Phillip P. Harnish

Preliminary evaluation of EVP 1001-1: a new cardiac-specific magnetic resonance contrast agent with kinetics suitable for steady-state imaging of the ischemic heart.

Rationale and Objectives:To investigate the potential of a novel manganese-based magnetic resonance (MR) contrast agent, EVP 1001–1 for the evaluation of myocardial ischemia. Methods:MR imaging with EVP 1001-1 was performed on 6 Yorkshire pigs, and T1 relaxation times were calculated. One animal served as a control, 2 were subjected to an acute coronary artery occlusion and 3 provided a model of chronic ischemia. Results:Administration of the agent in the control and acute coronary occlusion model demonstrated a short plasma half-life (∼1.5 minutes) and rapid myocardial uptake in nonoccluded regions, with long retention times in the myocardium (>1 hour) and no evidence of redistribution. In the chronic ischemia model, differential enhancement was observed between normal and ischemic tissue, particularly under dobutamine-induced stress. Conclusions:These properties suggest the use of EVP 1001-1 for steady-state imaging of myocardial perfusion. Contrast administration could be performed under stress conditions outside the scanner, with high-resolution MR images reflecting the stress condition acquired after the stress has subsided.

Reduced cerebrospinal fluid production in the rat and rabbit by diatrizoate. Ventriculocisternal perfusion.

The effect of the radiographic contrast agent diatrizoate on cerebrospinal fluid (CSF) production was determined by ventriculocisternal perfusion. The lateral ventricle and cisterna magna of anesthetized rats and rabbits were cannulated stereotactically and perfused continuously with a H-3 inulin-labeled artificial CSF solution. Baseline collections of CSF began after steady state outflow was established; then, diatrizoate was administered intravenously for 1 hour. The baseline rate of CSF production was compared with that measured during and after the diatrizoate infusion. The baseline CSF production rate was 3.7 +/- 0.1 and 18.6 +/- 1.4 microL/minute in the rat and rabbit, respectively. Diatrizoate decreased the CSF production rate to 2.9 +/- 0.1 and 13.9 +/- 0.9 microL/minute. This reduced rate continued for at least 90 minutes after the end of the diatrizoate infusion, averaging 3.0 +/- 0.1 and 12.0 +/- 0.6 microL/minute in the rat and rabbit, respectively. These results confirm that decreased CSF production induced by the intravenous administration of diatrizoate is not species specific and is observed with the ventriculocisternal perfusion method of measuring CSF production rates.

Magnetic resonance imaging of myocardial infarction using a manganese-based contrast agent (EVP 1001-1): Preliminary results in a Dog model

To investigate the MRI characteristics of an intracellular manganese‐based contrast agent, EVP 1001‐1 (Eagle Vision Pharmaceutical Corp.), in a canine model of myocardial infarction.

Tissue fluid shifts during renal arteriography with conventional and low osmolality agents.

The osmotic effects caused by conventional and low osmolality radiopaque agents have been studied in the isolated perfused canine kidney. Changes in vein flow, hematocrit, osmolality, and iodine content were measured at injection doses of 0.25 and 0.5 ml/kg (300 mgI/ml). Increases in osmolality and decreases in hematocrit were significantly greater with the conventional ionic monomer meglumine/sodium diatrizoate than with the low osmolality agents iohexol, iopamidol, and ioxaglate. The standard renal vein flow response for all agents was an increase (loss of renal water) followed by a decrease (gain of renal water). Diatrizoate produced the greatest increase in outflow at 0.25 ml/kg, but the differences between agents were not statistically significant. At the 0.5 ml/kg dose the differences in peak renal vein flow between agents were negligible. Renal vein iodine was highest with the dimer, ioxaglate and lowest with the diatrizoate. The nonionics iohexol and iopamidol produced essentially the same renal vein iodine levels and clearance. The new low osmolality agents have significantly less effect on osmolality and hematocrit and produce higher venous iodine levels than a conventional ionic monomer. The only difference between the low osmolality agents was the higher venous iodine seen with the dimer ioxaglate.

Iohexol Inhibits Adenylate Cyclase

Previous studies demonstrated that the intravenous administration of the ionic radiographic contrast agent, diatrizoate, and the nonionic agent, iohexol, causes a decrease in the rate of cerebrospinal fluid (CSF) production. Evidence suggests that adrenergic-mediated adenylate cyclase (AC) activity controls CSF production. Diatrizoate was found to inhibit AC activity. The authors now report that iohexol inhibits activity of this enzyme. Adenylate cyclase activity was measured in membrane fractions of bovine choroid plexus in the presence of various concentrations of iohexol. A concentration-dependent inhibition of basal and adrenergic-stimulated AC activity by the contrast agent was observed. The concentration of iohexol that produced a 50% inhibition was about 2.3 mM. This is similar to the concentration of diatrizoate that produced equivalent enzyme inhibition. These results support the contention that one mechanism for the action of contrast media in reducing CSF production involves inhibition of AC activity.

T1 efficacy of EVP-ABD: A potential manganese-based MR contrast agent for hepatic vascular and tissue phase imaging

To evaluate the T1 efficacy of EVP‐ABD, a new manganese (Mn)‐based contrast agent, for vascular and liver tissue enhancement in comparison with currently approved agents.

Intravascular contrast media and the blood-brain barrier. Testing the new nonionic agent ioxilan.

The effects of diatrizoate, iohexol, and ioxilan on the blood-brain barrier (BBB) were investigated in normal and hypertensive rats. Anesthetized Wistar rats received 14C-inulin as an indicator for BBB disruption. Diatrizoate, iohexol, or ioxilan (350 and 175 mgI/mL) or normal saline was then injected into the carotid artery (2 mL in 30 seconds). Twenty minutes later, the cardiovascular system was flushed, the brain removed, and each hemisphere was digested. BBB disruption, expressed as counts/minute/mg protein, was compared for each hemisphere in each group by analysis of variance. BBB damage in the diatrizoate-350 group was significantly greater than that in all other groups. No significant BBB damage resulted from iohexol or ioxilan relative to normal saline.

Contrast Media-Induced Blood-Brain Barrier Damage Potentiation by Hypertension

Large doses of an ionic contrast medium (CM) can disrupt the blood brain barrier (BBB) osmotically. Acute hypertension (HT) also is known to open the BBB. We tested the hypothesis that these two factors potentiate each other in a rat model. Adult male Wistar rats, anesthetized with pentobarbital, underwent tracheostomy. An external carotid artery catheter was placed so that it opened into the patent common carotid artery; arterial blood pressure was recorded continuously. Of three groups of animals, two (HT) groups received metaraminol to elevate and maintain blood pressure in the range of 165 to 190 mm Hg. The third (normotensive) group received an equivalent volume of saline. Five minutes after injection of Evans blue, either sodium/meglumine diatrizoate or saline was infused into the carotid cannula (2 mL in 30 seconds). Twenty minutes later the cardiovascular system was flushed with saline, and the brain was removed, frozen, and sectioned for gross and histofluorescent microscopic examination of BBB opening. The carotid injection of CM at a concentration of 1000 mosm/kg water did not produce gross evidence of BBB opening in the normotensive group. Similarly, hypertension at levels below 190 mm Hg did not produce gross evidence of opening in the carotid saline group. However, the combination of carotid CM and HT produced significant BBB opening. These results suggest that the risk factor of acute HT potentiates CM-induced BBB opening.

Deleterious Synergism of a Cardiac Glycoside and Sodium Diatrizoate

Studies were performed in mice to determine if the cardiac glycoside, Strophanthin-K, and the contrast medium, sodium diatrizoate, interact synergistically to produce death. Intravenous injections of lethal and near lethal doses of the two agents produced a significantly greater mortality than the individual agents alone. Low or near clinical doses of Strophanthin-K, when given with doses of diatrizoate in the lethal range, produced mortalities significantly greater than did the diatrizoate alone. Similarly, low or near clinical doses of diatrizoate given with doses of Strophanthin-K in the lethal range produced mortalities significantly greater than for the Strophanthin-K alone. Isotonic or hypertonic saline, when substituted for diatrizoate or Strophanthin-K did not produce synergistic increases in mortality. Thus neither the injection volume, nor agent hypertonicity or ionic strength, seem to be the primary factors in the synergism to produce death. The diatrizoate anion appears to be an important factor. Until more information is available from other animal models it appears that patients receiving cardiac glycoside should be considered to have a higher than normal risk of serious reactions to contrast media in intravenous urography.

Opiate Involvement in Contrast Media-induced Blood Pressure Changes

The intravenous administration of contrast media (CM) often alters blood pressure (BP). Osmolality plays a role, but the magnitude and even direction of change varies under similar (osmotic) conditions, indicating the involvement of other mechanisms. Male Wistar rats, anesthetized with pentobarbital, received sodium/meglumine diatrizoate, iohexol, or normal saline, 4 ml/kg, via a tail vein, while blood pressure was recorded continuously. Additional groups were pretreated with the opiate antagonist, naloxone (1 mg/kg, IV), or with an equal volume of normal saline 5 minutes prior to the diatrizoate injection. Comparisons of BP change were made with the Students t-test. Diatrizoate caused a significant (P less than .0002) increase in BP relative to the saline control group, iohexol did not. Thus, the increase with diatrizoate was significantly greater than with iohexol (P less than .00006). Neither the saline nor naloxone pretreatment altered BP significantly. Saline pretreatment did not alter the significant increase in BP produced by the diatrizoate. However, the diatrizoate-induced increase in BP was prevented by the naloxone pretreatment and was significantly less than after the saline pretreatment (P less than .0001). Based on these and previous results, the authors hypothesize that release of endogenous opioids may play a role in BP changes caused by intravenous CM and that significant CM-induced changes may be prevented pharmacologically with the selective opiate blocker, naloxone.