Elgavish Paramagnetics, Inc.

BIRMINGHAM, AL, United States

Elgavish Paramagnetics, Inc.

BIRMINGHAM, AL, United States
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Lenkey Z.,University of Alabama at Birmingham | Lenkey Z.,Elgavish Paramagnetics, Inc. | Lenkey Z.,University of Pécs | Varga-Szemes A.,University of Alabama at Birmingham | And 16 more authors.
Journal of Magnetic Resonance Imaging | Year: 2016

Purpose To test whether signal intensity percent infarct mapping (SI-PIM) accurately determines the size of myocardial infarct (MI) regardless of infarct age. Materials and Methods Forty-five swine with reperfused MI underwent 1.5T late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) after bolus injection of 0.2 mmol/kg Gd(DTPA) on days 2-62 following MI. Animals were classified into acute, healing, and healed groups by pathology. Infarct volume (IV) and infarct fraction (IF) were determined by two readers, using binary techniques (including 2-5 standard deviations [SD] above the remote, and full-width at half-maximum) and the SI-PIM method. Triphenyl-tetrazolium-chloride staining (TTC) was performed as reference. Bias (percent under/overestimation of IV relative to TTC) of each quantification method was calculated. Bland-Altman analysis was done to test the accuracy of the quantification methods, while intraclass correlation coefficient (ICC) analysis was done to assess intra- and interobserver agreement. Results Bias of the MRI quantification methods do not depend on the age of the MI. Full-width at half-maximum (FWHM) and SI-PIM gave the best estimate of MI volume determined by the reference TTC (P-values for the FWHM and SI-PIM methods were 0.183, 0.26, 0.95, and 0.073, 0.091, 0.73 in Group 1, Group 2, and Group 3, respectively), while using any of the binary thresholds of 2-4 SDs above the remote myocardium showed significant overestimation. The 5 SD method, however, provided similar IV compared to TTC and was shown to be independent of the size and age of MI. ICC analysis showed excellent inter- and intraobserver agreement between the readers. Conclusion Our results indicate that the SI-PIM method can accurately determine MI volume regardless of the pathological stage of MI. Once tested, it may prove to be useful for the clinic. © 2015 Wiley Periodicals, Inc.


Varga-Szemes A.,University of Alabama at Birmingham | Varga-Szemes A.,Elgavish Paramagnetics, Inc. | Kiss P.,University of Alabama at Birmingham | Kiss P.,Elgavish Paramagnetics, Inc. | And 13 more authors.
PLoS ONE | Year: 2016

Purpose: MRI contrast agents (CA) whose contrast enhancement remains relatively high even at the higher end of the magnetic field strength range would be desirable. The purpose of this work was to demonstrate such a desired magnetic field dependency of the longitudinal relaxivity for an experimental MRI CA, Gd(ABE-DTTA). Materials and Methods: The relaxivity of 0.5mM and 1mM Gd(ABE-DTTA) was measured by Nuclear Magnetic Relaxation Dispersion (NMRD) in the range of 0.0002 to 1T. Two MRI and five NMR instruments were used to cover the range between 1.5 to 20T. Parallel measurement of a Gd-DTPA sample was performed throughout as reference. All measurements were carried out at 37°C and pH 7.4. Results: The relaxivity values of 0.5mM and 1mM Gd(ABE-DTTA) measured at 1.5, 3, and 7T, within the presently clinically relevant magnetic field range, were 15.3, 11.8, 12.4 s-1mM-1 and 18.1, 16.7, and 13.5 s-1mM-1, respectively. The control 4 mM Gd-DTPA relaxivities at the same magnetic fields were 3.6, 3.3, and 3.0 s-1mM-1, respectively. Conclusions: The longitudinal relaxivity of Gd(ABE-DTTA) measured within the presently clinically relevant field range is three to five times higher than that of most commercially available agents. Thus, Gd(ABE-DTTA) could be a practical choice at any field strength currently used in clinical imaging including those at the higher end. © 2016 Varga-Szemes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Kirschner R.,University of Alabama at Birmingham | Kirschner R.,University of Pécs | Kirschner R.,Elgavish Paramagnetics, Inc. | Varga-Szemes A.,University of Alabama at Birmingham | And 16 more authors.
International Journal of Cardiovascular Imaging | Year: 2012

To determine the infarct affinity of a low molecular weight contrast agent, ,Gd(ABE-DTTA),duringthe subacute phase of myocardial infarct (MI). Dogs (n = 7) were examined,usinga closed-chest,reperfusedMI model. MI was generated by occluding for 180 min the Left Anterior Descending (LAD) coronary artery with an angioplasty balloon. DE-MRI images with Gd(ABE-DTTA) were obtained on days 4, 14,and28 after MI. Control DE-MRI by Gd(DTPA) was carried out on day 27. T2-TSE images were acquired on day 3,13and 27. Triphenyltetrazolium chloride (TTC) histomorphometry validated postmortem the existence of infarct. Gd(ABE-DTTA) highlighted the infarct on day 4,butnot at all on day 14 or on day 28, following MI. On day 4,the mean ± SD signal intensity (SI) of infarcted myocardium in the presence of Gd(ABEDTTA) significantly differed from that of healthy myocardium (45± 6.0 vs. 1±0 5.0, P < 0.05),but it did not on day 14 (11 ± 9.4 vs. 10± 5.7, P = NS),nor on day 28 (7 ± 1.5 vs. 7± 2.4, P = NS). The mean ± SD signal intensity enhancement (SIE) induced by Gd(ABE-DTTA) was 386 ± 165% on day 4,significantlydifferent from mean SIE on day 14 (9 ±20%),andfrom mean SIE on day 28 (12 ±18%),followingMI (P <0.05). The last two mean values did not differ significantly (P = NS) from each other. As control,Gd(DTPA)was used and it did highlight the infarct on day 27,inducinga mean SIE value of 312 ±40%. The mean SIE on day 3, 13,or27 did not vary significantly (P = NS) on the T2-TSE images (114 ±41%,123 ± 41%,and150 ±79%, respectively). Post mortem,theexistence of infarcts was confirmed by TTC staining. The infarct affinity of Gd(ABE-DTTA) vanishes in the subacute phase of scar healing, allowing its use for infarct age differentiation early on, immediately following the acute phase. © Springer Science+Business Media, B.V. 2011.


Kirschner R.,University of Alabama at Birmingham | Kirschner R.,University of Pécs | Kirschner R.,Elgavish Paramagnetics, Inc. | Toth L.,University of Alabama at Birmingham | And 22 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2010

Background. Standard extracellular cardiovascular magnetic resonance (CMR) contrast agents (CA) do not provide differentiation between acute and older myocardial infarcts (MI). The purpose of this study was to develop a method for differentiation between acute and older myocardial infarct using myocardial late-enhancement (LE) CMR by a new, low molecular weight contrast agent. Dogs (n = 6) were studied in a closed-chest, reperfused, double myocardial infarct model. Myocardial infarcts were generated by occluding the Left Anterior Descending (LAD) coronary artery with an angioplasty balloon for 180 min, and four weeks later occluding the Left Circumflex (LCx) coronary artery for 180 min. LE images were obtained on day 3 and day 4 after second myocardial infarct, using Gd(DTPA) (standard extracellular contrast agent) and Gd(ABE-DTTA) (new, low molecular weight contrast agent), respectively. Triphenyltetrazolium chloride (TTC) histomorphometry validated existence and location of infarcts. Hematoxylin-eosin and Masson's trichrome staining provided histologic evaluation of infarcts. Results. Gd(ABE-DTTA) or Gd(DTPA) highlighted the acute infarct, whereas the four-week old infarct was visualized by Gd(DTPA), but not by Gd(ABE-DTTA). With Gd(ABE-DTTA), the mean SD signal intensity enhancement (SIE) was 366 166% and 24 59% in the acute infarct and the four-week old infarct, respectively (P < 0.05). The latter did not differ significantly from signal intensity in healthy myocardium (P = NS). Gd(DTPA) produced signal intensity enhancements which were similar in acute (431 124%) and four-week old infarcts (400 124%, P = NS), and not statistically different from the Gd(ABE-DTTA)-induced SIE in acute infarct. The existence and localization of both infarcts were confirmed by triphenyltetrazolium chloride (TTC). Histologic evaluation demonstrated coagulation necrosis, inflammation, and multiple foci of calcification in the four day old infarct, while the late subacute infarct showed granulation tissue and early collagen deposition. Conclusions. Late enhancement CMR with separate administrations of standard extracellular contrast agent, Gd(DTPA), and the new low molecular weight contrast agent, Gd(ABE-DTTA), differentiates between acute and late subacute infarct in a reperfused, double infarct, canine model. © 2010 Kirschner et al; licensee BioMed Central Ltd.


Varga-Szemes A.,Elgavish Paramagnetics, Inc. | Kiss P.,Elgavish Paramagnetics, Inc. | Brott B.C.,University of Alabama at Birmingham | Wang D.,University of Alabama at Birmingham | And 2 more authors.
Catheterization and Cardiovascular Interventions | Year: 2012

Objectives: To develop a magnetic resonance imaging (MRI) compatible, percutaneous technique for the generation of nonreperfused myocardial infarct (MI). Background: Modeling nontreated MI has major importance in the development and preclinical testing of new therapeutic strategies for patients missing the time window suitable for revascularization following MI. Methods: In 31 male swine, nonreperfused MI was generated by permanent occlusion of either the LAD or LCX coronary artery using 900 μm Embozene™ microspheres. Animals were monitored for 90 min postocclusion. Surviving animals were followed up for 2 (n = 6), 4 (n = 6), 14 (n = 6), or 56 (n = 6) days. At the end of the planned study session, contrast enhanced MRI, triphenyl-tetrazolium-chloride staining, and microscopic histopathology were carried out. Results: The mortality rate in this study was 22.6%. Intraoperative arrhythmias occurred in 14 cases: premature ventricular complexes with (5) or without (3) ventricular tachycardia, 2nd degree atrio-ventricular block (1), and ventricular fibrillation (6). MRI, TTC, and histology confirmed the existence of MI in every case. Macroscopic pathology showed that the microspheres caused a practically total occlusion at the epicardial level of the coronary artery. Multiple infarcts were detected in one case, probably due to unintentional reflux of the microspheres. Microspheres retained in the coronary arteries did not cause any MRI artifact. Conclusions: The generation of nonreperfused MI is feasible by percutaneous injection of Embozene into the coronary artery system. The MI model thus obtained is suitable for the purposes of MRI experiments. © 2012 Wiley Periodicals, Inc.


Varga-Szemes A.,University of Alabama at Birmingham | Varga-Szemes A.,Elgavish Paramagnetics, Inc. | Varga-Szemes A.,University of Pécs | Kiss P.,Elgavish Paramagnetics, Inc. | And 7 more authors.
Catheterization and Cardiovascular Interventions | Year: 2013

Objectives To develop a magnetic resonance imaging (MRI) compatible, percutaneous technique for the generation of nonreperfused myocardial infarct (MI). Background Modeling nontreated MI has major importance in the development and preclinical testing of new therapeutic strategies for patients missing the time window suitable for revascularization following MI. Methods In 31 male swine, nonreperfused MI was generated by permanent occlusion of either the LAD or LCX coronary artery using 900 μm Embozene™ microspheres. Animals were monitored for 90 min postocclusion. Surviving animals were followed up for 2 (n = 6), 4 (n = 6), 14 (n = 6), or 56 (n = 6) days. At the end of the planned study session, contrast enhanced MRI, triphenyl-tetrazolium-chloride staining, and microscopic histopathology were carried out. Results The mortality rate in this study was 22.6%. Intraoperative arrhythmias occurred in 14 cases: premature ventricular complexes with (5) or without (3) ventricular tachycardia, 2nd degree atrio-ventricular block (1), and ventricular fibrillation (6). MRI, TTC, and histology confirmed the existence of MI in every case. Macroscopic pathology showed that the microspheres caused a practically total occlusion at the epicardial level of the coronary artery. Multiple infarcts were detected in one case, probably due to unintentional reflux of the microspheres. Microspheres retained in the coronary arteries did not cause any MRI artifact. Conclusions The generation of nonreperfused MI is feasible by percutaneous injection of Embozene into the coronary artery system. The MI model thus obtained is suitable for the purposes of MRI experiments. © 2012 Wiley Periodicals, Inc.


Varga-Szemes A.,University of Alabama at Birmingham | Varga-Szemes A.,Elgavish Paramagnetics, Inc. | Simor T.,University of Alabama at Birmingham | Simor T.,Elgavish Paramagnetics, Inc. | And 14 more authors.
International Journal of Cardiovascular Imaging | Year: 2014

To study the feasibility of a myocardial infarct (MI) quantification method [signal intensity-based percent infarct mapping (SI-PIM)] that is able to evaluate not only the size, but also the density distribution of the MI. In 14 male swine, MI was generated by 90 min of closed-chest balloon occlusion followed by reperfusion. Seven (n = 7) or 56 (n = 7) days after reperfusion, Gd-DTPA-bolus and con-tinuous- infusion enhanced late gadolinium enhancement (LGE) MRI, and R1-mapping were carried out and post mortem triphenyl- tetrazolium-chloride (TTC) staining was performed. MI was quantified using binary [2 or 5 standard deviation (SD)], SI-PIM and R1-PIM methods. Infarct fraction (IF), and infarct-involved voxel fraction (IIVF) were determined by each MRI method. Bias of each method was compared to the TTC technique. The accuracy of MI quantification did not depend on the method of contrast administration or the age of the MI. IFs obtained by either of the two PIM methods were statistically not different from the IFs derived from the TTC measurements at either MI age. IFs obtained from the binary 2SD method overestimated IF obtained from TTC. IIVF among the three different PIM methods did not vary, but with the binary methods the IIVF gradually decreased with increasing the threshold limit. The advantage of SI-PIM over the conventional binary method is the ability to represent not only IF but also the density distribution of the MI. Since the SI-PIM methods are based on a single LGE acquisition, the bolus-data-based SI-PIM method can effortlessly be incorporated into the clinical image post-processing procedure. © Springer Science+Business Media 2014.


Varga-Szemes A.,University of Alabama at Birmingham | Varga-Szemes A.,Elgavish Paramagnetics, Inc. | Varga-Szemes A.,University of Pécs | Ruzsics B.,University of Alabama at Birmingham | And 14 more authors.
Investigative Radiology | Year: 2012

Objective: To demonstrate the feasibility of using multidetector computed tomography with gadolinium contrast (Gd-MDCT) for the quantification of myocardial infarct (MI). Materials and Methods: MI was induced in male swine (n = 6). One week later, the animals received 0.2-mmol/kg gadopentetate dimeglumine and were sacrificed. On the excised hearts, Gd-MDCT with several tube voltages (80, 120, and 140 kV), late gadolinium enhancement MRI (LGE-MRI), and triphenyl-tetrazolium-chloride staining were then conducted. We used a 2-SD threshold for the CT images and several threshold limits (2, 3, 4, 5, 6 SD, and full width at half-maximum [FWHM]) for the LGE-MRI images to delineate the infarct area. Total infarct volume and infarct fraction of each heart were calculated. Results: MI size measured by MDCT at 140 kV showed good correlation with the reference triphenyl-tetrazolium-chloride value. Applying an 80-kV tube voltage, however, significantly underestimated MI size. In our study, the LGE-MRI method, using the 6-SD threshold, provided the most accurate determination of MI size. LGE-MRI, using the 2-and 3-SD threshold limits, significantly overestimated infarct size. Conclusions: The Gd-MDCT technique has been found suitable for the evaluation of MI in an ex vivo experimental setting. Gd-MDCT has the ability to detect MI even at low kV settings, but accuracy is limited by a high image noise because of reduced photon flux. © 2012 by Lippincott Williams & Wilkins.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase II | Award Amount: 1.77M | Year: 2010

DESCRIPTION provided by applicant The overall goal of this project is to demonstrate the ability of our acute myocardial infarct selective paramagnetic contrast agent Gadolinium ABE DTTA to differentiate between acute and chronic infarcts in a reliable manner using contrast enhanced magnetic resonance imaging ceMRI In our Phase I data we have shown that Gd ABE DTTA exclusively highlights acute infarcts by causing signal hyper enhancement but contrary to presently used contrast agents it does not cause hyper enhancement in week old infarcts A reliable noninvasive diagnostic differentiation between acute and older myocardial infarcts could be used to make decisions about which vessels and in what order should be reopened or bypassed by an interventional cardiologist or a cardiac surgeon in a patient with myocardial infarction MRI contrast agents presently used in the clinic are unable to make such differentiation Using a conventional MRI contrast agent to highlight all infarcts followed by an appropriate minimum time period to allow for this agent to clear from the heart muscle minutes and subsequently using Gd ABE DTTA one would elucidate which infarct area is due to a new acute infarction Using a canine model of myocardial infarction in the Phase I project we proved with statistical significance the ability of Gd ABE DTTA to show such differentiation In preparation for commercialization the objectives of Phase II are Investigation of the infarct age time frame for the disappearance or the decay of the affinity of Gd ABE DTTA to the myocardial infarct in the pig model of reperfused infarct Elucidation of the histological basis of this phenomenon in the same animal model Determination of the in vivo myocardial tissue kinetics of Gd ABE DTTA accumulation into subacute versus chronic myocardial infarct in pigs Determination of the kinetics of biodistribution of Gd ABE DTTA in pigs and its clearance kinetics in rabbits Determination of Gd ABE DTTA toxicity LD in mice Quantitative comparison of the effect of high dose of Gd ABE DTTA on Nephrogenic Systemic Fibrosis to that of FDA approved Gd DTPA PUBLIC HEALTH RELEVANCE A significant number of heart patients suffer a second heart attack after the first infarction was treated either by angioplasty or by bypass surgery It would be important to the cardiologist to be able to distinguish on the MRI image between the old and new infarct A reliable noninvasive diagnostic differentiation between acute and older infarcts could be used to make decisions about which vessels and in what order should be reopened or bypassed by an interventional cardiologist or a cardiac surgeon in a patient with multiple myocardial infarction MRI contrast agents presently used in the clinic are unable to make such differentiation The overall goal of this project is to demonstrate the ability of our acute myocardial infarct selective paramagnetic contrast agent Gadolinium ABE DTTA to differentiate between acute and chronic infarcts in a reliable manner using contrast enhanced magnetic resonance imaging ceMRI


PubMed | Leiden University, Elgavish Paramagnetics, Inc. and University of Alabama at Birmingham
Type: Journal Article | Journal: Journal of magnetic resonance imaging : JMRI | Year: 2016

To test whether signal intensity percent infarct mapping (SI-PIM) accurately determines the size of myocardial infarct (MI) regardless of infarct age.Forty-five swine with reperfused MI underwent 1.5T late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) after bolus injection of 0.2mmol/kg Gd(DTPA) on days 2-62 following MI. Animals were classified into acute, healing, and healed groups by pathology. Infarct volume (IV) and infarct fraction (IF) were determined by two readers, using binary techniques (including 2-5 standard deviations [SD] above the remote, and full-width at half-maximum) and the SI-PIM method. Triphenyl-tetrazolium-chloride staining (TTC) was performed as reference. Bias (percent under/overestimation of IV relative to TTC) of each quantification method was calculated. Bland-Altman analysis was done to test the accuracy of the quantification methods, while intraclass correlation coefficient (ICC) analysis was done to assess intra- and interobserver agreement.Bias of the MRI quantification methods do not depend on the age of the MI. Full-width at half-maximum (FWHM) and SI-PIM gave the best estimate of MI volume determined by the reference TTC (P-values for the FWHM and SI-PIM methods were 0.183, 0.26, 0.95, and 0.073, 0.091, 0.73 in Group 1, Group 2, and Group 3, respectively), while using any of the binary thresholds of 2-4 SDs above the remote myocardium showed significant overestimation. The 5 SD method, however, provided similar IV compared to TTC and was shown to be independent of the size and age of MI. ICC analysis showed excellent inter- and intraobserver agreement between the readers.Our results indicate that the SI-PIM method can accurately determine MI volume regardless of the pathological stage of MI. Once tested, it may prove to be useful for the clinic.

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