The blood-brain barrier: effects of nonionic contrast media with and without addition of Ca2+ and Mg2+.

Trypan blue and 197HgCl2 were used as markers of the increased leakage through the blood-brain barrier which developed after selective injection of different contrast media formulations into the internal carotid arteries of rabbits. Interest was focused on a new, experimental, nonionic medium (C-29) and possible effects resulting from the addition of Ca2+ and Mg2+ to nonionic contrast media. Using 197Hg, it was possible to quantitate the increase in extravasation produced by the contrast media. C-29 caused less damage than either metrizamide or meglumine iothalamate. The addition of Ca2+ and Mg2+ to nonionic contrast media seemed to stabilize the blood-brain barrier.

Contrast media-induced nephrotoxicity. Survey and present state.

Reports of renal failure induced by contrast media are increasing. Adverse effects of contrast media on kidney function include diuresis, changes in renal blood flow, osmotic nephroses, albuminuria, enzymuria and, most important, glomerular filtration rate. Animal studies indicate that the new nonionic contrast medium, iohexol, has fewer adverse effects on kidney function than the ionic media currently used. Three clinical studies offer some evidence of the effect of iohexol on renal function, but it is not yet possible to conclude that lower nephrotoxicity found in animals will also be found in man. Further clinical studies are warranted, and careful monitoring of contrast media clearance is recommended in all high-risk patients.

Metrizamide in experimental urography. V. Renal excretion mechanism of a non-ionic contrast medium in rabbit and cat.

The excretion mechanisms of the non-ionic contrast medium, metrizamide, and the ionic, sodium diatrizoate, are compared to investigate the potential usefulness of metrizamide in clinical urography. A mixture of 125I-labeled metrizamide and 131I-labeled diatrizoate was injected intravenously to rabbits or cats. Urine, bile and blood were analyzed for their concentration of iodine. From these concentrations the renal and total clearance was calculated. In the rabbit the excretion of metrizamide was also compared with that of 3H-inulin with or without influence of p-aminohippurate or probenecid. The earlier reported relatively low urinary iodine concentrations after intravenous injection to rabbits of low doses were explained by the following findings: In the rabbit the volume of distribution, the renal clearance and the total clearance of metrizamide were smaller than those measured for diatrizoate and inulin. The biological half-life in serum measured 30-150 min after injection was the same for all three compounds. No indication of tubular secretion was found. The excretion mechanism of the contrast media exhibits species differences as no differences between metrizamide and diatrizoate in the parameters mentioned above could be measured in the cat.

Renal excretion mechanism of a nonionic contrast agent.

The renal excretion mechanism of a nonionic experimental contrast agent, C-29, was investigated in rabbits in comparison with the ionic contrast agent sodium diatrizoate under conditions of free urine flow and ureteral stasis. The two contrast agents were injected as a mixture of 125I-C-29 and 131I-sodium diatrizoate, in doses of 25 and 250 mg I/kg. The results indicate that, during the period relevant for urographic examinations, C-29 may have a renal clearance as low as 0.7 times that of sodium diatrizoate under conditions of both free urine flow and ureteral stasis. The biologic half-life of C-29 is 41-50 min.

Metabolism of urographic contrast media.

The metabolism of ionic and nonionic contrast agents was examined in the rabbit and in humans by specific measurement of iodide present in urine at different time intervals after injection of high contrast medium doses. Interest was focused on the experimental model compound C-29, which was investigated using a 125I-labeled compound, permitting a study of iodide release and the appearance of other metabolites in serum, bile, and urine from rabbits. Large, quantitative, individual variations were found, but in most cases th urine collected from both rabbits and humans contained more iodide than had been injected. A mean of 0.07% of total injected iodine was found within three days after injection of the ionic contrast medium metrizoate. The results with rabbits indicated that this figure may increase to 1% using the nonionic media tested. Direct evidence of metabolism of C-29 was found in bile, where up to 35% of the total radioactivity present in the bile 4-6 hours after injection was identified as a metabolite.

Proteinuria produced by urographic contrast media.

All angiographic and urographic procedures expose the kidney to high contrast medium concentrations. The introduction of the triiodinated ionic contrast media has lowered the risk of contrast medium-induced renal damage. An increase in dose and use of "bolus urography" have, however, led to an increase in frequency of reports on renal damage following intravenous pyelography and angiography. The low general toxicity of the new nonionic contrast media should also include a lower toxicity towards the kidneys. The media are, however, concentrated in the kidney to twice the concentration of the ionic media, and this might blur the expected reduction in kidney toxicity. The authors examined this problem by studying enzymuria in rabbits and albuminuria in rats after injection of different ionic and nonionic contrast media. In the rabbit, the model should imitate a urography and in the rat, a nephroangiography. All contrast media resulted in enzymuria and albuminuria, but to different degrees. The time for maximum enzymuria differed from the time of maximum albuminuria. The proteinuria does not appear to be related to the osmotic pressure of the injected contrast medium. The clinical significance of these findings is discussed.

Mechanisms of action of contrast media on cranial vessels. Comparison of diatrizoate, ioxaglate, iohexol, mannitol, and NaCl on rabbit basilar and ear arteries.

The relaxant effects of the ionic contrast media diatrizoate and ioxaglate and the nonionic agent iohexol on the vascular wall were examined by a sensitive in vitro system. Control solutions of NaCl and mannitol were used to evaluate the relative importance of osmolality to the vasodilation response. The rabbit central ear artery and the basilar artery were precontracted by (1) potassium, causing depolarization of the sarcolemmal membrane, (2) noradrenaline, causing activation of alpha 1-adrenoceptors, and (3) histamine, causing activation of histamine H1 receptors. The contrast media caused concentration-dependent relaxation of both types of arteries; this effect was relatively insensitive to the agent used to precontract the vessels. Histamine-contracted arteries were thought more sensitive to the relaxant agents used than arteries contracted by potassium or noradrenaline. The relaxation induced by the contrast media correlates with the relaxation induced by equiosmolar amounts of NaCl or mannitol. Our results suggest that the artery dilator response seen after exposure to currently used contrast media is due primarily to changes in local osmolality rather than to a specific receptor involvement.

Metrizamide in urography. II. A comparison of 51Cr-EDTA clearance and metrizamide clearance in man.

In nine subjects undergoing urography with metrizamide measurements of total serum clearance of 51Cr-EDTA have been made before, during, and after the urography. During the urography both total serum clearances and renal clearances were determined for 51Cr-EDTA and metrizamide. The present study in man confirms the previous results from investigations in rabbits, that most of the intravenously injected metrizamide is excreted through the kidneys, that tubular reabsorption of metrizamide occurs and suggests that metrizamide might be used with advantage for urography.

Metrizamide in experimental urography. IV. Effects of bilateral ureteric stasis on urine iodine concentration after intravenous infection of an ionic and a non-ionic contrast medium.

The non-ionic contrast medium metrizamide was compared to the sodium salt of diatrizoate to investigate the potential usefulness of metrizamide in clinical urography when ureteric stasis is applied. After intravenous injection of the contrast media to rabbits at dose level 175 mg I/kg, the kidneys were subjected to temporary bilateral ureteric stasis. Urine was collected through ureteric catheters and analyzed for its concentration of iodine, sodium and potassium. After metrizamide injection the urine iodine concentration was twice as high as after sodium diatrizoate injection. This difference between one non-ionic and one ionic contrast medium was larger than what has been reported earlier during free flow of urine at the same dose. Furthermore, during the periods of ureteric stasis metrizamide was excreted faster than diatrizoate. When diatrizoate was given as its sodium salt, the sodium given was excreted at about the same rate as the diatrizoate given.

Measurement of renal function with iohexol. A comparison of iohexol, 99mTc-DTPA, and 51Cr-EDTA clearance.

The nonionic iodinated contrast medium, iohexol, introduced for clinical urography, is eliminated from the human organism mainly by glomerular filtration. The aim of this study was to analyze the applicability of iohexol for glomerular filtration rate (GFR) measurement by comparing the plasma clearance of iohexol to the plasma clearance of the traditionally employed substances, chromium-51-EDTA and technetium-99m-DTPA. Iohexol concentration was measured by x-ray fluorescence. To analyze for possible acute effect of iohexol on renal function, additional measurements of 99mTc-DTPA clearance were made prior to the injection of iohexol. In 15 patients having clearance values between 30 and 130 ml/min per 1.73 m2, there were close correlations (r = 0.95-0.98) among iohexol, 51Cr-EDTA, and 99mTc-DTPA clearance. No significant acute renal effect of iohexol was demonstrated. It is concluded that measurement of iohexol clearance provides information about GFR that is as valid as measurements of 51Cr-EDTA and 99mTc-DTPA clearance. Thus, it is possible to perform urography and a determination of GFR using a single injection of iohexol.

Contrast media for CT. An analysis of the early pharmacokinetics.

Iohexol and meglumine-sodium diatrizoate were injected intravenously into 18 pigs as either a 99:1 or 1:99 mixture. Blood samples were taken for 30 minutes and the concentration of each of the two contrast media was measured by means of a double labeling technique with 125I and 131I. Relative concentrations of iohexol were significantly higher during the first 3 minutes when it was injected as a moderately hyperosmolar (99% iohexol) solution than when it was injected as a very hyperosomolar (99% diatrizoate) solution. The greater intravascular dilution of the 99% diatrizoate solution by extravascular water may explain this finding as well as the significantly longer rapid disposition phase and the slightly lower distribution volume of iohexol.

Contrast enhancement of the liver and blood. Nonionic versus ionic contrast media in the pig.

The contrast enhancement of low-osmolality (iohexol) and high-osmolality (diatrizoate) contrast media was compared in 18 pigs following intravenous bolus administration. Liver and blood attenuation and blood sample iodine concentration were measured during the first 3 minutes after injection. Iohexol produced a significantly higher contrast enhancement in the blood during the period from 0.5 to 3 minutes after injection. Diatrizoate produced a significantly higher contrast enhancement in the liver during the period from 9 to 30 minutes after injection. The greater contrast enhancement of iohexol during the acute phase should be advantageous in dynamic CT.

Early effect of gadopentetate and iodinated contrast media on rabbit kidneys.

RATIONALE AND OBJECTIVES: The authors compared the physiologic and nephrotoxic effects of the magnetic resonance imaging contrast medium gadopentetate with two conventional radiographic contrast media. METHODS: Rabbits were injected intravenously with one of the following solutions: 1) gadopentetate (0.1 M); 2) iohexol (300 mg I/mL); 3) metrizoate (300 mg I/mL); and 4) NaCl (0.9%). Blood samples were taken before and 5, 15, 45, 90, and 180 minutes after injection of the solutions and were analyzed for creatinine, aldosterone, and contrast media levels. Urine was sampled before and 1, 2.5, and 5 hours after injection of the solutions, and creatinine, leucine amino peptidase (LAP), alkaline phosphatase (ALP), gamma glutaryl transferase (GGT), and N-acetyl beta-D-glucosaminidase (NAG) activities were quantified. RESULTS: Contrast media clearance was similar for gadopentetate, iohexol, and metrizoate. Plasma aldosterone was significantly higher in the two groups injected with iodinated contrast agents compared with the gadopentetate and saline groups in the 3-hour samples. During the 5 hours after injection, the excretion of brushborder enzymes LAP, ALP, and gamma GT was significantly higher for all contrast media compared with pre-contrast values and 0.9% NaCl controls. NAG, a lysosomal enzyme from tubular cells, showed a significant increase compared with pre-contrast values for all contrast media. CONCLUSIONS: Intravenous injection of gadopentetate in rabbits showed nephrotoxicity of the same order as that of conventional iodinated contrast media.

Urine profiles and kidney histology following intravenous diatrizoate and iohexol in the degeneration phase of gentamicin nephropathy in rats. Effects on urine and serum profiles.

Urine chemical profiles were followed for three or nine days after intravenous injection of diatrizoate, iohexol, or saline in 30 rats, where a tubulointerstitial nephropathy was induced by gentamicin given over an eight-day period. Another ten rats injected with saline served as controls. Compared to injection of saline, both iohexol and diatrizoate induced dysfunction. The excretion of the cytoplasmic enzyme lactate dehydrogenase was significantly greater following iohexol than following diatrizoate. No significant differences between the two media were shown by the various serum components examined. Among the gentamicin-treated rats, light microscopy showed prolonged occurrence of tubular necrosis and a more intensive round cell infiltration following iohexol than following diatrizoate and saline. Both contrast media induced further temporary renal dysfunction in rats with gentamicin nephropathy; iohexol induced more morphologic changes than diatrizoate.

Noninvasive estimation of kidney function by x-ray fluorescence analysis: biological half-time and clearance of contrast material in rabbits.

A noninvasive method for glomerular filtration rate-determination, in which the use of radioactive tracers and sampling of plasma and urine can be omitted, is described. After injection of iodinated contrast material in rabbits, the iodine content of tissue, serum, and urine is measured by means of x-ray fluorescence analysis. The disappearance rates of iodine in tissue and serum are found to be the same, and a strong correlation is found between clearance values calculated from serum and tissue measurements. This indicates the possibility of evaluating kidney function by x-ray fluorescence analysis of contrast material in tissue only.

Noninvasive estimation of kidney function by x-ray fluorescence analysis. Elimination rate and clearance of contrast media injected for urography in man.

A noninvasive method for the estimation of kidney function is described. The use of radioactive tracers and the sampling of plasma and urine are omitted. The method has been used in patients referred for urography and who had therefore been injected with routine amounts of iodine-containing urographic contrast medium. After urography, the elimination rates of urographic contrast medium from both serum and finger tissue were determined and compared during a 2-hour period that began two hours after injection of contrast medium. The elimination of iodine in finger tissue was measured noninvasively using x-ray fluorescence analysis. A strong degree of correlation was found between the elimination rates from serum and finger tissue and between the total clearances calculated from the serum and finger measurements. Thus, after urography estimation of kidney function may be obtained as a fringe benefit by x-ray fluorescence measurements of the elimination rate of an iodine-containing contrast medium from tissue or from serum.

Renal clearance of an ionic high-osmolar and a nonionic low-osmolar contrast medium.

One hundred patients with normal serum creatinine concentration underwent intravenous urography with either an ionic high-osmolar (diatrizoate) or a nonionic low-osmolar (iopamidol) contrast medium after randomization. Before injection of the contrast medium, a blood sample was drawn for determinating serum creatinine concentration, and a urine sample for measurement of urine osmolality. Using x-ray fluorescence, the plasma concentration of iodine (contrast medium) was determined on blood samples drawn approximately 3 and 4 hours after injection of the contrast medium. The glomerular filtration rate was calculated by two different formulas: one requiring only a single sample and one requiring at least two samples (standard). There were poor correlations between the standard contrast medium clearance and the serum creatinine concentration, the estimated creatinine clearance (calculated from a nomogram), as well as the urine osmolality. The 3-hour and the 4-hour single-sample values correlated well with the two-sample values for both contrast media. In patients with normal serum creatinine, the glomerular filtration rate determined by measuring the contrast medium concentration in a single plasma sample obtained at 3 hours, is almost identical to the value determined from two samples. Consequently, two samples are unnecessary.

MRI contrast media for the liver. Efficacy in conditions of acute biliary obstruction.

The authors investigated in a rat model the efficacy of magnetic resonance imaging (MRI) contrast media for evaluating the liver in conditions of acute biliary obstruction. Two liver-specific MRI contrast media, Cr-DEHIDA and Mn-DPDP, and the nonspecific agent Gd-DTPA were studied in normal rats and in rats whose bile ducts had been ligated before administration of the contrast medium. Images were made using a 2.4 T animal MRI system, and intensity enhancement of liver after contrast medium injection was calculated. Metal analyses of serum and liver tissue and T1 and T2 measurements on liver samples in vitro were performed. The differences in image intensity enhancement of liver between normal rats and rats with ligated bile ducts were not significant for any of the three contrast media. Imaging with Mn-DPDP resulted in the highest intensity enhancement of the liver compared with Cr-DEHIDA and Gd-DTPA. Contrast media concentrations in liver tissue were not significantly different between normal rats and rats with ligated bile ducts; however, Cr-DEHIDA concentrations in serum were higher after bile duct ligation. In vitro measurements of liver tissue indicated unique relaxation properties for Mn-DPDP. This investigation indicates that the contrast media studied may be useful in situations where suspected liver pathology is complicated by acute biliary obstruction.

A magnetic resonance imaging contrast medium for the liver and bile.

A pharmacokinetic investigation of a paramagnetic Cr-HIDA derivative was performed. Blood, bile, and urine were collected during the first 2 hours after injection of Cr-HIDA 0.01, 0.05, and 0.25 mmol/kg in rats or rabbits. The pharmacokinetics of the substance were found to be similar to those of the biliary iodinated contrast media in common use. Magnetic resonance imaging performed at 10 minutes after injection into the animals revealed that it was necessary to use doses higher than 0.01 mmol/kg to obtain a diagnostically significant increase in signal intensity from the liver. The gallbladder, however, was clearly defined at this dose level.

A comparison between IEEC, a new biodegradable particulate contrast medium, and iohexol in a tumor model of computed tomography imaging of the liver.

RATIONALE AND OBJECTIVES: Higher contrast between normal and pathologic tissues in the liver may enable detection of smaller lesions in computed tomography (CT). This can be obtained using a liver-specific contrast medium. The authors evaluate a new agent, IEEC (1'-Ethyloxycarbonyloxy)-ethyl-5-acetylamino-3-(N-methyl-acetylami no)-2,4,6- triiodo-benzenecarboxylate), in an animal model, as a potential contrast agent for CT scanning of the liver. The IEEC particulate contrast medium used is based on a prodrug ester design of metrizoic acid and accumulates rapidly in the liver. The particles are quickly degraded into well-known metabolites and excreted from the body. METHODS: Two groups of rabbits were inoculated with VX2-carcinoma directly into the liver by laparotomy. Computed tomography imaging studies were carried out 9 and 11 days after the inoculation. The investigation was designed as a crossover study. The first group was imaged both as controls (without contrast medium) and with the particulate contrast medium on the 9th day and with iohexol on the 11th day. The second group was imaged with iohexol on the 9th day and as controls, and with the particulate contrast medium on the 11th day. The contrast medium was administered in a dose of 100 mgI/kg. Iohexol was administered in a dose of 570 mgI/kg according to a standard clinical scheme in use at a radiology department for dynamic CT. Changes in normal liver/lesion contrast and the conspicuity of tumors were assessed. On completion of imaging studies on day 11, all animals were killed. The liver was removed and evaluated for the presence of tumors. RESULTS: At macroscopic inspection, all rabbits were found to have tumors ranging from 2 to 14 mm in diameter. The size and location of the tumors corresponded well with the CT images. In the images where the particulate contrast medium was used, the attenuation in the normal liver parenchyma and the contrast between normal liver and lesion was significantly higher compared with the images where iohexol was used or the controls. For all tumor sizes, the lesion detection capability with the particulate contrast medium was significantly higher compared with iohexol (P < .005) and controls (P < .05). CONCLUSIONS: VX2-carcinoma in rabbit liver is a useful model for studying the efficacy of contrast media in CT imaging. The particulate contrast medium IEEC improved visualization of liver tumors.