Max D. Adams

MRI contrast enhancement of necrosis by MP-2269 and gadophrin-2 in a rat model of liver infarction

Ni Y, Adzamli K, Miao Y, et al. MRI contrast enhancement of necrosis by MP-2269 and gadophrin-2 in a rat model of liver infarction. Invest Radiol 2001;36:97–103. rationale and objectives. The mechanisms of action leading to specific localization of necrosis-avid contrast agents (NACAs) such as gadophrin-2 are not well defined. It has been suggested recently that agents with a high degree of serum albumin binding may also serve as NACAs by virtue of nonspecific hydrophobic interactions. The present MRI-histomorphology correlation study was conducted to verify the likelihood of the proposed albumin-binding mechanism by comparing an albumin-binding blood pool agent, MP-2269, with gadophrin-2 in a rat model of reperfused liver infarction. methods.Reperfused infarction in the right liver lobe was surgically induced in six rats. Serial T1-weighted MRI was performed before and after intravenous injection of MP-2269 at 0.05 mmol/kg and repeated in the same rats 24 hours later after intravenous injection of gadophrin-2 at the same dosage (0.05 mmol/kg). The MR images were matched with corresponding histomorphological findings. The signal intensity and contrast ratio of infarcted and normal hepatic lobes were quantified and compared between the two agents during the postcontrast course. results.Before contrast, the infarcted lobe was indiscernible from normal liver on T1-weighted MRI. Shortly after injection of both MP-2269 and gadophrin-2, a negative contrast occurred between infarcted and normal liver because of a strong liver signal intensity enhancement and an inferior uptake in the necrotic liver. On delayed phase (>60 minutes), a necrosis-specific contrast enhancement (contrast ratio 1.6) developed with gadophrin-2 but not with MP-2269. The MR images matched well with corresponding histomorphological findings. conclusions.Although both MP-2269 and gadophrin-2 feature an albumin-binding capacity, only gadophrin-2 displayed a persistent necrosis-specific contrast enhancement in the rat model of reperfused liver infarction. Therefore, the role of albumin binding in the mechanisms of NACAs should be reevaluated.

Neurotoxicity of non-ionic X-ray contrast media after intracisternal administration in rats

The neurotoxicity of an X-ray contrast medium appears inversely related to the hydrophilicity of the agent. To further test this hypothesis, four non-ionic X-ray contrast agents, differing in hydrophilicity, (ioversol, iopromide, iohexol and iopamidol) were injected into the cisternal magna of ether-anesthetized rats. Iopromide demonstrated an acute median lethal dose of 122 mg I/kg. Other signs of toxicity included convulsions, apnea, dyspnea and hypoactivity. In contrast, ioversol, iohexol and iopamidol caused no deaths when administered intracisternally, up to a dose of 1000 mg I/kg. Animals treated with these nonionic agents displayed signs of convulsions, apnea, dyspnea, chewing and hypoactivity. Iopromide possesses a hydrophilicity (e.g., water to octanol partition coefficient) approximately 8.5 times smaller than ioversol, 4.6 times smaller than iohexol and 2.3 times smaller than iopamidol. These data support the hypothesis that tri-iodinated X-ray contrast materials with smaller degrees of hydrophilicity produce greater toxicity to the central nervous system.

The effect of sodium on the fibrillatory potential of ioversol.

Ralston WH, Robbins MS, Mosier LD, Barco SJ, Adams MD, Hopkins RM. The effect of sodium on the fibrillatory potential of ioversol. Invest Radiol 1988;23(Suppl 1):S140‐S143. The spontaneous ventricular fibrillation (VF) potential of the nonionic contrast media, ioversol (IOV), with and without the addition of sodium was examined during right coronary artery (RCA) injections into anesthetized closed‐chest dogs. Protocols included fixed volume (6 mL) and fixed rate (0.4 and 0.6 mL/sec) injections to compare two or more of the following: IOV, IOV + (0.075‐0.9% wt/vol) NaCl, and sodium/meglumine diatrizoate (DIA). In these studies, the incidence of VF for IOV alone was either greater that with IOV + NaCl for mulations or, if equivalent, the incidence of other arrhythmias was greater with IOV alone than with the sodium formulations. When DIA was included in the comparisons, the incidence of VF was always greater than IOV with or without sodium. There was a sodium‐related concentration prolongation in QT interval that, at 0.9% NaCl, approximated that with DIA, even though the incidence of VF for the sodium formulation was 0/15 vs. 6/12 for DIA. Thus, the addition of sodium to IOV appears to reduce the propensity for sponteneous VF in the canine model.

Development of a novel nonaromatic small-molecule MR contrast agent for the blood pool

The ideal contrast agent for MR angiography should be safe, efficacious, blood-persistent, and easily excreted. The binding of small Gd chelates to macromolecules has been shown to provide a mechanism of proton relaxation enhancement in MR images through longer rotational correlation times of the macromolecule-bound Gd-chelate complexes (1,2). Several effective macromolecules bearing such covalently attached Gd chelates have been synthesized and evaluated previously for MRA applications. These, however, either proved unsafe (protein precipitants) or had undesirably long blood retention, ie, were not easily excreted (3-6). Reversible noncovalent binding of small Gd chelates to serum albumin (via hydrophobic interactions) produces an efficacious, blood persistent alternative to macromoleculebased MR blood-pool agents without attendant clearance problems (7,8). A prime requirement for this approach is the presence of a lipophilic component on the Gd chelate that can undergo reversible protein binding. An MR blood-pool agent, MS-325, which takes advantage of the binding of aromatic side chains on a Gd-chelate compound to albumin, is under development (2,7,8). We now report the results of our attempt to develop a nonaromatic small Gd 3+ chelate as a contrast agent for MR angiography (ie, MP-2269, a water-soluble MR agent that binds blood proteins reversibly to yield an efficacious blood-pool agent).

A rat EEG model for evaluating contrast media neurotoxicity

Adams MD, Hopkins RM, Ferrendelli JA. A rat EEG model for evaluating contrast media neurotoxicity. Invest Radiol 1988;23 (Suppl 1):S217‐S219. The electroencephalographic (EEG) effects of intracisternally administered x‐ray contrast media were evaluated in rats as a means of assessing neurotoxicity. Rats were ventilated with a mixture of nitrous oxide and oxygen (70/30) sufficient to maintain light anesthesia/analgesia and neuromuscular blockade was induced to prevent movement artifacts. A femoral artery was catheterized for monitoring arterial blood pressure (BP), heart rate, blood gases, and pH. Four 22‐gauge stainless steel needle electrodes were inserted underneath the scalp for recording EEG. Approximately 1 hour after the start of EEG recording, test agents were injected via the cisterna magna and rats were placed in a 20° head‐down position. EEG and BP were monitored continuously for up to 160 minutes postinjection. Blood gases and pH were monitored periodically. The effects of meglumine iothalamate (IOT), metrizamide (MET), iogulamide (IOG), and ioversol (IOV) were compared at dose levels from 30 to 240 mgl/kg. Normal saline was injected as a control substance and caused no changes in EEG, blood gases, pH, and BP for up to 160 minutes postinjection. IOT (30 mg I/kg) produced profound EEG effects consistent with epileptogenic activity, followed by slowing and subsequent death in 3 of 4 animals. Metrizamide had minimal EEG effects at 30 mg I/kg but at 60 mg I/kg, and 120 mg I/kg produced moderate to severe EEG changes including epileptiform patterns and death in 33% of animals. IOV caused mild EEG abnormalities in 4 of 12 animals at 120 mg I/kg, mild EEG abnormalities in 6 of 11 animals, and moderate EEG abnormalities in 1 of 11 animals at 240 mg I/kg. IOG, in doses ranging from 60 to 240 mg I/kg, produced only slight EEG abnormalities in 1 of 4 animals at 120 mg I/kg, and in 1 of 10 animals at 240 mg I/kg.

Kinetics of a novel blood pool agent (MP-2269) with persistent high relaxivity for MR angiography.

Significant improvements in MR angiography (MRA) are obtained when the T1 value of blood is shortened using an MR contrast agent (1). Current, clinically approved agents are not confined to the intravascular space due to their small molecule size, and therefore, in most applications, show only a significant improvement in MRA during the first pass of the agent. This small acquisition-time window requires very fast MR acquisition techniques, thereby limiting the clinical application. Some applications like coronary artery angiography are not feasible in such a short acquisition window with current MR techniques due to inherently low gating efficiency. Therefore, the availability of blood-pool agents with a relatively longer blood half-life would be a significant advantage for both MR coronary angiography and other MR angiography applications. Initially, large molecular agents were proposed as blood-pool agents (2,3). However with large molecular agents, body clearance becomes a limiting factor in human use. While faster body clearance is obtained with smaller molecular agents, they are not confined to the intravascular space as well as large molecular agents. One solution to the dilemma of molecular size is an agent which binds reversibly to a blood macromolecule in vivo (4,5). A new