Andreas Mühler

A toxicologic risk for using manganese complexes? A literature survey of existing data through several medical specialties.

This article summarizes data from the literature about biologic functions, toxicity, and biokinetics of manganese to help the reader assess the importance of complex stability of manganese-based contrast agents. Free manganese may present a greater risk than free gadolinium, especially because it has a physiologic role and can therefore trigger multiple functions. Of particular interest are the deleterious effects of manganese on the central nervous system (it can cross the intact blood-brain barrier) and on developing life (it penetrates the placental barrier as well and is teratogenic). After intravenous contrast injection, normal (enteral) regulation mechanisms for manganese homeostasis are bypassed, and there is a danger of individual overdosing. Excess manganese, for example in patients with chronic liver disease or with chronic parenteral nutrition, has already been detected by magnetic resonance imaging in the basal ganglia and was found to coincide with neurologic symptoms. Decomplexation with release of free manganese substantially prolongs the elimination of the metal because manganese can be excreted only slowly via the biliary system. This may be of particular importance in patients with impaired hepatic function. Although minimal amounts of free manganese ions are not considered harmful to the human body, significant decomplexation of manganese complexes will require careful analysis of the diagnostic benefit versus the potential risk posed by the free metal ions.

Angiographic properties of Gd-DTPA-24-cascade-polymer — a new macromolecular MR contrast agent

PURPOSEnA new macromolecular MR contrast agent, Gd-DTPA-24-cascade-polymer, was assessed for MR angiography of peritumoral vessels in rats.nnnMATERIAL AND METHODSnHigh resolution 3D-SPGR (TR/TE 100/5ms, alpha = 90 degrees) angiograms were acquired in 10 Fischer rats bearing subcutaneous R3230 mammary adenocarcinomas. MRI was performed before, immediately and 40 min after administration of Gd-DTPA (0.1 mmol Gd/kg), and after either Gd-DTPA-cascade-polymer or albumin-(Gd-DTPA)30 (each 0.05 mmol Gd/kg). A semi-quantitative analysis of small peritumoral vessels and tumor rim enhancement was performed on maximum intensity projection (MIP) angiograms using a 4-point scoring system. A quantitative analysis compared vascular signal-to-background-(S/B), signal-to-noise-, and contrast-to-noise-ratio.nnnRESULTSnGd-DTPA produced a transient and low-scoring vessel definition (0.2 +/- 0.1), but strong rim enhancement (score 1.7 +/- 0.1). The cascade polymer resulted in better but submaximal vessel delineation (score 1.6 +/- 0.3, S/B 5.0 +/- 0.2) and strong rim enhancement (score 1.8 +/- 0.1). Albumin-(Gd-DTPA)30 produced the best and most time-persistent angiograms (score 2.6 +/- 0.2, S/B 7.4 +/- 0.2), but minimal rim enhancement (score 0.3 +/- 0.2).nnnCONCLUSIONSnThe Gd-DTPA-24-cascade-polymer demonstrated the useful combination of strong tumor rim enhancement and detailed angiographic definition of peritumoral vessels. These are advantages associated with extracellular and blood pool contrast media, respectively.

MRI of acute myocardial ischemia: comparing a new contrast agent, Gd-DTPA-24-cascade-polymer, with Gd-DTPA.

A new macromolecular contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd‐DTPA)‐24‐cascade‐polymer, was compared with Gd‐DTPA for time‐dependent delineation of acute myocardial ischemia. Acute myocardial ischemia was produced in 12 rats by occluding the anterior branch of the left coronary artery for 20–40 minutes. Dynamic spin‐echo magnetic resonance imaging (MRI) was performed for 30 minutes after injection of Gd‐DTPA (n = 6) or the cascade polymer (n = 6) using equimolar doses (0.1 mmol of Gd/kg). The contrast agent‐induced changes in signal intensity (ΔSI) in normal and ischemic myocardium were observed. In normal myocardium, both contrast agents caused a sharp increase in ΔSI, followed by a decline to baseline values over the 30‐minute period. Enhancement in the ischemic myocardium was attenuated. Gd‐DTPA showed greater ΔSI in ischemic myocardium than the cascade polymer, which gave rise to virtually no enhancement. Significant differences (P < 0.05) in signal enhancement between normal and ischemic myocardium persisted for only 6 minutes using Gd‐DTPA but for 18 minutes with the cascade polymer. Use of Gd‐DTPA‐24‐cascade‐polymer extends the temporal window of dynamic contrast‐enhanced MRI for the differentiation of ischemic and normal myocardium. Identification of the ischemic zone is easier with the cascade polymer, which demonstrates virtually no signal enhancement in this territory. J. Magn. Reson. Imaging 1999;9:204–208.

Differentiation of spontaneous canine breast tumors using dynamic magnetic resonance imaging with 24-Gadolinium-DTPA-cascade-polymer, a new blood-pool agent. Preliminary experience.

RATIONALE AND OBJECTIVESnThe author assess the enhancement characteristics over time of spontaneous breast tumors in dogs comparing gadopentetate dimeglumine with a new blood-pool agent (24-gadolinium [Gd]-DTPA-cascade polymer).nnnMETHODSnEighteen dogs with spontaneous breast tumors (5 carcinomas, 4 adenomas, and 9 benign mixed-tissue tumors) underwent dynamic magnetic resonance imaging after intravenous injection of gadopentetate dimeglumine and the blood-pool agent. Signal intensity time curves were followed up to 30 minutes after injection of both agents in the same animal. A nonlinear fitting routine enabled calculation of the delivery and clearance half lives of the contrast agent kinetics in each tumor.nnnRESULTSnFor gadopentetate dimeglumine, a fast signal increase was found immediately after intravenous injection, with a subsequent signal decay in all tumors. No difference was observed between the enhancement kinetics of different tumor types after gadopentetate dimeglumine application. Similar kinetics were found in benign lesions after injection of the blood-pool agent. However, in carcinomas the blood-pool agent displayed a slower delivery, delayed peak enhancement, and slower tumor tissue clearance or even a signal plateau of more than 30 minutes.nnnCONCLUSIONSnDynamic magnetic resonance imaging of breast neoplasms using a blood-pool agent may help to better differentiate between benign and malignant lesions because it demonstrates the enlarged interstitial space and increased capillary permeability in carcinomas.

ELIMINATION OF GADOLINIUM-ETHOXYBENZYL-DTPA IN A RAT MODEL OF SEVERELY IMPAIRED LIVER AND KIDNEY EXCRETORY FUNCTION : AN EXPERIMENTAL STUDY IN RATS

RATIONALE AND OBJECTIVESThe authors investigated whether gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) can be eliminated in the absence of the two usual excretory pathways (urinary or biliary) and whether a remaining excretory pathway is able to compensate for impaired liver or kidney function. METHODSThe study was performed using two groups of animals: group A animals underwent ligation of the common bile duct, and group B animals underwent ligation of the renal blood vessels. A dose of 0.1 mmol/kg Gd-EOB-DTPA or Gd-DTPA (control) was injected via a tail vein. Bile or urine were collected in fractions of 0 to 1, 1 to 2, 2 to 4, and 4 to 8 hours after administration of either contrast agent. At the end of the experiments, detainment of the contrast agents was determined by measurement of Gd concentrations. RESULTSMost of the Gd-EOB-DTPA was rapidly cleared from the body: 89.4% ± 7.5% of the injected dose within 4 hours after bile duct ligation (group A) and 87.0% ± 6.0% within 1 hour after ligation of renal vessels (group B). Eight hours after injection of Gd-EOB-DTPA, 3.0% ± 2.4% of the administered dose of this contrast agent was found in the car-casses of group A animals, and 1.3% ± 0.6% in carecasses of group B animals. By comparison, at 8 hours after injection, 1.9% ± 3.2% of the injected Gd-DTPA was found in the carcasses of group A animals (no statistical significant difference as compared with Gd-EOB-DTPA), and 96.3% ± 3.3% in carcasses of group B animals. CONCLUSIONSIn the rat model, the magnetic resonance imaging contrast agent Gd-EOB-DTPA is rapidly and effectively eliminated by virtue of its dual-elimination pathway. The dysfunction of liver or kidney may be fully compensated by the remaining elimination pathway.

Complete elimination of the hepatobiliary mr contrast agent Gd-EOB-DTPA in hepatic dysfunction: An experimental study using transport-deficient, mutant rats

Mutant Wistar rats (TR− rats) are characterized by a defect in the canalicular transport system for organic anions in the hepatocytes. Anionic hepatobiliary contrast agents for X-ray and MR imaging usually depend on this transport system for biliary secretion. The current study investigated in rats whether Gd-EOB-DTPA, a hepatocyte-directed MR contrast agent, can be completely eliminated in the absence of biliary excretion, and whether urinary elimination may compensate for the hepatic dysfunction. In TR/t- rats elimination of Gd-EOB-DTPA almost completely depended on renal excretion: following intravenous administration of 25µmol kg−1 Gd-EOB-DTPA only 2.4±0.4% of the injected dose underwent biliary excretion. Nevertheless only 2% of a 10-fold higher dose (250µmolkg−1 Gd-EOB-DTPA) was still detected in the body 24 hours p.a., and less than 0.5% 7 days p.a. (no statistically significant differences as compared to values in control rats). In TR− rats, renal and liver signal intensities on T1-weighted MR images returned to baseline within 24 hours following administration of 25µmol kg−1 Gd-EOB-DTPA. In control rats, return to baseline values was observed already 6 hours after injection of the contrast agent. In conclusion, the hepatobiliary MR contrast agent Gd-EOB-DTPA is effectively and completely cleared from the body even in the virtual absence of biliary excretion. The urinary elimination pathway is able to fully compensate for the deficient hepatic transport system.

Assessment of myocardial perfusion using contrast-enhanced MR imaging: Current status and future developments

Excellent inherent tissue contrast is one of the great promises of clinical magnetic resonance (MR) imaging, but functional information is relatively limited. However, MR imaging complemented by the administration of contrast agents can provide such functional assessment. The perfusion status of the myocardium is one of the most important functional information in cardiovascular imaging. Because the clinical acceptance of a contrast agent is measured by its ability to improve patient outcome and to guide therapy, it is unlikely that detection of myocardial infarction, the final stage of ischemic heart disease, should be the target for contrast media development. It would obviously be better if occult regional myocardial perfusion deficits could be reliably detected. The current article was prepared to help the clinical radiologist to keep pace with new strategies for myocardial enhancement and their potential clinical applicability for detection of early perfusion deficits.Several techniques for noninvasive measurement of myocardial perfusion are currently evolving which have the potential to be introduced into routine MR imaging. Most investigators favor a first-pass analysis of the contrast agent bolus through the myocardium using ultrafast sequences. However, such a technique may require clinical introduction of a blood pool agent. There are good resons to favorT1-weighted sequences over susceptibility imaging in such first-pass studies. In the future, assessment of myocardial perfusion status using contrast-enhanced MR imaging may be done producing perfusion maps with high spatial resolution (e.g., 256×128), with sequences available on most scanners without special hardware requirements (e.g., IR-Turboflash, keyhole imaging), and requiring only a short period of time for examination (≈3 min).

Biodistribution and excretion of 153Gd-labeled gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid following repeated intravenous administration to rats

RATIONALE AND OBJECTIVESnWe investigated the distribution of radioactivity in tissues and organs and its disappearance following repeated intravenous (i.v.) administration of 153Gd-labeled gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) to rats.nnnMETHODSnA high total dose of 250 mumol/kg of 153Gd-labeled Gd-EOB-DTPA (a daily injection of 50 mumol/kg is equivalent to 92.5 kBq per animal on 5 consecutive days) was given to conscious rats by fast i.v. injection via a tail vein. The organ distribution and the body elimination into urine and feces were investigated at time points 3, 7, 14, and 21 days following the last injection; five animals were used at each time point. All samples were measured by gamma counting of 153Gd over a 10-min period.nnnRESULTSnThe radioactivity quickly disappeared from the body, mostly through feces. In the liver, no radioactivity could be detected at 3 days postinjection. At 21 days postinjection, only 0.002% of the gadolinium injected was detected, the vast majority (approximately 95%) of which was found in the kidneys.nnnCONCLUSIONnAfter repeated i.v. administration of a total dose of 250 mumol/kg of 153Gd-labeled Gd-EOB-DTPA, the elimination from the body was found to be 99.998% complete. Only negligible long-term retention of radioactive gadolinium was observed despite the relatively high dose injected. No perceptible evidence for decomplexation of Gd-EOB-DTPA could be found.

Contrast-enhanced MR imaging of two superparamagnetic RES-contrast agents: functional assessment of experimental radiation-induced liver injury.

The purpose of this study was to compare liver contrast‐enhancing characteristics of two superparamagnetic reticuloendothelial system (RES)‐directed agents with different particle sizes, polycrystalline iron oxide nanocompounds (PION) and carboxydextran‐coated maghemite (DDM128N/389, later referred to as DDM128), in an experimental model of focal radiation‐induced hepatitis. PION, for the small particle size (31 nm), and DDM128, for the large particle size (59 nm), RES‐directed agents were compared for liver enhancement after radiation‐induced liver injury. A single x‐irradiation exposure varying from 10 to 60 Gy was delivered to one side of the liver. T2‐weighted spin‐echo magnetic resonance imaging was performed 3 days after x‐irradiation at 30 minutes post‐contrast. Using the RES‐directed PION, the normal, non‐irradiated portion of the liver decreased in signal intensity with a maximum negative enhancement of −66%, while the irradiated portion of the liver decreased in signal intensity by −24% (60 Gy). The signal intensity decline of irradiated liver tissue using PION was dose dependent, but was found at all radiation dose levels (10–60 Gy). The difference in signal intensity between irradiated (−63%) and non‐irradiated (−82%) portions was also statistically different using DDM128 at 60 Gy. However, lower irradiation doses (10 and 30 Gy) failed to produce a statistically significantly different enhancement in the irradiated and non‐irradiated portion of the liver. Sensitivity of liver enhancement with RES‐directed agents is size dependent. The smaller particle (PION) is more sensitive for detection of radiation‐induced hepatitis than the larger particle (DDM128). The relative insensitivity of DDM128 enhancement for diffuse liver injury will be clinically advantageous for detecting focal lesions in the presence of diffuse hepatic injury.J. Magn. Reson. Imaging 1999;10:52–56.

Early Distribution Dynamics of Polymeric Magnetic Resonance Imaging Contrast Agents in Rats

Contrast agents that highlight the vascular system after intravenous injection are desirable for all diagnostic imaging modalities, especially for the high-resolution modalities X-ray and magnetic resonance imaging (MRI). It is imperative that diagnostic agents not produce side effects in addition to their “therapeutic effect”—their diagnostic efficacy. Generally speaking, a compound that circulates in an organism for a long time carries more risk than an agent that is eliminated more quickly. Several strategies have been investigated since the early development of computed tomography (CT), digital subtraction angiography (DSA), and MRI (1–7). Most of the first strategies exhibited good blood-pool properties, but because of the relatively large doses, poor elimination, and tolerance problems, none of the compounds were developed for commercial use. Later investigations focused on compounds that stay in the bloodstream long enough to allow for angiographic studies (up to several hours). Because of the rapid development in imaging technologies (with imaging becoming faster and faster), the ideal properties of such blood-pool contrast agents has seemed to be constantly in flux as well. What are the ideal physiological properties? A blood-pool contrast agent should exhibit a small volume of distribution, ideally reflecting the blood/plasma volume, and a high and stable signal intensity in the vascular system for the duration of the imaging procedure. After diagnosis, the exobiotic agent should leave the body. Its concentration in the blood should decrease over time, characterized by a certain halflife, or, to be more precise, certain half-lives. Various contrast agents have been developed, and their imaging properties and blood transit times have been studied in experimental animals. It has become obvious that studies in animals do not perfectly predict the clinical situation for humans, mainly because of the shorter circulation times and different glomerular filtration rates of the animals. A good human blood-pool agent may not be an ideal rat diagnostic. However, when the mechanism of the blood concentration decrease is known, screening can take place in animals such as rats in order to make a reasonably good estimate of the pharmacokinetic profile in humans. The purpose of this study was to describe the early distribution of potential MR blood-pool agents of different molecular sizes and identify their rates of renal excretion and extravasation from the blood space into the interstitial space. The relative proportion subject to the extravasation and elimination processes was determined after single intravenous injection in rats.