Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2001-03-28
2003-07-08
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009320, C424S009360, C424S009363, C424S009364
Reexamination Certificate
active
06589506
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the application of hyperpolarized gases to magnetic resonance imaging (MRI).
In particular, this invention relates to a method for the dynamic regional measurement of lung perfusion and ventilation using magnetic resonance imaging based on the use of hyperpolarized noble gases.
TECHNICAL BACKGROUND
In the techniques of nuclear magnetic resonance (NMR) a magnetic field acts on the nuclei of atoms with fractional spin quantum numbers and polarizes them into alignment within some selected orientations. During measurements, radio-frequency pulses of given resonance energy are applied that flip the nuclear spins and disturb the orientation distribution; then the nuclei return (relax) to the initial state in a time dependent exponential fashion, thus giving signals which are electronically processed into recordable data. When the signals are spatially differentiated and of sufficient level, the data can be organized and displayed as images on a screen. For instance, computing the signals generated by the protons (
1
H) of the water in contact with organic tissues enables to construct images (MRI) allowing direct visualization of internal organs in living beings. This is therefore a powerful tool in diagnostics, medical treatment and surgery.
There exist proton MRI techniques for tissue perfusion measurements, such as contrast enhanced MRI using very short echo time sequences (Berthezène Y et al., Contrast enhanced MR imaging of the lung: assessment of ventilation and perfusion. Radiology 7992, 183: 667-672; Habutu H. et al. Pulmonary perfusion: qualitative assessment with dynamic contrast-enhanced MRI using ultra-short TE and inversion recovery Turbo FLASH, Magn. Reson. Med. 1996; 36: 503-508) or spin labelling techniques (Mai V M and Berr S S: MR perfusion imaging of pulmonary parenchyma using pulsed arterial spin labelling techniques: FAIRER and FAIR. J. Magn. Reson. Imag. 1999; 9: 483-487) but are unfortunately difficult to perform in the lungs. Lung perfusion MRI is first hampered by a low proton density. Magnetic susceptibility effects due to the numerous air/tissue interfaces also shorten the effective transverse relaxation time T
2
(Durney C. et al.—Cutillo, A G, editor; Application of Magnetic Resonance to the study of lung. Armonk: Futura Publishing Company; 1996, p. 141-175).
Recently, it has been proposed to use in the MRI of patients isotopes of some noble gases in hyperpolarized form. Although the signal from these isotopes in the naturally polarized state is very weak (5000 times weaker than from
1
H), hyperpolarization will effectively raise it about 10
4
to 10
5
times. Furthermore, the spin relaxation parameters of the hyperpolarized gases are very strongly influenced by the nature of the environment in which they distribute after administration (i.e. they provide a detailed array of signals of different intensities), which makes them very interesting contrast agents in MR imaging.
Hyperpolarizing noble gases is usually achieved by spin-exchange interactions with optically excited alkali metals in the presence or in the absence of an externally applied magnetic field (see e.g. G. D. Cates et al.,
Phys. Rev. A
45 (1992), 4631; M. A. Bouchlat et al.
Phys. Rev. Lett.
5 (1960), 373; X. Zeng et al.,
Phys. Rev. A
31 (1985), 260). With such techniques, polarization of 10% or more is possible, the normal relaxations (T
1
, T
2
) being so long (from several minutes to days in the case of Xe ice that subsequent manipulations (use for diagnostic purposes) are quite possible. Otherwise, hyperpolarization can be achieved by metastability exchange, for instance by exciting
3
He to the 2
3
S
1
metastable state which is then optically pumped with 1083 nm circularly polarized laser light to the 2
3
P
0
state. Polarization is then transferred to the ground state by metastability exchange collisions with the ground state atoms (see e.g. L. D. Schaerer,
Phys. Lett.
180 (1969), 83; F. Laloe et al., AIP Conf. Proc. #131 (Workshop on Polarized 3He Beams and Targets, 1984).
WO-A-95/27438 discloses use of hyperpolarized gases in diagnostic MRI. For instance, after having been externally hyperpolarized, the gases can be administered to living subjects in gaseous or liquid form, either alone or in combination with inert or active components. Administration can be effected by inhalation or intravenous injection of blood that has previously been extracorporally contacted with the gas. Upon administration, the distribution of the gas within the space of interest in the subject is determined by NMR, and a computed visual representation of said distribution is displayed by usual means. No practical example of administration of a parenteral contrast agent composition or formulation, no identification of the additional components is provided.
In an article by H. Middleton et al.,
Mag. Res. Med.
33 (1995), 271, there is disclosed introducing polarized
3
He into the lungs of dead guinea-pigs and thereafter producing an NMR image of said lungs.
P. Bachert et al.
Mag. Res. Med.
36 (1996), 192 disclose making MR images of the lungs of human patients after the latter inhaled hyperpolarized
3
He.
WO-A-99/47940 discloses a method for imaging pulmonary and cardiac vasculature and evaluating blood flow using dissolved polarized
129
Xe. This method is carried out by positioning a patient in a magnetic resonance apparatus and delivering polarized
129
Xe gas to the patient via inhalation such as with a breath-hold delivery procedure, exciting the dissolved gas phase with a large flip angle pulse, and generating a corresponding image.
Compared to the clinical scintigraphy technique used for functional pulmonary ventilation and perfusion assessment, and based on the inhalation of radioactive gas (
133
Xe,
81
Kr), noble gas MRI offers an improved spatial and temporal resolution without ionizing radiation (Alderson P O and Martin E C, Pulmonary embolism: diagnosis with multiple imaging modalities, Radiology 1987; 164:297-312). However, MRI using laser-polarized gas has failed, to date, to assess lung perfusion function in a satisfactory way. For instance, the method according to WO-A-99/47940 is not sufficiently accurate, due to the difficulties to distinguish the signals from the gas dissolved in tissues and the gas dissolved in the blood. Furthermore, one has to deal with low signal intensities from dissolved gas.
SUMMARY OF THE INVENTION
Therefore, the problem underlying the present invention was that of providing a method for simultaneously assessing lung perfusion and ventilation, which could overcome the drawbacks of the prior art methods, both those based on proton MRI techniques and those based on hyperpolarized noble gases.
Such a problem has been solved, according to the invention, by a method for the assessment of pulmonary ventilation and lung perfusion through Magnetic Resonance Imaging (MRI), comprising the steps of:
positioning a human subject in an MRI apparatus,
delivering a hyperpolarized noble gas to the subject by inhalation, followed by a breath-hold period, during which a bolus of a contrast agent for MRI is injected intravenously,
acquiring, during said breath-hold period, at least one MR image of the lungs prior to said bolus intravenous injection and at least one MR image thereafter.
The MRI image acquired after the bolus intravenous injection is taken during the passage of the contrast agent in the pulmonary vasculature.
The contrast agent for MRI used in the present method preferably contains a compound selected among the group comprising superparamagnetic iron oxide nanoparticles (SPIO), ultrasmall superparamagnetic iron oxide nanoparticles (USPIO), gadolinium complexes and manganese complexes.
The SPIO and USPIO are preferably employed as stabilized suspensions.
Examples of suitable suspensions of SPIO and USPIO are provided by the following products:
SBPA (Bracco Research Geneva—Pochon S. et al., Circulating superparamagnetic particles with high T2 relaxivity, Acta Radiologica 1997; 38 (suppl. 412): 69-72): Fe
Berthezene Yves
Cremillieux Yannick
Viallon Magalie
Bracco International B.V.
Hartley Michael G.
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