As part of a clinical Phase III study of the nonionic, dimeric contrast medium iotrolan, differences in opacification, tolerance, and effects on the electroencephalogram after myelography were examined in a double-blind comparison with iohexol. Two groups of 25 patients each received either 10 ml iotrolan 240 mg I/ml or 10 ml iohexol 240 mg I/ml for lumbar myelography, and two groups of 50 patients each received either 10 ml iotrolan 300 mg I/ml or 10 ml iohexol 300 mg I/ml for lumbar, thoracic or cervical myelography. The overall assessment of the opacification in the subarachnoid space, which was moderate in only one case of each group and otherwise good, showed no differences between the preparations. The tolerance of both concentrations of iotrolan proved to be significantly better than those of iohexol: at a significance level in the chi-square test of p less than 0.001 in a simple size of 25 patients per preparation with 240 mg I/ml and at a significance level of p +/- 0.05 in a sample size of 50 patients per preparation with 300 mg I/ml.
In a double-blind comparative study between the nonionic, dimeric iotrolan and the nonionic, monomeric iopromide the urographic image quality in the dose 300 mg I/kg body weight is better after iopromide up to 20 minutes after the injection. This result appears to be in contradiction to the results of the animal experimental studies. Possible reasons are discussed.
The liver and kidney tolerance of iopromide 370 in comparison to that of sodium meglumine diatrizoate 370 or iopamidol 370 in doses of 2 ml/kg body weight was examined in two controlled double-blind studies with intravenous digital subtraction angiography on the basis of enzyme assays in serum and urine. In patients with normal kidney function no changes were observed in the levels of the liver enzymes GPT, GOT, and gamma glutamyl transpeptidase (GGT) serum up to 72 hours after injection of iopromide or sodium meglumine diatrizoate. Among the kidney-specific enzymes, the excretion of GGT in urine increased after injection of iopromide and iopamidol. The maximum increase of GGT excretion was, however, statistically significantly lower in the group treated with iopromide than in the iopamidol group. Within 72 hours, the activities had been returned to the initial values in both groups.
Iotrolan, a nonionic, hexaiodinated dimer, is an extremely hydrophilic compound (P = 0.005). Due to its larger Stokes' radius compared with monomeric compounds such as metrizamide, the diffusion time through membranes is extended. Iotrolan deforms erythrocytes only minimally. There is practically no binding to plasma proteins. The new contrast agent has been shown to exert a very limited effect on the complement system (in vitro); it does not inhibit lysozyme (a standard enzyme) in concentrations less than 100 mg I/ml. To inhibit activity of the enzyme collagenase, much higher concentrations of iotrolan than of metrizamide or iopamidol are needed and this could offer an advantage when used for diskography preceding diskolysis with collagenase. After a single intravenous injection in rats, iotrolan has an LD50 of 28.3 g I/kg - the best general tolerance known for water-soluble contrast media thus far. The superior tolerance of iotrolan compared with iohexol and iopamidol (p less than or equal to 0.05) in rats is statistically significant. On the basis of preclinical experience, iotrolan is a very promising contrast medium for intrathecal and intravascular use.
Iotrolan was used in concentrations of 240 and 300 mg I/ml for indirect lymphography in a total of 70 patients, and permitted a diagnostic evaluation of the peripheral lymphatics in all cases. The contrast quality was found to correlate with the concentration used. The concentration of 300 mg I/ml Iotrolan was judged to provide the better contrast density and definition. Side effects were limited to transient local erythema and pain during the infusion in one patient and a protracted reaction resembling serum sickness in another patient (Iotrolan 240 mg I/ml). Because of its excellent tolerance, Iotrolan is particularly suitable after subepidermal infusion for indirect lymphography, during which the local lymph drainage of cutaneous regions of interest can be evaluated.
The influence of increasing doses of contrast medium (CM; 0.75, 1.0, 1.5, and 2.0 ml iopromide/kg body weight; 300 mg I/ml) was examined in a randomized, double-blind study. An increase of the dosage resulted in a statistically significant improvement of the quality of the radiographic visualization. This was most pronounced with an increase from 0.75 to 1.0 ml/kg body weight and least pronounced with the increase from 1.5 to 2.0 ml/kg body weight. This improvement was not only visible in the overall quality, but in each part of the urinary tract, the calyces, the pelves, the ureters, and most especially at the parenchyma. Due to economic considerations at the present, a dose of 1.0 ml/kg (300 mg I/ml) is viewed as adequate. Doses below this level should be avoided due to the poorer image quality that results. From a purely medical point of view, the injection of 1.5 ml of nonionic CM/kg body weight is considered optimal.
A clinical study was designed to determine whether the lower solute load after intravenous injection of nonionic contrast medium (CM) produced significant changes in nephrographic and pyelographic quality. For equal iodine doses (300 mg I/kg), the lower solute load of nonionic CM produced better nephrogram and pyelogram scores than ionic CM or nonionic CM with mannitol, both of which had higher solute loads. The higher scores associated with nonionic CM were statistically significant for the pyelogram phase but not for the nephrogram phase. These observations were matched by lesser changes in urinary osmolality and higher urinary iodine concentrations with the nonionic CM.
In order to examine the radiopacity, safety, and usefulness of iotrolan, a new dimeric, nonionic, water-soluble contrast medium for myelography, a multicenter clinical study was performed in lumbar myelography using metrizamide as the reference drug. Both media were injected at a strength of 190 mg I/ml in 90 patients each. Both contrast media showed good opacification; there was no significant difference between the two media. The incidence and severity of side effects were significantly lower with iotrolan than those with metrizamide. No severe side effects, such as convulsion and shock, were observed with either medium.
The difficulties with comparing data on the risks involved in the use of conventional contrast media and new low-osmolar contrast media are presented. These difficulties are a result of the necessary size of the groups to be compared and the problems of obtaining data. Prospective studies, carried out by a single researcher, probably have the greatest reliability. In multicentered studies with a larger number of participants, a number of factors must be reckoned with. The assessment of the same reaction can vary considerably, depending on the initial illness and interest of the patient or physician. This will, of course, influence the collection of the data. Due to the fact that complications and side effects are more frequent than deaths, the reduction of the first two through the use of new contrast media is statistically easier to ascertain. It can be assumed from the studies performed thus far that the risk of mortality is also reduced. Definite statistical guarantees do not as yet exist, and it is possible that they will never be produced.
The effects of coronary arteriography with ionic, monomeric diatrizoate (iodine content, 370 mg/ml; osmolality, 2.10 Osm/kg) and nonionic, dimeric iotrolan (iodine content, 280 mg/ml; osmolality, 0.27 Osm/kg) were intraindividually compared in five patients with coronary heart disease. According to an open protocol, both contrast media were injected into the left (LCA) and right coronary arteries (RCA), 8 ml and 5 ml, respectively. Before, during, and 60 seconds after each injection, electrocardiograms (ECG) were recorded and heart rate and aortic pressure were measured. Whereas diatrizoate markedly decreased heart rate (LCA, -36%; RCA, -20%) and aortic pressure (LCA, -26%; RCA, -16%), iotrolan administration kept heart rate virtually unchanged (+/- 1%) and only slightly increased aortic pressure (LCA, 5%, RCA, 8%). After iotrolan injection ECG changes (axis shift of QRS and T waves) were still demonstrable, yet the effects of diatrizoate proved to be more significant (prolongation of QRS and QT intervals as well as shifts of QRS and T axis). The opacification of the coronary arteries was always more pronounced after diatrizoate due to its higher iodine content, but the contrast produced by iotrolan usually was satisfactory. No side effects were observed during the study. Thus, this isosmotic contrast medium prevents bradycardia and hypotension during coronary arteriography. The lower iodine content, however, leads to poorer contrast compared with conventional contrast media.
Contrast media have been successfully used as a diagnostic aid in radiology for decades. It has, however, been necessary to accept certain, in some cases unexplained, undesirable side effects because of their physicochemical properties. The conventional preparations available have for more than 40 years been iodinated salts or acids, whose major disadvantage has been high osmolality. For some years now, a new generation of contrast media has been available. These contrast media exhibit a far lower osmolality due to the lack of ionicity. As a result of the volume load of the left ventricle by levocardiography, there is usually an increase of the left ventricular end-diastolic pressure in the pathologic range over 12 mmHg. We were able to prove this in 120 consecutive patients whom we examined. The pressure increase with the use of nonionic contrast media was considerably lower. The differentiated observation of various risk groups showed no signs of valid predictive parameters.
The urinary excretion of kidney-specific marker proteins before and 120 hours after intravenous injection of either high- or low-osmolar contrast media (CM; diatrizoate, iopamidol 370) was monitored in patients after digital vascular imaging. Inclusion criteria for the randomized clinical study in a total of 40 patients (15 women, 25 men; mean age, 64.5 years) were at least 50 years of age or diabetes mellitus with normal creatinine concentration in serum. Compared with the control period, the elimination of tubular indicator enzymes alanine aminopeptidase, gamma-glutamyltranspeptidase, alkaline phosphatase, as well as of glomerular localized angiotensinase A was significantly higher in all patients after injection of the CM. The most significant differences were observed after 48 hours. In contrast, lysosomal N-acetyl-beta-D-glucosaminidase activity in urine specimens reacted less clearly and appears to be a less sensitive parameter in assessing CM nephrotoxicity. Elimination of brush border as well as of glomerular marker proteins was significantly lower after intravenous injection of low-osmolar CM iopamidol 370 (832 mOsm/kg) than after meglumine diatrizoate 76 (2100 mOsm/kg). In all 40 patients a significant decrease in creatinine clearance was observed; however, patients receiving diatrizoate had a significant decrease in creatinine clearance (period 0 versus 24 to 48 hours after CM), whereas patients after administration of iopamidol had not. No difference was found between creatinine clearance after 48 hours of CM injection within both groups of CM. Due to noninvasive parameters of kidney damage nonionic, low-osmolar CM are less nephrotoxic in potential risk patients, and should be preferred to conventional CM.
The use of low-osmolar, nonionic, monomeric contrast media has made gastrointestinal diagnosis with water-soluble contrast media less hazardous with a greater diagnostic yield. Since, however, even this group of compounds is hypertonic in comparison with blood, water is still drawn from the body into the bowel, resulting in water and electrolyte shifts and distal dilution of the contrast material with deterioration of the image quality. The use of iotrolan, which is isotonic in comparison with blood, therefore, appears to offer advantages for selected groups of patients. The superiority of the contrast medium iotrolan over iohexol was demonstrated in a double-blind study. A further 72 examinations in an open-ended study confirmed this result.
A comparison of the renal excretion and computed tomography (CT) enhancement of nonionic, monomer and dimer contrast media (CM) (iopamidol and iotrolan) was planned to determine if the latter provides additional and prolonged enhancement in dogs. The excretion studies show almost identical performance of both CM with respect to plasma concentration and renal excretion. However, the lower osmolality of iotrolan permits greater renal concentration in the medulla, papilla, and urine. The potential for this further enhancement of the kidney in CT or urography is marginal.
After injection of iopromide or iopamidol into a central vein in 40 patients ages 57 +/- 14 years and 57 +/- 11 years, respectively, with normal renal function, iodine concentration and total iodine excretion were determined in pooled urine over 0 to 2 hours and 2 to 24 hours after injection. Iopromide excretion of 46.4 +/- 9.8% of the dose during the first 2 hours after injection was significantly (p less than 0.05) higher than that of iopamidol, which amounted to 41.4 +/- 10.5% of the dose. This is presumably due to the fact that iopromide has lower protein binding than iopamidol. Excretion of the two nonionic contrast media up to 2 hours after injection decreased constantly with increasing age. In the case of iopromide, a mean excretion of 55% of the dose in a patient 25 years old decreased to about 40% for a patient 90 years of age (p less than 0.05). The clinical relevance of the observed differences and correlations is discussed.
Iosimide is a new synthetic, nonionic, monomeric contrast medium in which a new substance, triiodine-trimesine acid, is used. It has definite advantages compared with the basic substances used in the past, diaminobenzoic acid and monoaminoisophthalic acid. Due to the high stability, the possibility of the formation of toxicologically questionable, free nuclei amino compounds disappears. Only the slightest probability of a cross-reaction with present antibodies exists, because of the low frequency in the environment. On the basis of the hydrophilic structure of the side chains, there is only a slight chemotoxicity. In a controlled, double-blind study on 100 randomized patients iosimide was tested in cerebral angiography against ioxaglate. Ioxaglate is an ionic contrast medium, popular because of its low osmolality. In this study iosimide exhibited no differences in comparison with ioxaglate with respect to the contrast, the neurological status or the liver or renal tolerance. In examining cardiovascular tolerance there is only a slight tendency toward liver changes with iosimide. Examination of the general tolerance, however, shows a statistically significant lower incidence of sensation of heat and pain with iosimide than with ioxaglate.
Radiographic iodized contrast media impair the antithrombin effect of the fibrin clot. The extent of the impairment correlates with dosage and lipophilicity. Normally, 90% of the thrombin activity of 2.3 IU/ml are inactivated by a fibrin clot generated by 2 mg/ml fibrinogen. The effect is due to contrast media-induced protein denaturation with subsequent impairment of thrombin binding to the fibrin clot. Two hepatogenic, two ionic, nephrotopic, and four nonionic contrast media were assayed by this test system at different concentrations. Clear-cut differences were found between the three main groups. Smaller, yet statistically significant, differences could be established between ioglicate and diatrizoate and between iosimide, iopromide or iohexol and iotrolan. No differences were found between iotroxate and iodoxamate. The results are in concordance with the partition coefficients (water/n-butanol) of these contrast media. The assay sensitivity is suitable as a screening system of the chemotoxicity of contrast media. It is easily performed, inexpensive, and assays the clinically important contrast media interaction with fibrinogen.
Solutions of different low osmolar contrast media (CM) obviously show clinically relevant differences in the osmolality despite equal iodine concentrations and similar molecular structure. To obtain precise and comparable data, the osmolality of five batches (usually) each of contrast media, iopamidol, iohexol, iopromide, and ioxaglate-all preparations commercially available-were measured by means of the vapor pressure method. The osmolality of the solutions of sodium meglumine ioxaglate with the same iodine concentration is lower than that of the nonionic CM examined. Iopromide showed the lowest osmolality and iohexol the highest value of the nonionic preparations. The differences are statistically significant as a rule. They are attributed to a varying association and hydration of the CM molecules in the solution.
Ten milliliters of iotrolan containing 240 mg I/ml were injected into the lower lumbar subarachnoid space of ten patients. Plasma level and urinary and fecal excretion were monitored for 3 days after injection. The mean iodine concentration in the plasma of about 50 micrograms/ml (6% of the dose given in the total plasma volume) peaked at 1 to 2 hours after injection. After reaching the maximum values, the iotrolan concentration in the plasma decreased with a half-life of about 4 hours (median value). About 90% of the injected dose was found in the urine and about 1% was detected in the feces.
