[Experiment compared between iodoxamidic acid and ioglycamic acid, in flasks drop by drop. Observations of adverse reactions].
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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.
In 16 baboons, reproducible bronchograms could be achieved by inhalation of 400--800 mg of powdered calcium ioglycamic acid. Anesthesia, tracheal intubation, or premedication were not necessary. In patients and volunteers, the inhalation of the contrast medium dust caused strong cough. Local anesthesia allowed inhalation for about 10 minutes, which resulted in successful demonstration of the pharynx, larynx, and trachea with bifurcation. Lobular and segmental bronchi were demonstrated only after a longer inhalation time. The contrast medium was completely eliminated and did not cause any recognizable adverse reaction. Nonspecific inflammatory reaction of the bronchial mucosa was seen microscopically in baboons.
Ioglycamic acid (IGA) is effectively eliminated in young and adult rats via urine and bile. After administration of low doses hepatic excretion dominates whereas following high supply renal elimination surpasses biliary excretion. Hepatic transport of IGA is active, indicated by the occurrence of a transport maximum in vivo and by a distinct accumulation of this drug within liver slices in vitro. Renal removal of IGA is preferentially caused by glomerular filtration. A tubular reabsorption obviously does not occur because forced diuresis (mannitol, furosemide) does not increase renal excretion of this substance. As calculated from our clearance data and as a result of accumulation experiments in vitro on renal cortical slices the active tubular secretion of this organic anion can be excluded. In principle there are no qualitative changes in IGA elimination between the 20th and 55th day of life, but active hepatic transport of the drug is significantly lower in young, immature rats. After bile duct ligation, renal excretion of IGA increases distinctly in both age groups, whereas in adult rats bilateral nephrectomy (NX) is followed by a significant decrease in its hepatic excretion in dependence on time after kidney removal. In young rats NX is without consequences on hepatic excretion of IGA. It is possible to stimulate renal and/or hepatic excretion of IGA by repeated administration of T3, dexamethasone, or phenobarbital. The effect of stimulation is different in kidney and liver and depends on age, too.
Iodine-131 labelled Biligram has been evaluated as a radiopharmaceutical for dynamic scintiscanning of the liver and biliary tract. In 10 normal subjects there was good visualisation of the liver and gallbladder. In 18 patients 131I Biligram was found to be unsatifactory for differentiating parenchymal liver disease from biliary tract obstruction owing to inability to demonstrate the gallbladder when liver function was more than mildly deranged. Quantitative analyses of blood clearance and hepatic activity curves for 131I Biligram were not clinically helpful. Urinary excretion of 131I Biligram increased with the degree of hepatic dysfunction.
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Thyroid function was studied for 42 days in 58 patients, 28 of whome had euthyroid goiter, after urography (diatrizoic acid), cholangiography (ioglycamic acid), and cholecystography (Naiopanoate). After urography and cholangiography short-lived increases of the serum thyroxine occurred in a few patients, but the mean thyroxine and triiodothyronine concentration did not change. By contrast, 7 days after oral cholecystography serum thyroxine had risen consistently by 22% with a concomittant rise of the free thyroxine, while triiodothyronine declined by 15%. The thyroxine metabolite 3,3',5'-triiodo-1-thyronine (reverse T3) rose by 50% and serum thyrotropin concentration doubled. After 42 days thryoxine and triiodothyronine had returned to baseline, and none of the 58 patients developed clinical hyperthyroidism. In patients with severe myxoedema kept on a constant replacement dose with 1-thyroxine NA-iopanoate produced similar changes with the exception of the rise of the serum thyroxine. The primary event after Na-iopanoate seems to be a fall of the serum triiodothyronine, which in turn augments thyrotropin and indirectly thyroxine secretion. the marked and sometimes sustained rose of serum thyroxine after cholecystography may lead to the erroneous diagnosis of hyperthyroidism.
Pharmacokinetical properties of eight triiodobenzene derivatives, X-ray contrast agents, were studied in the hemoglobin-free perfused rat liver with emphasis on the structural relation to biliary transport. With chemical modification of the basic structure, these agents showed different characteristics in the processes of diffusion into hepatocytes, accumulation in the cells and active transport into the bile, and were separated into four groups; [I]: Iotroxic acid (1), Iodipamic acid (2), Iodoxamic acid (3), and Ioglycamic acid (4) which showed faster rates of diffusion into hepatocytes [(1) greater than or equal to (2) greater than (3) greater (4)] and also of biliary excretion [(1) greater than (2) greater than (4) greater than (3)], [II]: Diatrizoic acid and Metrizamide showed poor diffusion and biliary excretion, [III]: Iopodic acid showed the highest permeability into and accumulation in hepatocytes with little biliary excretion, [IV]: ZK73 215 was slowly transported into the bile, yet, showed little permeation through the cell membrane. Characteristics of (1), (2) and (3) observed in the perfused liver were, in principle, confirmed in the pharmacokinetical profile observed in vivo. However, the fast diffusion of (2) into the hepatocytes appears to be hampered by high binding ability with serum proteins, whereas the relatively poor profile of the biliary excretion of (3) was improved by its low protein-binding in blood in vivo. Superiority of (1) as a cholangiographic agent was demonstrated by the fast biliary excretion in both the case of experimental systems and moderate protein-binding.
In a patient with a previous history of a serious reaction after intravenous injection of the cholangiographic agent ioglycamic acid (Bilivistan), intravenous cholangiography appeared to be necessary. Therefore intradermal tests were performed in the patient and four controls with three radiographic contrast media closely related in chemical structure. In addition a Prausnitz-Kustner test with heated and unheated patient serum was performed. These tests demonstrated the presence in this patient of selective immediate-type reactivity to ioglycamic acid which was probably IgE mediated. Intravenous cholangiography with iodipamide seemed justified and resulted in no adverse reactions. Although this case may be exceptional, the results suggest that intradermal skin tests at proper concentrations may be useful in choosing the administration of radiographic contrast medium to patients with a history of prior adverse reactions.
Intravenous injection of the divalent X-ray contrast medium ioglycamic acid ("Biligram") induced intravascular precipitation and sudden death of a patient owing to reaction with his monoclonal macroglobulin. Mice reacted similarly in passive transfer experiments. The corresponding monovalent compound, acetrizoic acid, was also bound to the IgM but did not induce precipitation and had no apparent ill-effects on mice in passive transfer experiments.
In vivo and in vitro studies have been performed in a group of patients with immunoproliferative diseases to evaluate the risk of serious reactions due to serum jelling after intravenous injection of iodinated contrast media. Sol-jell convertion and/or turbidimetric variations have not been observed when either sera or plasmas have been mixed with variable amounts of a methylglucamine salt of ioglycamic acid (MGI) and other compounds. In addition, no side-effects have been clinically recorded in three patients with Waldenströms macroglobulinaemia (WM) whose sera and/or plasmas had been studied in vitro, when they have been submitted to intravenous contrast examinations. The results suggest that there is not an evidence of a relationship between iodinated contrast media and fatal reactions due to sol-jell alterations in patients with WM and therefore a radiological examination using contrast media may be carried out in those patients.
Two methods of diagnosing acute cholecystitis--cholescintigraphy and infusion cholecystography--were compared in a prospective study of 105 patients. Sensitivity and specificity were very high (96-99% and 91%, respectively), without difference between the two methods. Infusion cholecystography gave transient rise in liver enzyme levels in more than half of the patients. Cholescintigraphy gave no side effects. Cholescintiscan could be performed at moderately elevated bilirubin levels. It also gave information concerning liver malignancy in four patients. On these grounds, cholescintigraphy is the preferable of the two methods.
The value of infusion cholecystography 99mTc HIDA cholescintigraphy and ultrasonography was compared in 51 patients presenting with a clinical diagnosis of acute cholecystitis. Of the 35 patients with proven gallbladder disease, the presence of gallstones was correctly predicted in 31 (88 per cent) by infusion cholecystography, 32 (90 per cent) by 99mTc HIDA cholescintigraphy and 27 (77 per cent) by ultrasonography. There were no false positive investigations. Infusion cholecystography may be of particular interest to surgeons with no ready access to isotope scanning techniques.
The effect of ethacrynic acid (EA), an agent which increases bile acid independent bile flow, on the biliary excretion and concentration intravenously administered biliary contrast agent ioglycamide was studied on cholecystectomized anesthetized dogs equipped with Thomas cannula through which the common bile duct could be cannulated. One hour after cannulation i.v. infusion of ioglycamide at a rate of 4 mu mol./min./kg. was started. Two hours later 1 mg./kg. of ethacrynic acid was injected intravenously. This procedure was repeated three times on four dogs, five dogs receiving comparable volume of saline at comparable time serving as controls. Bile was collected at 15 min. intervals and simultaneous i.v. blood samples were taken. EA injection caused decrease in biliary ioglycamide concentration and biliary excretion of ioglycamide and a slight but statistically not significant decrease in bile flow. Since EA is an organic anion and the increase in bile flow induced by it has been shown to be related to the biliary excretion of its metabolites, it may be suggested that EA as an organic anion inhibited biliary excretion and hepatic uptake of ioglycamide but having lower choleretic effect its excretion could not increase the bile flow.
Patients with the clinical diagnosis of acute cholecystitis were studied with intravenous cholecystography and cholescintigraphy. The two examinations alternated in a random order. The final diagnosis was ascertained by surgery in most patients. Either cholecystography or cholescintigraphy could be used in the diagnostics of patients with suspected acute cholecystitis. The methods have about the same accuracy. However, cholescintigraphy is performed more easily and more rapidly than intravenous cholecystography.
Biliary excretion of ioglycamide was studied in Wistar and Gunn rats. A hepatic transport-maximum (Tm) was observed. Higher Tm-values were found in Gunn rats, which have a greater bile flow compared to the parent Wistar rats, in spite of having a similar bile acid output. This suggests that the Tm is related to the bile acid-independent bile flow. In bile acid-depleted Wistar rats, bile acid output was 30% of control values whereas bile flow and ioglycamide-Tm had only decreased by approximately 15%. Ioglycamide excretion could not be increased by taurocholate infusion. An additional 22.0 ml of bile was excreted per mmol of biliary ioglycamide. Loads of the contrast agent markedly exceeding the Tm resulted in a decrease of its own biliary excretion and its choleretic properties. These presumed 'toxic' effects were counteracted by near-physiological amounts of taurocholate. Thus, the effect of taurocholate varies greatly depending upon the amounts of the contrast agent and the taurocholate administered.