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Iodinated contrast material: studies relating to complement activation, atopy, cellular association, and antigenicity.

There are multiple problems of iodinated contrast physiology and iodinated contrast reactions that remain unresolved. The author's recent work has included studies in four of these areas. (I) In evaluating complement activation following contrast reactions, significant drops in total hemolytic complement were found, as well as that the reactors had lower baseline complement levels than nonreactors. (II) The leukocytes of atopics and of nonatopics were incubated with contrast and a greater release of histamine was found among the atopics than among the normal subjects. (III) Since histamine can be shown to be released from leukocytes by contrast, I-125-sodium diatrizoate was incubated with blood to detect any cellular association for the contrast. Significant retention of radioactivity was demonstrated by the leukocytes and not the erythrocytes. (IV) The gluteraldehyde technique was used to conjugate diatrizoate bovine serum albumen. After injection of this conjugate into a rabbit, antibody activity in the rabbit serum to the diatrizoate was demonstrated via the enzyme-linked immunospecific assay system.

Antibody Formation↗

Contrast media-induced side effects on excitation and conduction of electrical activity in the heart on intracardiac application. Investigations in anaesthetized dogs.

In several series of experiments with intracardiac application in anaesthetized dogs, the following contrast media were tested for their adverse effects on excitation and conduction of electrical activity in the heart. Diatrizoate, lysine-diatrizoate, lysine-sodium-diatrizoate, ioxaglate, iopamidol, iodamide, ioxitalamate, ioglicinate and metrizamide. Blood pressure and, using the His' bundle-ECG technique, the parameters P0-P1 (heart rate), A1-H1 period (conduction time in the AV-node), and H1-V1 period (conduction time in the TAWARA branches) were measured. A statistical correlation exists between osmolarity and blood pressure (higher osmolarity causes a greater decrease in blood pressure), as well as between osmolality and decrease in heart rate (higher osmolarity causes a greater decrease in heart rate). The delay in conduction time in the AV-node correlates only with viscosity and sodium content (increased viscosity with increased sodium content delays the time of conduction). A tendency towards delay in conduction in the TAWARA branches could not be correlated to any one of the physico-chemical parameters studied.

Anesthesia, General↗

Effect of iodinated contrast media on ionic calcium.

This study was conducted to characterize the alterations in serum ionized calcium induced by contrast media (CM) and to determine the cause of the change. Fresh human blood samples as well as an electrolyte solution (ES) containing 1.2 mM calcium ions were diluted with CM and alterations in ionized calcium were measured using an electrometer. The CM tested were diatrizoate, iopamidol, iohexol, ioxaglate, isotonic saline, Na2-Ca-EDTA and pure meglumine. When CM were mixed with blood, ionic CM produced a greater decrease in ionized calcium than nonionic CM or saline. When mixed with ES, a significant reduction of ionized calcium was induced by ioxaglate and diatrizoate in comparison with saline. Na2-Ca-EDTA and meglumine caused no reduction in ionized calcium. Ioxaglate and diatrizoate caused calcium binding due to anions; binding induced by the latter was more prominent than that by the former. These observations suggest that a nonionic CM is more desirable for coronary arteriography of high-risk patients.

Adult↗

Complement abnormalities during contrast media procedures.

Complement changes following the administration of the two most commonly used intravascular contrast media (CM) diatrizoate and iothalmate were studied in 26 patients by measuring complement component C3 levels and the total hemolytic function. Blood from these patients was obtained in plastic tubes containing 10 mM ethylene diamine tetra-acetic acid (EDTA) prior to and 15 min after contrast media infusion. In thirteen patients who received iothalamate a 28% drop in C3 concentration and a 19% change in total hemolytic complement was seen. In the second group of thirteen patients diatrizoate caused a 20% C3 decrease and a 15% reduction in total hemolytic complement. Since iothalamate is a hyperosmolar and hyperviscous solution compared to diatrizoate, it is likely that these factors are responsible for changes in complement level which may present potential risk to patients with depressed immunologic status. This study suggests that screening of patients for their total complement profile may provide useful information in minimizing adverse reactions to contrast material.

Adult↗

Ozonation: a tool for removal of pharmaceuticals, contrast media and musk fragrances from wastewater?

A pilot plant for ozonation and UV-disinfection received effluent from a German municipal sewage treatment plant (STP) to test the removal of pharmaceuticals, iodinated X-ray contrast media (ICM) and musk fragrances from municipal wastewater. In the original STP effluent, 5 antibiotics (0.34-0.63 microgl(-1)), 5 betablockers (0.18-1.7 microgl(-1)), 4 antiphlogistics (0.10-1.3 microgl(-1)), 2 lipid regulator metabolites (0.12-0.13 microgl(-1)), the antiepileptic drug carbamazepine (2.1 microgl(-1)), 4 ICM (1.1-5.2 microgl(-1)), the natural estrogen estrone (0.015 microgl(-1)) and 2 musk fragrances (0.1-0.73 microgl(-1)) were detected by LC-electrospray tandem MS and/or GC/MS/MS. ICM, derived from radiological examinations, were present with the highest concentrations (diatrizoate: 5.7 microgl(-1), iopromide: 5.2 microgl(-1)). By applying 10-15 mgl(-1) ozone (contact time: 18 min), all the pharmaceuticals investigated as well as musk fragrances (HHCB, AHTN) and estrone were no longer detected. However, ICM (diatrizoate, iopamidol, iopromide and iomeprol) were still detected in appreciable concentrations. Even with a 15 mgl(-1) ozone dose, the ionic diatrizoate only exhibited removal efficiencies of not higher than 14%, while the non-ionic ICM were removed to a degree of higher than 80%. Advanced oxidation processes (O(3)/UV-low pressure mercury arc, O(3)/H(2)O(2)), which were non-optimized for wastewater treatment, did not lead significantly to a higher removal efficiency for the ICM than ozone alone.

Contrast Media↗

Effects of different contrast media on glutathione peroxidase and superoxide dismutase activities in the heart and kidneys of normal and streptozotocin-induced diabetic rats.

BACKGROUND/PURPOSE: Hemodynamic changes and contrast nephropathy are well known complications of contrast media injection. However, the mechanisms of toxicity leading to these complications remain unclear. We hypothesized that contrast media toxicity would manifest as a change in antioxidant enzyme activity, thus leading to tissue damage. METHODS: This study investigated the effects of injection of ionic high-osmolar diatrizoate, ionic low-osmolar ioxaglate, and nonionic low-osmolar iopromide on the activities of two antioxidant enzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), in the heart and kidney tissue of normal male Wistar rats (n = 51) and streptozotocin (STZ)-induced diabetic rats (n = 54). Activities of GPX and SOD were assayed spectrophotometrically. RESULTS: Renal GPX activities were significantly decreased in both normal (458.3 +/- 64.6 to 385.5 +/- 63.4 mU/mg, p = 0.005) and diabetic rats (669.0 +/- 98.1 vs. 564.0 +/- 153.3 mU/mg, p = 0.035) at 1 hour after diatrizoate injection. Renal SOD activities were not affected after contrast injection. Ioxaglate and iopromide injection did not cause any change in renal antioxidant enzyme activity. In contrast to kidney tissue, there was no significant change in GPX and SOD activities in heart tissue at 1 hour after injection of different contrast media. CONCLUSION: Intravenous injection of ionic high-osmolar diatrizoate reduced renal GPX activity during the first hour in both normal and STZ-induced diabetic rats. Heart tissue was not prone to antioxidant enzyme activity changes after intravenous contrast media injection. GPX activity reduction can be an important mechanism of nephrotoxicity after contrast media injection.

Animals↗

Evaluation of an experimental low-attenuation gastrointestinal contrast agent for CT imaging of intestinal ischemia in an animal model.

RATIONALE AND OBJECTIVES: The authors evaluated the use of MRX-320, a low-attenuation, expansile oral contrast agent, for the demonstration of intestinal ischemia in an animal model. MATERIALS AND METHODS: Nine dogs were given either MRX-320, water, or diatrizoate as an oral contrast agent through a jejunostomy tube. Two dogs received no oral contrast agent. Helical computed tomography (CT) was performed before the intravenous injection of 2.5 mL/kg iohexol at 4 mL/sec, during the arterial phase, and during the portal venous phase. Mesenteric ischemia was surgically induced, and the imaging protocol was repeated. Three readers rated the randomly assigned images for quality and demonstration of ischemia. Attenuation values for the intestinal lumen and wall were recorded. RESULTS: Examinations performed with MRX-320 provided the best discrimination between ischemic and nonischemic conditions (P < .05), followed by examinations with no oral contrast medium, examinations with water, and examinations with diatrizoate. Images obtained with MRX-320 also scored significantly higher on measures of image quality than those obtained with water or no oral contrast medium (P < .05). On images obtained with MRX-320, the bowel lumen measured -836.5 HU (P < .05 compared with other techniques). Water provided the least uniformity of distention, and diatrizoate provided the least mucosal detail. CONCLUSION: The use of MRX-320 as an oral contrast agent with an intravenous bolus of iohexol at CT increased reader confidence for the diagnosis of intestinal ischemia and improved subjective measures of image quality.

Administration, Oral↗

Effect of radiocontrasts on selected membrane transport systems.

BACKGROUND: This study was aimed at examining the effects of radiocontrast agents on selected membrane transport functions. METHODS: The effect of diatrizoate sodium (DS), diatrizoate meglumine (DM), and diatrizoate compound (DC) on Na+/K+ pump activity and number, L-arginine, and choline transports were evaluated in erythrocytes of normal individuals and patients undergoing cardiac catheterization. RESULTS: Norrmal individuals' erythrocytes potassium influxes were 1.50+/-0.35, 1.32+/-0.37, 1.28+/-0.30, and 1.01+/-0.25 mmol/L cell/h in control, DS, DM, and DC groups, respectively (P=0.004; DC vs. control). Patients exposure to Hypaque M-76 significantly diminished Na+/K+ pump activity (1.40+/-0.36 before, vs. 1.27+/-0.40 mmol/L cell/h after; P=0.039). The number of Na+/K+ pumps was reduced (156+/-36 vs. 143+/-34 pumps/erythrocyte; P=0.015) in presence of DS. L-arginine and choline transports changed only at high radiocontrast concentrations. CONCLUSION: Selective changes in erythrocytes membrane transport function take place on exposure to radiocontrasts.

Analysis of Variance↗

Evaluation of angiographic contrast media and platelet function with impedance aggregometry and the PFA-100 'platelet function analyser'.

BACKGROUND: Angiographic contrast media are used in balloon angioplasty and may influence thrombotic complications of the procedure. We studied the effect of different media on platelet aggregation in whole blood using impedance aggregometry and the PFA-100 'platelet function analyser' (Dade, USA). METHODS: Venous blood samples from 18 healthy volunteers were split into four aliquots and mixed with 10% normal saline control, non-ionic medium (iohexol), low-molecular weight ionic medium (ioxaglate) and high-molecular weight ionic medium (diatrizoate). Samples were studied with impedance aggregometry and the PFA-100. RESULTS: All media caused significant inhibition of aggregation compared with control with both methods (P<0.001). Antiplatelet potency was greatest with diatrizoate, intermediate with ioxaglate and least with iohexol with both methods (P<0.01). Electron microscopy of the PFA-100 membrane demonstrated occlusion of the experimental aperture with platelet thrombus in the control. Inhibition of platelet thrombus was seen with all media, greatest with diatrizoate, intermediate with ioxaglate and least with iohexol. CONCLUSIONS: The media studied significantly inhibited platelet aggregation in vitro and potency was greater with ionic than non-ionic media. These methods use a combination of shear and chemical agonist with whole blood and may reproduce in vivo arterial conditions better than other techniques.

Journal Article↗

Contrast absorption and pancreatic inflammation following experimental ERCP.

The effect of saline and contrast agents intraductally injected into the pancreatic duct in sufficient volume to cause acinarization was studied in normal rats and in rats with acute pancreatitis. The effect of pancreatic inflammation on the disappearance of injected contrast material was investigated by injecting meglumine diatrizoate and 125I into the pancreatic duct. The activity appeared quickly in the venous blood of normal rats (peak activity at 5 minutes after injection). In rats with sodium taurocholate-induced pancreatitis, the appearance of activity in the blood was retarded. Ninety-two percent of the rats demonstrated pancreatic atrophy or pancreatitis histologically four days following acinarization of intraductally injected saline or metrizamide, meglumine diatrizoate, or meglumine sodium diatrizoate.

Animals↗

Evaluation of the dehydration-rehydration method for production of contrast-carrying liposomes.

We measured the amounts of three types of radiographic contrast media (RCM) that could be entrapped in liposomes prepared by the dehydration-rehydration vesicle (DRV) technique. To make DRVs, one initially makes water-containing, small unilamellar vesicles, adds contrast media and lyophilizes the mixture. Upon rehydration, the DRVs re-form, passively entrapping RCM. Diatrizoate, iohexol and iotrolan proved to be entrappable in similar amounts (diatrizoate was best), but all of these amounts were less than for other small molecules, such as carboxyfluorescein (P less than 0.05). Entrapment was directly proportional to lipid concentration (r = 0.76; P less than 0.002), and inversely related to iodine concentration (r = 0.86; P less than 0.002). Under ideal conditions with neutral lipids, 19.45 +/- 9.9% of diatrizoate was entrapped, corresponding to 1.05 +/- 0.50 g I per g lipid. These values are close to those achievable for large unilamellar vesicles. Use of an automated mixing device (the Microfluidizer) in place of sonication, facilitated production of large liposome batches and improved entrapment (P less than 0.05). Computed tomography (CT) scans of rats showed 30 and 218 HU of liver and spleen enhancement, respectively, per g I/kg injected DRVs. These studies showed this method (possible augmented by the Microfluidizer) allows efficient production of contrast-carrying liposomes.

Animals↗

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.

Adenylyl Cyclase Inhibitors↗

[Preclinical evaluation of iotrolan as a contrast medium for angiography and urography].

Efficacy and tolerability of iotrolan, a nonionic isotonic dimer, as a contrast medium for angiography and urography were investigated in animals. In the arteriography of rabbit femur, the efficacy of iotrolan 280 mgI/ml was as good as iopamidol 300 mgI/ml and better than meglumine diatrizoate 306 mgI/ml. In rat urography, the efficacy of iotrolan 280 mgI/ml was better than both iopamidol 370 mgI/ml and iohexol 350 mgI/ml. Vascular pain was less with iotrolan 280 mgI/ml than with iohexol 300 mgI/ml in rats. Effect of iotrolan on the pulmo-cardiovascular parameters, arterial pO2, hematocrit and plasma osmolality was less than iopamidol and diatrizoate in rabbits. Iotrolan induced no renal dysfunction and diuresis where iopamidol induced diuresis in rats. Effect of iotrolan on the blood coagulation was similar to nonionic monomers and less than diatrizoate in rabbits. Because of its isotonicity, iotrolan induced little water shift in the blood vessel and urinary tract, which would result in good efficacy and tolerability. These results suggest that iotrolan is superior to ionic and nonionic monomers for angiography and urography.

Angiography↗

[Alteration of the ionized calcium level in coronary sinus blood during coronary arteriography].

Injection of contrast medium into the coronary circulation produces a decrease in the concentration of ionized calcium in blood and thus causes a deterioration of myocardial contractility. In this study, changes in the ionized calcium level in the coronary sinus during coronary arteriography were compared for four different contrast media in human subjects. The contrast media used were meglumine sodium diatrizoate, iohexol, iopamidol and meglumine sodium ioxaglate. Blood samples were collected from the coronary sinus before and 5, 15 and 30 seconds after the first injection of contrast medium into the left coronary artery. The ionized calcium level of each specimen was measured using an ion specific electrode, and hematocrit was measured using the centrifuge method. Diatrizoate produced the greatest changes in both hematocrit and ionized calcium. The time concentration curve of hematocrit was similar for all four contrast media, but diatrizoate and ioxaglate produced a prolonged decrease in ionized calcium. The cause of this phenomenon is not clear, but it may be related to differences in the ionic status of the contrast media. Nonionic low-osmolality contrast media with added calcium may be preferable for coronary arteriography with respect to maintenance of the ionized calcium level.

Adult↗

Separation of bovine lymphocytes and granulocytes from blood by use of elutriation.

Bovine blood mononuclear cells were separated into 2 fractions by use of centrifugal elutriation. Total recovery, as well as recovery of each fraction, was greater than that obtained by use of Ficoll-sodium diatrizoate separation. The lymphocyte fraction contained less than 1% granulocytes, and the granulocyte fraction contained only 7% lymphocyte contamination. The technique was reproducible and results proved to be comparable with those of Ficoll-sodium diatrizoate density-gradient centrifugation; furthermore, the method is considerably cheaper and less time-consuming for processing large volumes of blood. Viability of cells separated by elutriation always was greater than 98%, whereas viability of cells separated by Ficoll-sodium diatrizaote was greater than 95%. Also, mitogen activation of lymphocytes separated by elutriation was superior to that of lymphocytes separated by Ficoll-sodium diatrizoate centrifugation.

Animals↗

Acute lethality after enteral administration of contrast media in anaesthetized rats with intestinal ischaemia.

The acute lethality was evaluated during enteric follow-through in anaesthetized rats with a ligature applied to the anterior mesenteric artery and vein. In 121 animals 3 ml of either sodium diatrizoate, iohexol or barium sulphate was administered via orogastric tube. Alternatively, they had the oro-gastric tube inserted but no test substance instilled (controls). A total of 103 rats was observed until spontaneous death while 18 were sacrificed after 8 hours of observation. The survival time in the sodium diatrizoate group was significantly shorter than for the other three groups (p less than 0.006). The 50% survival time was 5 h 42 min (range 2 h 48 min to 12 h 45 min) for sodium diatrizoate as compared with 8 h 4 min to 8 h 26 min for the other three groups; iohexol 8 h 4 min (range 2 h 4 min to 14 h 43 min), barium 8 h 13 min (range 4 h 55 min to 16 h 26 min) and no instilled substance 8 h 26 min (range 3 h 38 min to 16 h 10 min) with no significant differences between these 3 groups. The use of hyperosmolar contrast media in enteric follow-through significantly shortens the survival of rats with acute intestinal ischaemia. A more rapid spread of intestinal bacteria through the distended bowel wall and the ensuing septicaemia, accompanied by enhanced dehydration, are probably the mechanisms responsible for the earlier deaths.

Anesthesia↗

[Clinical study of the tolerance for 2 iodine containing contrast media for computerized tomography of the skull].

Clinical tolerance of two iodine contrast media (Na-methylglucamine-diatrizoate and Na-ioxitalamate) was tested in 1,628 patients requiring enhancing during computed tomography. Na-methylglucamine-diatrizoate was administered to 53.1% and the rest received Na-ioxitalamate. Infusion time was 4-6 min and the administered contrast quantity was 250 ml. Contrast medium injection was withheld from patients with known severe allergic disease, but in cases with known mild allergic reactions the contrast medium was given only after prophylactic administration of cortisone. Na-ioxitalamate was extremely well tolerated, causing only 0.11% (one patient) adverse effects, whereas in the case of Na-methylglucamine-diatrizoate a total of 42 side reactions were observed in 2.87% (22) of the patients. These reactions chiefly consisted of nausea and vomiting, which disrupted the CT examination and may endanger patients because of possible lung aspiration. Good tolerance of ioxitalamate seems mainly due to the chemical configuration of the organic iodine compound and the sodium salt of the contrast medium. The slow infusion time of 4-6 min - which is desirable in CT examination - contributes further to the good tolerance of ioxitalamate when different infusion times for this contrast medium are compared. The differing amount of iodine in the two contrast media and their different toxicity for the blood-brain barrier did not influence their enhancing quality, nor did these two factors modify relevant aspects for the diagnosis of intracranial lesions.

Clinical Trials as Topic↗

Radiocontrast media induced endothelin-1 mRNA expression and peptide release in porcine aortic endothelial cells.

Endothelin-1 (ET-1) is a powerful vasoconstrictor, primarily secreted by vascular endothelial cells. It may be an important mediator for radiocontrast-induced renal vasoconstriction, which may cause acute renal failure in susceptible subjects. This study measured the release of ET-1 by cultured porcine endothelial cells under incubation with various radiocontrast agents. Compared with the control group, the conventional ionic radiocontrast, diatrizoate, induced a dose- and time-dependent increase in ET-1 release. The lowest concentration of diatrizoate required to induce an increase in ET-1 secretion was 1 mM, less than the estimated serum level (about 5.2 mM) in clinical radiographic practice, suggesting that a direct release of ET-1 from endothelial cells may take place in clinical image studies. The stimulation effect of the following contrast agents on endothelial ET-1 release was compared: diatrizoate (ionic monomer), ioxaglate (ionic dimer), iohexol (nonionic monomer), iotrolan (nonionic dimer). Higher levels of ET-1 release were stimulated by ionic agents compared to the nonionic agents, but no difference in the degree of stimulation was observed between the monomeric and dimeric forms. All agents significantly increased ET-1 release compared with the control group. ET-1 production stimulated by radiocontrast agents was independent of hyperosmolality and was primarily seen as an increase in ET-1 mRNA. The increase in ET-1 release was actinomycin D-sensitive, and ET-1 mRNA abundance was greatly enhanced by cycloheximide. The augmented ET-1 mRNA expression to radiocontrast treatment was not secondary to the enhanced message stability. The data suggest that the contrast media-induced increments in ET-1 release are transcription-dependent and that both ionic and nonionic radiocontrast agents have a renal vasoconstrictive effect that is mediated by ET-1 and may potentially be nephrotoxic in susceptible subjects. Nonionic agents may be less toxic.

Animals↗