Effect of structure on biological tolerance. Comparison of triiodobenzene derivatives.

Synthesis of basic structures of contrast media is reviewed. Biological tolerance of ionic and nonionic derivatives of triiodobenzene are related to the degree of withdrawal of electrons from their aromatic systems.

Effects of angiographic contrast media on venous endothelium of rabbits.

The effects of ionic and nonionic contrast media on rabbit venous endothelium were examined. In anesthetized animals, caudal mesenteric veins were exposed and perfused with the ionic contrast medium, diatrizoate, and the nonionic contrast media iopromide and iotrolan for 2 minutes at 5 mL/minute. Control animals were similarly perfused with physiologic saline or a 23% sorbitol solution. The specimens were fixed in situ by perfusing 4% glutaraldehyde, and ultrathin stained sections were examined with an electron microscope. The hyperosmolar contrast medium diatrizoate produced shrinkage in cell cytoplasm and in nuclear material. There also were minor structural alterations in endoplasmic reticulum and widening of intercellular junctions. The nonionic contrast media iotrolan and iopromide caused mild to moderate changes in endothelial cells. Sorbitol infusion, however, affected venous endothelium more intensely than the ionic and nonionic contrast media, suggesting hyperosmolality as the causal factor in endothelial damage.

Biotransformation of ioglycamic acid, iodoxamic acid and iotroxic acid in man.

The biotransformation of the 131I-labeled cholegraphic media ioglycamic acid, iodoxamic acid and iotroxic acid in man is investigated. Plasma, urine and fistular bile were analyzed for unchanged and metabolized constituents of the administered substances using thin layer chromatography. No metabolites were found in plasma, but up to two were found in urine in addition to unchanged contrast media (a total of 50% of the total elimination in 24 hr. urine). A metabolite was only found in the fistular bile after the injection of iotroxic acid.

Determination of lethal dose in a protozoa: screening of contrast media toxicity.

Suitability of a protozoan culture for determination of contrast media (CM) toxicity was investigated. A culture of Blepharisma americanum was exposed to varying concentrations of CM and the time elapsed until 50% cell mortality was determined. The cultures were standardized using solutions of Na iothalamate and/or Metrizamide. A standardized culture responded reproducibly between days 6 and 10 of the culture age. Comparison of concentrations of CM needed to achieve LD50 at 7 minutes ranked CM in order of decreasing toxicity as follows: oral cholecystopaques, intravenous cholecystopaques, and urographic agents; ie ionic monomers, ionic dimers, monovalent dimers, nonionic monomers, nonionic dimers. Comparison of CM toxicity determined by protozoa LD50 at 7 minutes with i.v. LD50 in mice showed a good correlation, suggesting usefulness of the protozoan assay as a complementary or screening toxicologic method.

Osmolality-related effects of injections into the central nervous system.

Hypertonic and hypotonic contrast media and/or solutions were injected intracerebrally and into the subarachnoid space of rats, and the effects on the central nervous system (CNS) were investigated. Additionally, rabbits were injected intracisternally with nonionic contrast media that were either isotonic or hypertonic to the cerebrospinal fluid, and their behavior was observed. Both hypertonic and hypotonic contrast media and/or control solutions caused CNS depression, but not excitation. Even slight hypertonicity affected motor coordination. The sedating effect of nonionic contrast media, when given in the large doses customary in in vivo experiments, can mask their inherent epileptogenicity and give a false impression of a high safety margin.

New Media. Pharmacology of nonionic dimers.

Nonionic dimers enable us for the first time to produce highly concentrated, blood isotonic contrast media. If the toxicity of contrast media is dependent on molar quantity, molar concentration, or the motility of small molecules, nonionic dimers could have advantages over the monomeric contrast media. Their higher viscosity is a basic disadvantage. Solutions of the nonionic dimers with an iodine concentration of up to 400 mg/ml often have an osmotic pressure that is lower than that of blood. THe new contrast media are extremely hydrophilic, show no binding to protein, and lead to complement activation only in extremely high concentrations. They do not cause the deformation of the erythrocytes that is known to occur with other contrast media. The LD50 after fast intravenous injection in the rat is higher that with all other known contrast media. In peripheral arteriography, the nonionic dimers are tolerated painlessly by rats, and in carotid angiography they cause as few side effects as metrizamide. The neural tolerance is better than that of metrizamide. In circulatory investigations no drop in blood pressure was found after intravenous injection. Elimination is almost exclusively renal. As with other nonionic contrast media, properties of the dimers that appear to be problematic are formation of supersaturated solutions and nephrotoxicity after extremely high doses.

Iotasul, a water-soluble contrast agent for direct and indirect lymphography. Results of preclinical investigations.

Iotasul, a non-ionic dimeric water-soluble contrast agent with outstanding physico-chemical properties is well suited for direct as well as indirect lymphography, as demonstrated in experimental animals. The contrast medium is eliminated practically completely within 24 hours by the renal route. The tolerance of this agent is far better than that of oily contrast media.

Pharmacokinetics of GdDTPA/dimeglumine after intravenous injection into healthy volunteers.

Pharmacokinetic studies of GdDTPA/dimeglumine in man show a rapid renal clearance and no evidence for dissociation or retention of the complex in the body. These features, in conjunction with its strong proton relaxation enhancement and its low toxicity suggest that this complex may be an excellent contrast medium for magnetic resonance imaging.

Experimental urography in dogs: diagnostic quality and pharmacokinetic behavior of iotrolan in comparison to nonionic and ionic, monomeric contrast media.

A dose of 0.3 g I/kg iotrolan yields much better opacification of the renal parenchyma in dogs (n = 6, intraindividual comparison) than sodium diatrizoate or iopromide, and imaging of the urinary tract is practically equally as good. The plasma iodine levels of all three agents 2 minutes after the bolus injections are 3 mg/ml and the half-lives in the blood are 8 to 10 minutes. The injection of iotrolan causes the hematocrit value to drop by maximum 3.8% 10 minutes after the injection, and corresponding figure after iopromide is 10.8% and that for sodium diatrizoate at 4 minutes is 18.9%. In a further study in dogs (n = 4, intraindividual comparison; dose 0.6 g I/kg) it was found that in the period 10 to 240 minutes after a bolus injection of iotrolan or iopamidol the iodine concentration in the urine was 1.5 to 2 times higher after iotrolan than after iopamidol. Iopamidol causes much higher urinary flow than iotrolan, especially in the first 20 minutes after injection. The properties of iotrolan described here appear to indicate that this novel nonionic, dimeric contrast medium has certain advantages over the monomeric, ionic and nonionic agents for urographic indications.

Renal excretion of iopromide and iopamidol after intravenous administration in digital subtraction angiography.

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.

Pharmacokinetics of iohexol, iopamidol, iopromide, and iosimide compared with meglumine diatrizoate.

Four nonionic contrast media (iohexol, iopamidol, iopromide, and iosimide) are compared in this clinical study in their pharmacokinetic behavior with an ionic reference preparation (meglumine diatrizoate). At a dose of 1 ml of contrast medium per kilogram of body weight with approximately the same iodine content, virtually no differences could be established in the pharmacokinetic behavior. The osmotic diuresis of the ionic substance, compared with that of the nonionic preparations--implies an increased osmotic diuresis, thus, a lower maximal iodine concentration in the urine. The elderly patients included in this study have a reduced glomerular filtration rate, which in turn implies a prolonged half-life in the blood and a retarded renal elimination.

Hemorrheologic effects of iotrolan after intra-arterial injection in rabbits: comparison with other types of contrast media.

Aqueous solutions of the x-ray contrast media (CM) iotrolan and meglumine diatrizoate with and without gelatin added were injected into the rabbit aorta just above the bifuraction in a dose of 0.3 g I/kg and the duration of opacification of the vessel was measured. The difference between the periods recorded for iotrolan and the viscous diatrizoate solution (4 to 6 seconds) and those for the pure diatrizoate solution (3 to 4 seconds) was statistically significant (p less than or equal to 0.05). The differences are directly correlated to the viscosity of the CM solutions. At first the intra-aortal injection of iotrolan causes a somewhat more marked decline in femoral artery blood flow than diatrizoate. The increase in blood flow, which begins 10 seconds after injection is, however, significantly (p less than or equal to 0.05) less after iotrolan than after diatrizoate. This is attributable to the differences in the osmolalities of the two CM. Due to the fact that it is isotonic to blood and because of its viscosity, iotrolan has certain advantages over conventional agents for arteriography that are relevant to clinical practice.

Contrast media for computer tomography of the liver.

A simple phantom experiment indicates that the enhancement of abdominal organs should be twice the SD of noise in a CT image. The enhancement of liver tissue by urographic and biligraphic contrast media is analysed in clinical series and animal experiments. Various substances, applied alone and in combination, were investigated. At present, only the infusion technique of urographic media provides a sufficient enhancement of liver tissue.

Tolerance to iotrolan after subarachnoid injection in animals.

Neural tolerance after intracisternal administration of iotrolan was compared with that after iohexol, iopamidol, and metrizamide in mice, rats, and guinea pigs. Around the level of the ED50 (approximately two to four times the human dose) tolerance to iotrolan appeared to be much better than tolerance to the other agents. A study in rabbits comparing iotrolan with iohexol produced approximately the same result. High doses of iotrolan, iohexol, and iopamidol were almost equally well tolerated by rats, as were iotrolan and iohexol by rabbits. Tolerance to metrizamide by rats and to iopamidol by guinea pigs was vastly inferior. In support of this very good general tolerance histologic examinations of the spinal tract and of the brain did not reveal any substance-related changes in beagles after lumbar administration of a high dose. An investigation in rats using mannitol and sorbitol formulations with differing osmotic pressures indicates that contrast tolerance is influenced primarily by the chemotoxicity and not by increased osmotic pressure. As shown by the results of the preclinical investigations, iotrolan should be ideal for use in myelography and also appears highly suitable for the examination of other body cavities.

Tissue distribution and excretion of iotrolan after intravenous and suboccipital injections in animals.

The fate of iotrolan in the body is determined by its physicochemical characteristics and biologic inertness. Iotrolan is distributed in the extracellular space after intravenous or intracisternal injections. No absorption occurred after oral administration. Iotrolan is eliminated almost exclusively by renal excretion in an unmetabolized form. The results found are very similar to those published for other x-ray contrast agents used in uroangiography.

Pharmacokinetics of iotrolan after intravenous injection into healthy volunteers.

In man Iotrolan is distributed in the extravascular space after intravenous injection with a half-life of about 11 minutes, the elimination half-life being about 108 minutes. After intravenous injection 99.2 +/- 1.8% of the dose was found in the urine and 0.5 +/- 0.1% in the feces within 5 days. No metabolization occurred in man and the pharmacokinetic behavior of iotrolan is comparable to that of known nonionic contrast media (e.g., iohexol, iopromide) (7, 9, 13).

Whole body autoradiographic distribution studies on nonionic x-ray contrast agents in pregnant rats.

The time course of the distribution of radioactive label in organs and tissues was investigated after intravenous administration of iotrolan, iopamidol, iopromide, and iohexol in a concentration of 60 mg I/ml (2.2 MBq 125I/mg I) as aqueous solution to pregnant rats (18th day after conception) by a whole-body autoradiographic technique. All contrast agents were rapidly distributed within the organism, showing equal distribution patterns of radioactivity, and were rapidly excreted, mainly by the kidney. Passage of radioactivity across the blood-brain and placental barriers could not clearly be shown. No specific and long-lasting retention of radioactivity could be seen in any organ or tissue with the exception of the thyroid.

Plasma level and renal excretion of iotrolan after lumbar injection in patients.

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.