Animal experimental studies of indirect lymphography of the eye, face and neck regions using Iotasul.
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Biomedical subjects
Publications and source records attributed to H M Siefert.
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Radiological, light microscopic and electron microscopic findings after direct and indirect lymphography with Iotasul, a new non-ionic water-soluble (not oily) contrast medium, are reported. The results of the studies in 18 dogs clearly show that the roentgenological demonstration of the lymph system following intralymphatic administration of Iotasul in the dog is not inferior to that following the use of conventional oily con contrast medium passes quickly to the lymphatic system and the lymph nodes and is eliminated within 24 hours. The complications and tissue reactions known from oily contrast media are not observed following use of the new water-soluble contrast medium. Furthermore, studies of the fine structures show unequivocally that no morphologically detectable changes attributable to the contrast medium occur either in the region of the injection or in the lymph vessels, lymph nodes and organs such as kidney, liver, lung, spleen and myocardium. Preliminary studies indicate that the new contrast medium offers the possibility of indirect demonstration of lymph vessel regions and groups of lymph nodes (indirect lymphography) which have largely escaped detection by the previous routine lymphographic examination.
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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.
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The general, neural and cardiovascular tolerance of iotroxic acid (Biliscopin) and its deleterious effect on membranes were investigated in comparison with iodipamic- (Biligrafin), ioglycamic- (Biligram, Bilivistan) und iodoxamic acids in different experimental models. Tolerance (DL50) of iotroxic acid after i.v. injection in the rat proved to be significantly better than that of all the reference substances. The difference was most apparent in animals which had previously been given histamine. Neural tolerance was found to be best after iotroxic acid and iodipamic acid and poorest after iodoxamic acid. In in vitro investigations the erythrocyte membranes were far less damaged by iodoxamic acid and iotroxic acid than by iodipamic acid. Iotroxic acid was also particularly well tolerated after intracisternal injection and after injection into the carotid artery of the rat. The effect of iotroxic acid on the cardiovascular system of the cat was distinctly weaker than that of ioglycamic acid and, when given in high doses, evidently also weaker than that after administration of iodoxamic acid. The excellent general tolerance of iotroxic acid can be explained by the fact that its deleterious effect on membranes is less than that of iodipamic acid and that its neurotoxicity is distinctly lower than that of iodoxamic acid.
A battery of tests for toxicity assessment of new contrast media is reviewed. Cell toxicity in a protozoan culture (Blepharisma americanum); lethal dose determination in mice; EEG Spectral analysis following cisternography in rabbits; ED50 and LD50 determination by intra- and pericerebral injection in rats; intracisternal injection in chronically cannulated, nonanesthetized rats; and aversive conditioning by intracisternal injection in rats were found complementary. By these methods, novel nonionic media phenyl-sugar-ether DS-1-132 and DL-2-99 were found comparable to iopamidol, while all three compounds were superior to metrizamide.
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.
Pain caused by x-ray contrast media in peripheral arteriography was assessed by behavioral changes of nonanesthetized, unrestrained rats. All ionic monomeric contrast media caused severe pain in a concentration of 300 mg I/ml. Dilution of contrast media markedly reduced pain. Sodium salt solutions were considerably more painful than meglumine salt solutions. The intravenous cholegraphic agent iodipamide did not cause vascular pain in a concentration of 300 mg I/ml, although its systemic toxicity is high. Pain in arteriography was attributable primarily to the high osmotic pressure of contrast media solutions rather than to their chemotoxicity.
A new zwitterionic iodinated molecule, 2-[3-(N-ethyl-2-hydroxyethyl) amino-acetamido-2, 4, 6-triiodobenzyl]-butyric acid (RCK-136) was synthesized, and its potential as an oral cholecystopaque was tested. In rats, 15 minutes following intravenous injection, RCK-136 reached maximum biliary concentration; 84% of the dose was excreted into bile. Biliary excretion of RCK-136 elicited a strong choleresis (44 ml of bile flow per mmol compound). Intravenous LD50 in rats averaged 390 mgI/kg. ED50 in rats, intradiencephalic, averaged 1.98 mgI/kg. The average densities of cholecystograms produced in three dogs with iosumetic acid and/or RCK-136 were comparable.