein.
Many researchers are also interested in the possibility of using inhaled
129
Xe for imaging white matter perfusion in the brain, renal perfusion, and the like. While the inhaled delivery
129
Xe methods are suitable, and indeed, preferable, for many MRI applications for several reasons, such as the non-invasive characteristics attendant with such a delivery to a human subject, it may not be the most efficient method to deliver a sufficiently large dose to more distant (away from the pulmonary vasculature which is proximate to the lungs) target areas of interest. In addition, due to the dilution of the inhaled
129
Xe along the perfusion delivery path, relatively large quantities of the hyperpolarized
129
Xe are typically inhaled in order to deliver a small fraction of the gas to the more distal target sites or organ systems. For example, the brain typically receives only about 13% of the total blood flow in the human body. Thus, the estimated 40 cubic centimeter quantity of hyperpolarized
129
Xe taken up into the pulmonary vessels from the 1-liter inhalation dose can be reduced to only about 5 cubic centimeters by the time it reaches the brain.
Further, the hyperpolarized state of the gas is sensitive and can decay relatively quickly due to a number of relaxation mechanisms. Indeed, the relaxation time (generally represented by a decay constant “T
1
”) of the
129
Xe in the blood, absent other external depolarizing factors, is estimated at T
1
=4.0 seconds for venous blood and T
1
=6.4s for arterial blood at a magnetic field strength of about 1.5 Tesla. See Wolber et al.,
Spin
-
lattice relaxation of laser
-
polarized xenon in human blood,
96 Proc. Natl. Acad. Sci. USA, pp. 3664-3669 (March 1999). (The more oxygenated arterial blood provides increased polarization life over the relatively de-oxygenated venous blood). Therefore, for about a 5 second transit time (the time estimate for the uptaken hyperpolarized
129
Xe to travel to the brain from the pulmonary vessels), the
129
Xe polarization is reduced to about 37% of its original value. In addition, the relaxation time of the polarized
129
Xe in the lung itself is typically about 20-25 seconds due to the presence of paramagnetic oxygen. Accordingly,
129
Xe taken up in the latter portion of the breath-hold cycle can decay to have only about 50% of the starting polarization (the polarization level at the initial portion of the breath hold cycle). Thus, generally stated, the average polarization of
129
Xe entering the pulmonary blood can be estimated to be at about 75% of the starting inhaled polarization value. Taking these effects into account, the delivery to the brain of the inhaled
129
Xe can be estimated as about 1.4 cubic centimeters of the inhaled one-liter dose of
129
Xe polarized to the same level as the inhaled gas (0.75×0.37×5 cc's). This dilution reduces delivery efficiency, i.e., for remote target areas (such as the brain), the quantity of delivered
129
Xe is typically severely reduced to only about 0.14% of the inhaled
129
Xe. Nonetheless, at least one researcher has made coarse images of
129
Xe in rat brains, but this inhalation administration delivery required large quantities of
129
Xe to be inhaled over a relatively long period of time. See Swanson et al.,
Brain MRI with laser
-
polarized xenon in human blood,
38 Mag. Reson. Med., pp. 695-698 (1997). Unfortunately, the extended inhalation time period and/or associated large quantity dosage of the gas may not be desirable for certain clinical applications.
In an alternative delivery mode, Bifone et al. proposes the use of injectable formulations to deliver hyperpolarized
129
Xe to regions of interest. Bifone et al., NMR of laser polarized xenon in human blood,
93 Proc. Natl. Acad. Sci. USA No. 23, pp. 12932-12936 (1996). Albert et al., supra, also describes such formulations. As described by Bifone et al., the injectable formulation consists of a biocompatible fluid in which hyperpolarized
129
Xe is dissolved. Such formulations can then be injected intravenously to deliver hyperpolarized
129
Xe. For fluid injection, the formulation is described as preferably formed such that the biocompatible fluid has a high solubility for xenon while also providing a relatively long
129
Xe relaxation time. Examples of particular suggested biocompatible fluids include saline, lipid emulsions, and perfluo
Brookeman James R.
Driehuys Bastiaan
Fujii Dennis
Hagspiel Klaus D.
Hartley Michael G.
Medi--Physics, Inc.
Myers Bigel & Sibley & Sajovec
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