Magnetic resonance characterization of the peri-infarction zone of reperfused myocardial infarction with necrosis-specific and extracellular nonspecific contrast media.

BACKGROUND: Because ischemically injured myocardium is frequently composed of viable and nonviable portions, a method to discriminate the two is useful for clinical management. METHODS AND RESULTS: Ischemically injured myocardium was characterized with extracellular nonspecific (Gd-DTPA) and necrosis-specific (mesoporphyrin) MR contrast media in rats. Relaxation rates (R1) were measured on day 1 and day 2 by inversion-recovery echoplanar imaging. Spin-echo imaging was used to define contrast-enhanced regions and regional wall thickening. Gadolinium concentration, area at risk, and infarct size were measured at postmortem examination. DeltaR1 ratio (DeltaR1(myocardium)/DeltaR1(blood)) after administration of Gd-DTPA was greater in ischemically injured myocardium (1.20+/-0.15) than in normal myocardium (0.47+/-0.05, P<0.05), which was attributed to differences in gadolinium concentration and water content. The Gd-DTPA-enhanced region on day 2 was larger (32.8+/-0.9%) than true infarction as demonstrated by triphenyltetrazolium chloride (TTC) (24.6+/-1.4%, P<0.001, r=0.21). Bland-Altman analysis revealed that the Gd-DTPA-enhanced region overestimated true infarct size by 7.8+/-5.9%. On the other hand, the mesoporphyrin-enhanced region (26.9+/-1.8%, P=NS, r=0.87) and true infarct size were identical. The difference in the areas demarcated by the 2 agents is the peri-infarction. Systolic and diastolic MR images revealed no wall thickening in the mesoporphyrin-enhanced region (0.3+/-3.3%) but reduced thickening in the Gd-DTPA-enhanced rim (8.5+/-5.5%, P<0.05). CONCLUSIONS: The Gd-DTPA-enhanced region encompasses both viable and nonviable portions of the ischemically injured myocardium. The Gd-DTPA-enhanced area overestimated infarct size, but the mesoporphyrin-enhanced area matched true infarct size. The salvageable peri-infarction zone can be characterized with double-contrast-enhanced and functional MR imaging; the mismatched area of enhancement between the 2 agents shows residual wall thickening.

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.

Influence of gadolinium chelates on phosphorus-31 magnetic resonance spectroscopy of the liver.

RATIONALE AND OBJECTIVES: The potential of gadolinium compounds (Gd-ethoxybenzyl-DTPA [Gd-EOB-DTPA], gadopentetate dimeglumine [Gd-DTPA], and Gd-chloride [GdCl3]) to enhance the signals from intracellular phosphorus-31 nuclei in the liver was investigated. METHODS: After intravenous administration of Gd-EOB-DTPA, Gd-DTPA, and GdCl3 to rats, liver phosphorus metabolites (inorganic phosphate [Pi], phosphomonoester [PME], and adenosine triphosphate [ATP]) were measured by phosphorus-31 magnetic resonance spectroscopy (MRS). The dose of each compound was 0.2 mmol Gd/kg. Saline was used as a control. RESULTS: The intensities of the phosphorus metabolite signals in the liver showed only minor changes after administration of Gd-DTPA and GdCl3, but increased after Gd-EOB-DTPA. The signals of Pi and PME were enhanced more than those of ATP. The alpha peak of ATP increased by 21.7%, Pi by 61.2%, and PME by 49.2%. CONCLUSIONS: The signal intensities of the phosphorus metabolites in the liver were not influenced by GdCl3. Using Gd-DTPA, only a slight enhancement could be detected. The greatest enhancement was observed with Gd-EOB-DTPA, which has access to the phosphorus metabolites within the hepatocytes. The injection of Gd-EOB-DTPA results in better detectability of the Pi signal.

Elimination of gadolinium-ethoxybenzyl-DTPA in a rat model of severely impaired liver and kidney excretory function. An experimental study in rats.

RATIONALE AND OBJECTIVES: The 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. METHODS: The 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. RESULTS: Most 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 carcasses of group A animals, and 1.3% +/- 0.6% in carcasses 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. CONCLUSIONS: In the rat model, the magnetic resonance imaging contrast agent Gd-EOB-DPTA 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.

Investigation of mechanisms influencing the accumulation of ultrasmall superparamagnetic iron oxide particles in lymph nodes.

RATIONALE AND OBJECTIVES: The current study was designed to investigate the lymph node accumulation mechanisms of dextran-coated ultrasmall superparamagnetic iron oxide particles (USPIO) in rats. METHODS: The iron deposition in the lymph nodes after intravenous administration of USPIO at a dose of 200 mumol Fe/kg was measured in vitro by inductively coupled plasma atomic emission spectrometer in control rats, in rats after depletion of complement C3, after induction of antidextran antibodies, and with prior ligation of afferent lymphatic vessels. The results were correlated with baseline iron concentration and histology. RESULTS: A significant increase in iron concentration but unequal distribution between central and peripheral nodes occurred after administration of USPIO in rats. Much less accumulation was observed in guinea pigs. In rats, the nodal uptake of USPIO was not impaired by depletion of complement C3 using cobra venom factor. The central lymph nodes (mesenteric nodes) showed significantly more accumulation of iron particles in the presence of antidextran antibodies induced by dextran preimmunization. Afferent lymphatic vessel ligation did not effect iron particle accumulation. CONCLUSIONS: Accumulation of USPIO in lymph nodes is largely species-dependent but is independent of afferent lymphatic flow and of C3 complement opsonization in plasma. However, regional distribution of particles can be influenced by preimmunization using dextran.

Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers.

RATIONALE AND OBJECTIVES: Gadobutrol is a new gadolinium-based hydrophilic and neutral macrocyclic contrast medium for magnetic resonance imaging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg. METHODS: Gadobutrol was investigated after single intravenous administration in two phase-1 studies testing low (0.5 mol/L) and high concentrations (1 mol/L) in healthy, male volunteers using a double-blind, randomized, placebo-controlled study with n = 55 for the low concentration (0.04, 0.1, 0.2, 0.3, and 0.4 mmol/kg body weight), followed by n = 36 for the high concentration (0.3, 0.4, and 0.5 mmol/kg body weight). Vital signs and laboratory parameters were measured for all dose groups investigated, whereas for the calculation of the pharmacokinetic parameters, the dose groups 0.04, 0.1, and 0.4 mmol/kg body weight were selected. RESULTS: Gadobutrol was well tolerated up to doses of 0.5 mmol/kg, and no relevant changes in vital signs and laboratory parameters occurred. The terminal disposition half-life of gadobutrol in plasma was approximately 1.5 hours. Total clearance approximated renal clearance and approximated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution indicated predominantly extracellular distribution of gadobutrol. No metabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order kinetics of gadobutrol. CONCLUSION: Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg body weight. These factors suggest that gadobutrol will be a safe magnetic resonance imaging contrast agent.

In vivo and in vitro evaluation of Gd-DTPA-polylysine as a macromolecular contrast agent for magnetic resonance imaging.

Polylysine covalently linked to moieties of gadopentetate (Gd-DTPA), for use as a macromolecular blood pool marker for contrast material-enhanced magnetic resonance imaging (MRI), was characterized by means of physicochemical measurements and pharmacokinetics in rats and rabbits and compared with Gd-DTPA. Gd-DTPA-polylysine was composed of a series of polymers of different molecular sizes that on average were labeled with 60 to 70 Gd-DTPA moieties (average molecular weight, 48,700 daltons [D]). For the macromolecular compound Gd-DTPA-polylysine, relaxivity was three times higher than that of Gd-DTPA. The LD50 value of 17 mmol/kg reflects a fairly high acute intravenous tolerance of the macromolecular compound in mice. Even though the volume of distribution of Gd-DTPA-polylysine in rabbits approached the extracellular fluid space (indicating that the macromolecular compound was also leaking slowly into the interstitial space), the half-life of distribution of the macromolecular compound in the extracellular fluid space was significantly prolonged, thus making the compound suitable as a blood pool marker for MRI. In rats the elimination of Gd-DTPA-polylysine occurred predominantly via the renal route. High-pressure liquid chromatography-size-exclusion chromatography of the fractionated urine samples revealed that the renal clearance must be the integral sum of the separate clearances of each molecular weight species. No biodegradation of the polypeptide was observed, and biodistribution studies revealed only minimal retention of Gd in the body of the rat.

Magnetic resonance imaging of pulmonary ventilation. Initial experiences with a gadolinium-DTPA-based aerosol.

RATIONALE AND OBJECTIVES: The authors investigate whether a modified gadolinium (Gd)-DTPA formulation can be aerosolized and used as a contrast agent for magnetic resonance (MR) ventilation imaging of the lungs. METHODS: Gadolinium-DTPA (gadopentetate dimeglumine, Schering AG, Berlin, Germany, 100 mmol Gd/L) was modified by addition of mannitol (Sigma, Deisenhofen, Germany, 10 mg/mL) and the surface active detergent Lutrol F68 (BASF, Mannheim, Germany, 2 mg/mL). The imaging was performed in an anesthetized rat model after inhalation of the contrast agent aerosol (PulmoSonic, De Vilbiss, Germany, 10-minute nebulization). T1-weighted spin echo images (repetitive time [TR]/echo time [TE] = 40/3 mseconds) were acquired at 2 T (SIS 85; Sisco, Fremont, CA) before and as long as 120 minutes after administration of the contrast agent. RESULTS: The modified Gd-DTPA aerosol elicited high and relatively homogeneous enhancement of the lung directly after nebulization. The enhancement was more pronounced than that obtained with a Gd-DTPA formulation without additives. CONCLUSIONS: Gadolinium-DTPA-based aerosol appears to be a suitable contrast agent for MR ventilation imaging in an experimental animal model. Modification by mannitol (to increase proton density through a slight additional osmotic effect) and a detergent (to reduce droplet size by decreasing surface tension) is suitable and effective in increasing signal intensity compared with Gd-DTPA without modification.

Hepatic kinetics and magnetic resonance imaging of gadolinium-EOB-DTPA in dogs.

RATIONALE AND OBJECTIVES: To measure the hepatic uptake and biliary elimination kinetics of gadolinium (Gd)-EOB-DTPA in dogs. METHOD: Two groups of four beagles each were anesthetized and given an intravenous bolus of 25 mumol/kg or 250 mumol/kg of Gd-EOB-DTPA. Blood, hepatic bile, and urine were collected over 140 minutes, and liver samples were obtained immediately after the dogs were killed. Conventional T1-weighted spin echo sequences of the liver were performed on a 1.5-Tesla (T) magnetic resonance imager during sampling. A ninth beagle received a bolus of 25 mumol/kg followed 140 minutes later with a bolus of 250 mumol/kg of Gd-EOB-DTPA. Wedge liver biopsies were obtained for Gd estimation at various times after dosing, and Gd concentration was measured by inductively coupled plasma atomic emission spectroscopy. RESULTS: The plasma concentration of Gd-EOB-DTPA decreased in a biexponential manner with half-lives of approximately 4 minutes and 60 minutes for the distribution and elimination phase independent of the dose given. Gadolinium bile concentration reached peak values between 80 and 140 minutes: 6.3 +/- 1.6 mmol/L for the low dose (LD) and 11.6 +/- mmol/L for the high dose (HD). Bile Gd output was 62.0 +/- 8.8 (LD) and 78.3 +/- 30.2 (HD) nmol/minute-kg 50 to 80 minutes after injection. Gadolinium-EOB-DTPA was excreted by the biliary route to 24.8 +/- 2.6 (LD) and 3.6 +/- 1.2 (HD) percent of the dose within 140 minutes. Liver Gd concentration was 0.43 +/- 0.14 (LD) and 4.3 +/- 0.5 (HD) mmol/kg liver tissue at the conclusion of the studies. Calculated concentrations in the hepatocyte were 60 (LD) and 15 (HD) times higher than in plasma at 25 minutes after dosing. Whereas the low dose exhibited excellent contrast enhancement for the whole period, the high dose displayed a biphasic signal enhancement with a decreasing signal caused by the too-high hepatic gadolinium accumulation. CONCLUSIONS: Transport of the Gd-EOB-DTPA into the hepatocyte exceeded elimination from hepatocyte to bile. The high dose defined a biliary transport maximum for Gd-EOB-DTPA of 78.3 +/- 30.2 nmol/minute-kg. The liver accumulation results from fast transport into the hepatocyte and rate-limited slower transport from hepatocyte to bile. The accumulation occurs against a strong concentration gradient, suggesting energy-dependent active transport into the hepatocyte.

In vivo microscopic evaluation of the microvascular behavior of FITC-labeled macromolecular MR contrast agents in the hamster skinfold chamber.

RATIONALE AND OBJECTIVES: The extravasation properties of two macromolecular MR imaging contrast media (CM) in relation to structural differences of the terminal vascular bed were investigated to determine whether differentiation between normal (physiological) and tumor (pathological) tissue can be achieved by means of extravasation characteristics. METHODS: Gd-DTPA-polylysine (50 kD, CM1) and Gd-DOTA cascade polymer (Gadomer 17; 20 kD, CM2) were labeled with fluorescein isothiocyanate (FITC) to enable in vivo fluorescence microscopy of the microcirculation. After implantation of a dorsal skinfold chamber and 7 days (range, 6-8) after induction of an amelanotic melanoma (A-Mel-3), 14 male hamsters weighing 85 g (range, 70-95 g) received 200 micromol/kg of CM1 by intravenous injection into the jugular vein. CM2 was similarly investigated after an interval of 24 hours. Fluorescence microscopy was performed in areas of subcutaneous tissue, striated muscle, and tumor tissue. Microscopic images were registered by a charge-coupled-device video camera and transferred to a video system. Distribution intensities of CM were evaluated on a digitally based measurement system. A control investigation was performed with FITC-dextran (150 kD). RESULTS: Gd-DTPA-polylysine showed no extravasation into physiological tissue for the first 10 minutes after injection. After this period, however, the first signs of leakage became apparent. Gd-DOTA cascade polymer was extravasated after 5 minutes into the tumor-free tissue. In tumor capillaries, Gd-DTPA-polylysine could be detected in the extravasal space as well as in physiological tissue after 15 minutes. After injection of Gd-DOTA cascade polymer, direct leakage from tumor capillaries was observed, with a contrast maximum between tumor and surrounding tissue occurring 3 to 5 minutes after CM injection. Good delineation of tumor vascularization from striated muscle and subcutaneous tissue was achieved. CONCLUSIONS: The CM studied showed different microvascular permeation properties. Faster leakage of Gd-DOTA cascade polymer was observed in areas with neoplastic tumor vessels, whereas extravasation in physiological tissue was detected after a period of 5 minutes. Gd-DTPA-polylysine demonstrated nonspecific leakage at later time points.

Magnetic resonance angiography with gadomer-17. An animal study original investigation.

RATIONALE AND OBJECTIVES: Our purpose was to investigate a "blood pool" contrast agent for abdominal and thoracic MR angiography by comparison with standard ionic and nonionic gadolinium-based contrast agents, which redistribute into the extracellular fluid compartment. METHODS: Abdominal and thoracic MR angiography was performed in three adult dogs using a three-dimensional spoiled gradient echo pulse sequence before and after intravenous administration of one of three gadolinium-based contrast agents (gadopentetate dimeglumine, gadobutrol, and gadomer-17). Each compound was tested at five different doses in all three dogs. Quantitative analysis of signal-to-noise ratio (SNR) was performed in the aorta, inferior vena cava (IVC), liver, spleen, kidney (medulla and cortex), fat, and muscle. RESULTS: Gadomer-17 improved visualization of vascular anatomy at doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg with three-fold greater aorta SNR during the arterial phase and more than four-fold greater aorta and IVC SNR during the equilibrium phase, in comparison with gadopentetate dimeglumine and gadobutrol at equal doses. CONCLUSIONS: Gadomer-17 is a promising contrast agent for both arterial phase and equilibrium phase MR angiography.

Clinical trial of iotrol for lumbar myelography.

Iotrol, a new nonionic, water-soluble, hexiodinated dimeric contrast medium for myelography, was used in clinical trials in 29 patients. The purpose of the study was to acquire information on local and general tolerance, distribution and excretion, and image quality. Preliminary results show that iotrol is well suited for lumbar and thoracolumbar myelography. Side effects observed with the use of iotrol were fewer and less severe than those reported with metrizamide. Iotrol is cleared from the cerebrospinal fluid and excreted by glomerular filtration within the same time range as other water-soluble contrast media.

Gadolinium-DTPA in MR imaging of glioblastomas and intracranial metastases.

In 14 patients with the diagnosis of glioblastoma (n = 7) or intracranial metastases (n = 7), magnetic resonance (MR) imaging was performed using a variety of spin-echo (SE) pulse sequences before and after intravenous injection of 0.1 mmol gadolinium-DTPA (Gd-DTPA) per kilogram of body weight. In 10 patients, tumor tissue could not be adequately differentiated from perifocal edema on unenhanced scans with any of the applied pulse sequences. In four cases of intracranial metastases, poor differentiation between tumor and perifocal edema was possible in T2-weighted (SE 1600/70 and SE 1600/105) unenhanced scans. After administration of Gd-DTPA, tumor tissue showed marked contrast enhancement, and tumor delineation was consistently possible on SE 800/35 images. Tumor tissue could be differentiated from perifocal edema on SE 800/70 scans. Gd-DTPA is likely to increase the potential of MR imaging and refine the evaluation of glioblastomas and intracerebral metastases.

Producing parallel x rays with a bent-crystal monochromator and an x-ray tube.

A bent Laue monochromator and a conventional x-ray tube were used to produce a fan beam that was parallel in the plane perpendicular to the plane of the fan. The x-ray fan beam was tunable in energy and had about 12% energy bandwidth at a slice height of 5 mm when tuned to 50 keV. The beam's energy was slightly coupled to the vertical position on the beam's height. The slice height could be varied from 1 to 10 mm. The flux at 50 keV was approximately 2x10(6) photons/mm2/s with a rotating anode tungsten x-ray tube operating at 120 kVp and 100 mA. The narrow energy bandwidth of the beam produced is advantageous over a conventional divergent polychromatic beam for all radiography applications, while the parallelism of the beam enhances its intensity by about threefold and offers some advantages for computed tomography.

Preliminary evaluation: magnetic resonance of urography using a saturation inversion projection spin-echo sequence.

A saturation inversion projection (SIP) spin-echo technique is reported which allows a reliable direct visualization of the urogenital system as well as its functional performance in magnetic resonance imaging. We used an imaging sequence with a 90 degree saturation pulse and two 180 degree inversion pulses followed by a short spin-echo (SE) pulse sequence. The three time intervals in the 90 degree-180 degree-180 degree-SE pulse train were adjusted to suppress the signals of soft tissues and fat. After intravenous injection of the contrast agent Gd-DTPA, a shortening of the kidney T1 and the T1 of the urogenital system is obtained below the T1 values of fat and soft tissues, and these remaining ultra-short T1 tissues were imaged with the SIP sequence. Using a sequential measuring technique a quantitative evaluation of the glomerular filtration rate seems to be possible with a time resolution of 18 sec per image. In addition, magnetic resonance urography using the SIP sequence provided a good visualization of the urogenital system and may show several clinical utilities in further clinical studies.

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

RATIONALE AND OBJECTIVES: We 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: After 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.

Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging.

The Gd(3+)-complex of 10-(2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclo dodecane-1,4,7-triacetic acid(gadobutrol) is a new, neutral Gd-chelate for use as an extracellular contrast agent in magnetic resonance imaging (MRI). The blood level in dogs after intravenous (i.v.) injection decreased with a terminal half-life of about 45 min, the clearance was about 3.75 ml/min per kg and the distribution volume of 0.23 l/kg suggested an extracellular distribution. Biodistribution experiments in rats revealed that only a very small amount (0.16%) of the dose was left in the body 7 days after i.v. injection. Measurable amounts of Gd could be detected only in the liver, kidneys and bones. The osmolality (0.57 osmol/kg at 0.5 mol/l and 1.39 osmol/kg at 1 mol/l) is in the range of other low osmolality contrast media for MRI. Only very little interaction with biologically relevant molecules was suggested by a histamine release test and a lysozyme inhibition test. An i.v.-LD50 of 23 mmol/kg in mice combined with a comparatively high T1-relaxivity (5.6 l/mmol per s at 0.47 T and 6.1 l/mmol per s at 2 T) in plasma promises a high margin of safety. In preliminary imaging experiments, gadobutrol caused high enhancement in different lesions (cerebral infarct, brain tumor) of the rat. Tripling of the typical clinical dose of 0.1 mmol/kg was shown to provide additional diagnostic gain in lesions of this type.

[Animal experimental studies on the application of dynamic computed tomography to liver tumors]. / Tierexperimentelle Studien zum Einsatz der dynamischen Computertomographie bei Lebertumoren.

Experiments on rabbits with implanted liver tumours have shown that iso-dense tumours, which are not visible on CT, may be demonstrated by dynamic CT following intravenous contrast injection. They may appear as hypodense areas during a period of maximal organ perfusion, if the tumours have not taken up the contrast. The ability to recognise tumours depends largely on intravascular and, only to a smaller extent, on interstitial contrast enhancement.

[Determination of hematocrit and iodine concentrations following intravenous bolus administration of ionic and nonionic monomeric and dimeric contrast media--an animal experimental study]. / Hämatokrit- und Jodkonzentrationsbestimmungen nach intravenöser Bolusapplikation ionischer und nichtionischer monomerer und dimerer Kontrastmittel--Tierexperimentelle Studie.

A monomeric ionic (meglumine diatrizoate), a monomeric non-ionic (iopromide) and a dimeric non-ionic contrast medium were intravenously administered (V. jugularis) to 15 rabbits. Blood iodine concentration as well as haematocrit were determined from blood samples taken from the femoral artery immediately after injection until the 90th second p.i. The contrast media showed clear differences concerning the haematocrit, i.e. the isotonic non-ionic dimer induced its lowest decrease. The direct determination of the blood iodine concentration revealed no significant deviations between the contrast media studied. Only non-ionic dimers are iso-osmolar with plasma at the iodine concentrations employed in diagnostic radiology. Compared with monomeric compounds this study provides fundamental evidence that isotonic, non-ionic dimeric contrast media cause only slight effects on blood cells. This confirms experimentally the clinically reported good tolerance of dimeric contrast media in patients.

[Oral contrast media for magnetic resonance tomography of the abdomen. 1. Comparative animal studies of positive and negative contrast media]. / Orale Kontrastmittel für die magnetische Resonanztomographie des Abdomens. Teil 1: Tierexperimenteller Vergleich positiver und negativer Kontrastmittel.

Beagle dogs were investigated by MRI (Siemens Magnetom, 0.35 T) after oral administration of aqueous solutions of Gd-DTPA (n = 4), ferric ammonium citrate (n = 1), and magnetite dextran (n = 2). High signal intensity of the GI-tract versus adjacent structures was obtained with Gd-DTPA and ferric ammonium citrate. Magnetite showed negative contrast versus adjacent structures. However, magnetite displayed lower contrast relative to liver, muscle and gut wall compared to Gd-DTPA and ferric ammonium citrate. In relatively T2-weighted sequences labeling of poorly filled bowel loops was significantly better with Gd-DTPA and ferric ammonium citrate. For GI-tract contrast enhancement we conclude that positive contrast media are of higher diagnostic value compared to negative contrast agents.