Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-01-18
2001-08-07
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009323, C424S009400
Reexamination Certificate
active
06270748
ABSTRACT:
This application relates to image contrast enhancing agents for magnetic resonance imaging (MRI) or x-ray.
Imaging, whether x-ray or magnetic resonance, is a well-known and commonly used medical diagnostic technique. In the case of X-ray imaging, an x-ray sensitive film is placed behind an object under study, and the object is bombarded with x-rays. The film is then developed and reveals an image (usually a negative image showing white x-ray-opaque structures on a black background). In some instances, it may be difficult to identify and inspect different structures in the human body through x-ray imaging since many structures are x-ray transparent or translucent and faintly represented structures over-lie one another, obscuring the resulting image. Accordingly, it has become commonplace to introduce x-ray image enhancing agents prior to x-ray diagnosis. The two most common types of x-ray contrast agents are barium salts and a large class of halogenated agents. Barium salts are typically used exclusively for imaging the gastrointestinal tract. Halogenated agents are used to image a variety of areas of the body including the liver, spleen, kidneys, bile-duct, and major arteries such as those found near the heart. Essentially any organic compound substituted with bromine, or especially iodine, will significantly attenuate x-rays leading to improved contrast with respect to surrounding tissue.
In MRI, an image of an organ or tissue is obtained by placing a subject in a strong magnetic field and observing the interactions between the magnetic spins of the protons in the subject and radio frequency electromagnetic radiation. After bombardment with RF energy, the protons undergo relaxation. Relaxation is the process whereby nuclear magnetization returns to its resting state following a perturbation, such as by a radio frequency pulse. Magnetic resonance is characterized by three forms of relaxation, T
1
(longitudinal or spin-lattice) relaxation, T
2
(transverse or spin-spin) relaxation, and T
2
* relaxation. We are most concerned here with T
1
and T
2
which are of primary importance in the generation of the image. Magnetic resonance imaging is a complicated but well-known procedure to those skilled in the art and will not be set forth here.
T
1
and T
2
differ in different tissues in the body and depend on the chemical and physical environment of protons in various organs or tissues. The use of MRI to differentiate between healthy and diseased tissues is most successful in areas of the body where the relaxation times (T
1
and T
2
) of adjacent tissues is varied. For instance, the relaxation times of protons in cerebral spinal fluid and cerebral tissue are quite different, and images resulting from the use of MRI normally possess high contrast. However, in other areas of the body, the relaxation times of the protons in different tissues may be similar. Such areas may be difficult to successfully image, and the MRI image obtained may lack definition and clarity.
Without contrast agents, MRI provides a means of making definitive diagnoses noninvasively. Nevertheless, it has been found that the addition of contrast agents in many cases improves the sensitivity and/or specificity of this imaging technique. In areas of the body where adjacent tissues have similar proton relaxation times, such agents may be preferentially attracted to one of the two similar tissues, changing the proton-relaxation time for that tissue and leading to a high contrast MRI image.
MRI image enhancing agents generally fall into one of three categories: paramagnetic, ferromagnetic, and superparamagnetic. These agents affect the properties of contacted water molecules, thereby enhancing the tissue contrast and improving the diagnostic capability of MRI. A wide range of compounds in all categories have already been investigated. However, few compositions have both the efficacy and the non-toxicity required for extensive use in humans.
Ferromagnetic materials generally contain iron, nickel, and/or cobalt. These materials include magnets, and various objects one might find in a patient, such as aneurysm clips, parts of pacemakers, shrapnel, etc. These materials have a large positive magnetic susceptibility, i.e., when placed in a magnetic field, the field strength is much stronger inside the material than outside. Ferromagnetic materials are also characterized by being made up of clusters of 10
17
to 10
21
atoms called magnetic domains, that all have their magnetic moments pointing in the same direction. The moments of the domains are random in unmagnetized materials, and point in the same direction in magnetized materials. The ability to remain magnetized when an external magnetic field is removed is a distinguishing factor of ferromagnetic materials when compared to paramagnetic, superparamagnetic, and diamagnetic materials. Diamagnetic materials are not used as contrast enhancing agents. In MRI images, ferromagnetic materials cause susceptibility artifacts characterized by loss of signal and spatial distortion. This can occur with even fragments too small to be seen on plain x-ray. This is a common finding in a cervical spine MRI post anterior fusion.
Diamagnetic materials have no intrinsic atomic magnetic moment, but when placed in a magnetic field weakly repel the field, resulting in a small negative magnetic susceptibility. Materials like water, copper, nitrogen, barium sulfate, and most tissues are diamagnetic. The weak negative magnetic susceptibility contributes to the loss of signal seen in bowel on MRI after administration of barium sulfate suspensions.
Superparamagnetic materials consist of individual domains of elements that have ferromagnetic properties in bulk. Their magnetic susceptibility is between that of ferromagnetic and paramagnetic materials. Examples of superparamagnetic materials include iron-containing contrast agents for bowel, liver, and lymph node imaging.
Paramagnetic materials include oxygen and ions of various metals like Fe, Mg, and Gd. These ions have unpaired electrons, resulting in a positive magnetic susceptibility. The magnitude of this susceptibility is less than one one-thousandth of that of ferromagnetic materials. The effect on MRI is an increase in the T
1
and T
2
relaxation rates (decrease in the T
1
and T
2
times). Gd is used as an MRI contrast agent. At the proper concentration, Gd contrast agents cause preferential T
1
relaxation enhancement, causing increase in signal on T
1
-weighted images. At high concentrations, as is sometimes seen in the urinary bladder, loss of signal is seen instead, a result of the T
2
relaxation effects dominating.
Paramagnetic metal ions suitable as MR contrast agents are all potentially toxic when injected IV at or near doses needed for clinical imaging. With chelation of these ions, acute toxicity is reduced and elimination rate is increased thereby reducing the chance of long term toxicity. One of the more studied complexes is gadolinium diethylenetriamine pentaacetate chelate (GdDTPA). The gadolinium in the chelate contributes a large number of unpaired electrons and consequent large magnetic moment. Enhancement of the relaxation rate of water increases with an increasing number of unpaired electrons, making this an effective MRI image enhancing compound. GdDTPA has proven useful in the imaging of the brain by virtue of its inability to pass through the blood brain barrier. It is quite effective for illuminating lesions of the brain because these lesions compromise the blood-brain barrier allowing the contrast to infiltrate the lesion preferentially over the remainder of the brain.
However, GdDTPA lacks site specificity. When introduced into the vascular system, GdDTPA diffuses throughout the organs and muscular system. Thus, large quantities of contrast agent are usually required to produce adequate contrast. This is particularly problematic for efforts to image the blood pool. Consequently, differentiation among different tissues decreases significantly with time, as the material diffuses.
Accordingly, there remains a need
Annan Nikoi
Langenmayr Eric Jon
Reynolds Charles Howard
Shaber Steven Howard
Hartley Michael G.
Rohm and Haas Company
Rosedale Jeffrey H.
LandOfFree
Contrast enhancing agent having a polymeric core and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Contrast enhancing agent having a polymeric core and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Contrast enhancing agent having a polymeric core and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2453131