Acta Radiologica

Iodixanol (Visipaque) is a new nonionic roentgen contrast medium intended for general use. Visipaque is a pharmaceutical formulation of iodixanol which is isotonic and iso-osmotic with blood. Two synthetic routes from 5-nitro-isophthalic acid to iodixanol are described. The chemical structure is confirmed by spectroscopical data (¹H-NMR, ¹³C-NMR, FAB-MS, electrospray-MS, UV, IR and Raman). Chromatographic characteristics are related to the isomerism of iodixanol.

Iodixanol, the radiopaque in Visipaque, is a new nonionic, dimeric roentgen contrast medium for intravascular use. Compared to aqueous solutions of nonionic monomers, which have a higher osmolality than blood, aqueous solutions of iodixanol have a lower osmolality due to the dimeric structure of the molecule. As a consequence of this advantageous property, solutions of all clinical concentrations of iodixanol can be made isotonic by the addition of salts of the key electrolytes sodium and calcium to the formulation. The viscosity of all iodixanol (Visipaque) solutions is less than or equal to that of iohexol (Omnipaque) 350 mg I/ml. Iodixanol itself is an amorphous and hygroscopic solid which is freely soluble in water. Partition coefficients show that iodixanol is even more hydrophilic than the nonionic monomers such as iohexol. The high hydrophilicity and the good aqueous solubility of iodixanol are due to the hydroxyl group in the dimer linkage and the hydrophilic amide side chains of the molecule.

Even at its highest concentration, 320 mg I/ml, Visipaque – based on the nonionic dimer iodixanol – is isosmotic to blood plasma, whereas Omnipaque (300 mg I/ml) – based on the nonionic monomer iohexol – has an osmolality of about twice that of the plasma. However, the fact that a solution is isosmotic to plasma does not necessarily mean that it is isotonic to plasma. An isosmotic solution can still cause a net movement of water over the plasma membranes of, for example, erythrocytes and endothelial cells.

Determination of the tonicity of Visipaque 320 mg I/ml and comparison with that of Omnipaque 300 mg I/ml and hypertonic NaCl have been performed.

No change in the water content of human erythrocytes was seen after mixing whole blood 10:1 with either Visipaque 320 mg I/ml or 155 mM NaCl, whereas a significant decrease in water content occurred with Omnipaque 300 mg I/ml and 620 mM NaCl. No difference in the water content of rat erythrocytes was evident after mixing whole blood with Visipaque 320 mg I/ml or isotonic NaCl. However, as with human erythrocytes, a significant decrease in water content occurred after rat blood was mixed with Omnipaque 300 mg I/ml.

In conclusion, Visipaque 320 mg I/ml does not cause any net movement of water over the human or the rat erythrocyte plasma membrane, i.e., Visipaque is isotonic to human and rat blood plasma.

The viscosity of 8 commercially available contrast media (CM) at 2 or 3 concentrations were measured as a function of concentration and temperature, using a rotational viscosimeter. Further on, by use of an automated injector, injection pressures were measured for 3 of the CM at various concentrations, temperatures, catheter lengths, catheter diameters and flow rates. The experiments were performed as fractional factorial designs.

The correlation between the injection pressure and the viscosity was found to be log-linear, and an empiric equation was established for this relationship. The relative reduction of viscosity – and thereby injection pressure – with increasing injection temperature, was largest for the most concentrated CM.

Iodixanol and iotrolan, the 2 nonionic dimers investigated, demonstrated an increased viscosity compared to the nonionic monomers at equal concentrations. However, all CM investigated could be used with an acceptable injection pressure either by relatively small changes in catheter conditions or by adjustment of injection temperature closer to body temperature.

Iodixanol (Visipaque) is an isotonic, electrolyte-balanced roentgen contrast medium for intravascular use. The patented and well-proven formulation and the rationale for it are described, and the efficacy and safety are documented. The stability of iodixanol is well within the specifications under all relevant conditions, both in glass and polypropylene bottles; the product has a recommended shelf-life of at least 36 months when stored at room temperature and protected from light. Heating to body temperature before use is acceptable and recommendable, and storage at 37°C for 1 month does not jeopardize product quality. Iodixanol has no apparent immediate in vitro incompatibility reactions with drugs often used in connection with roentgen contrast examinations.

The iodine-specific detection techniques X-ray fluorescence spectrometry, neutron activation analysis and radiochemical detection of ¹²⁵I-labelled substance are well suited for quantification of iodixanol in biological samples. The limit of detection is 60 μg iodixanol/ml for X-ray fluorescence analysis and 1 to 10 μg iodixanol/ml for neutron activation analysis. Reversed-phase high-performance liquid chromatography (HPLC) has been employed when selective determination of iodixanol was needed for identificational purposes or when quantification of very small amounts of iodixanol was essential. An optimized HPLC method for quantification of iodixanol in rat serum and urine is presented. The limit of detection for this method is 0.20 μg iodixanol/ml for rat serum and 3.0 μg iodixanol/ml for rat urine.

When samples were analyzed by HPLC and thin layer chromatography, no metabolites of iodixanol were observed in rat, monkey or human urine, or in rat kidney and bile. Studies with equilibrium dialysis and HPLC determination of iodixanol showed no protein binding of the contrast agent in human plasma; the 95% confidence interval for the result was 0.0±2.1%.

To document the safety of iodixanol and to assess its pharmacokinetic properties, extensive tests have been performed. Iodixanol was rapidly excreted, mainly via the kidneys, with a plasma half-life in rats and monkeys of 25 and 76 min, respectively. The pharmacokinetic data were consistent with an extracellular distribution of iodixanol. During the 24 hours post-dosing, the urinary excretion was from 72 to 100% in rats, and 78% in monkeys. Biliary excretion was 1.5% during the first 4 hours in rats. Fecal excretion was about 7% in rats and 0.8% in monkeys over the first 24 hours after injection. Approximately 0.5 and 1% of the dose was found in the kidneys of rats and monkeys, respectively, 24 hours after dosing.

Acute toxicity of iodixanol in rats was low, with an LD₅₀ greater than 21 g I/kg. In mice, the LD₅₀ was 21 g I/kg and the approximated median lethal dose (ALD₅₀) was found to range from 15 to 21 g I/kg. A single dose of 1 and 3 g I/kg was well tolerated in monkeys. As for other roentgen contrast media, a reversible, dose-related, vacuolation of the proximal tubules in the kidneys was seen in the acute and subacute studies in rats and monkeys. No relationship was seen between the vacuolation and kidney function. Local tolerance studies demonstrated a low irritation potential for iodixanol when injected by a variety of intravascular and extravascular routes.

The reproductive capacity of male and female rats was unaffected by iodixanol when administered daily at doses up to 2 g I/kg/day. No teratogenic potential in rats and rabbits of iodixanol was observed. Further, no toxic effects on pups were seen when rats were dosed during the lactation period. Each of 4 standard genotoxicity tests was negative. No antigenic potential of iodixanol was observed when assessed by the passive cutaneous anaphylaxis test and the active systemic anaphylaxis test in guinea pigs.

The intravascular tolerability of iodixanol is high and, therefore, iodixanol should be considered as a safe roentgen contrast medium for intravascular use.

Anaphylactoid reactions following administration of roentgen contrast media (CM) have occasionally been described. In this investigation, blood samples from nonallergic human volunteers were exposed to the CM iodixanol (Visipaque), iohexol (Omnipaque), ioxaglate (Hexabrix) and metrizoate (Isopaque 350). The degree of activation of the complement cascade and the amount of free histamine in the samples were estimated. By using a hemolytic assay, a dose-independent complement consumption was detected when salt-free dilutions of the CM were added to human serum.

Very little complement consumption was detectable when the concentrations of salts in the CM solutions were adjusted toward normal plasma concentrations, indicating that the lack of salts in the CM formulations was responsible for causing the consumption of complement rather than the CM molecules themselves. By using an ELISA assay for determination of the terminal complement complex (TCC), no increase in TCC level was detected following the addition of iodixanol to human serum.

The results indicate that iodixanol does not activate the complement cascade when added to human serum, and that it is unlikely that anaphylactoid reactions observed in man after CM administration are caused by CM-induced anaphylatoxins. No histamine release was observed following the addition of ioxaglate, metrizoate, iohexol or iodixanol to blood from nonallergic individuals.

Patient safety should be in focus when using contrast media (CM) in diagnostic and interventional cardiac procedures. Side-effects that occur during cardioangiography due to hemodynamic effects of CM include direct effects on the heart, effects on the systemic and the pulmonary circulation, and effects on the blood volume.

Although not a totally inert solution, iodixanol (Visipaque) has less pronounced direct inotropic effects on the heart than have other CM; its vasodilatory effects on peripheral arteries are smaller, and the increase in blood volume is smaller after administering iodixanol than after other CM.

Thus, iodixanol represents a further step forward in terms of reducing side-effects during contrast-enhanced diagnostic and interventional cardiac procedures.

Since the first animal coronary arteriogram in 1933 there have been many innovations in techniques and contrast media. From 1933 through the late 1950s the procedures used involved nonselective aortic injections and the use of acetylcholine to slow the heart. The first selective coronary arteriogram in animals was performed by West, Kobayashi & Guzman in 1958 (45) and in 1959 Guzman & West (7) observed ventricular fibrillation with some media but not others. In 1967 Judkins (14) described the catheter designs for right and left coronary catheterizations that we still use today. In the 1970s and 80s many authors observed that ionic monomeric contrast media reduced plasma calcium causing fibrillation and myocardial depression. Supplementation of ionic media with calcium was shown to moderate these adverse effects.

Almén's vision of low osmolality contrast media and the creation of metrizamide (1) stimulated the rapid development of monomeric and dimeric nonionic contrast media. The ionic dimeric medium ioxaglate also provided low osmolality. Digital frame grabbers and computers lead to the development of digital subtraction angiography and new applications of arteriography, frequently using dilute media. Unexpectedly, during prolonged right coronary arteriography in animals, dilute nonionic media were found to produce increased fibrillation as compared to dilute ionic media. The addition of sodium to nonionic media significantly reduced the incidence of fibrillation. Animal studies with the nonionic medium iodixanol supplemented with sodium and calcium (Visipaque) have demonstrated minimal incidences of fibrillation and myocardial depression.

Contrast media (CM) affect normal cardiac electrophysiology when injected into the coronary arteries. High-osmolality CM cause more pronounced electrophysiological effects than do low-osmolality CM. Further, both high- and low-osmolality ionic CM have more pronounced effects than the nonionic CM. The CM-induced electrophysiological effects involve regional disturbances of depolarization and repolarization, thereby causing disturbances of impulse conduction as well as dispersion of refractoriness. Recent experimental studies have demonstrated that the addition of sodium or a balanced electrolyte supplement to nonionic CM reduces the risk of ventricular fibrillation (VF), particularly when the CM is injected in a wedged catheter situation. The reduced risk of VF may be due to the small and transient lengthening of repolarization seen in the CM-perfused area of the myocardium. Iodixanol, which is an isotonic nonionic dimer supplemented with NaCl and CaCl₂, is as well tolerated as iohexol during free coronary flow. However, when flow is restricted, such as when CM is injected through a wedged catheter, the risk of VF is less with iodixanol than with iopamidol, iohexol and ioxaglate.

A review of the literature on the effects of adding electrolytes to ionic as well as nonionic contrast media (CM) in the isolated heart model reveals that both ionic and nonionic CM favor from such addition, if the addded electrolytes are balanced with respect to each other. By enriching nonionic monomeric as well as dimeric CM with such a balanced electrolyte solution, the risk of ventricular fibrillation is reduced and myocardial contractility is improved compared to nonionic CM without such enrichment.

The new nonionic dimer iodixanol is slightly hypotonic to plasma in concentrations suitable for coronary arteriography. The water solution of iodixanol therefore contains an osmotic space in which electrolytes can be added, thereby making it isotonic with plasma.

The present review deals with the side-effects of contrast media (CM) on cardiac function during coronary angiography. A physiological approach is used to redefine existing concepts of CM osmotoxicity and chemotoxicity in terms of osmolal, ionic and molecular effects. The main idea conveyed is that purely ionic effects are of central importance during and immediately following the transit of a brief coronary bolus. Ionic effects result largely from rapid transient washout of normal extracellular ions, but are also influenced by ions present in the CM. In particular, the calcium (Ca) and sodium (Na) ions controlling cardiac function are easily affected. The myocardial Na–Ca exchange, which is mainly a physiological mechanism for cellular Ca efflux during cardiac relaxation, is therefore highlighted in detail.

The importance of avoiding a potential Na–Ca mismatch is shown by examples from basic physiology, cardiac surgery and coronary angiography and by results of experiments with Visipaque. In the isosmolal and isotonic CM Visipaque, which is based on the dimer iodixanol (320 mg I/ml), an available osmolal space is filled with an appropriately balanced supplement consisting of NaCl (19 mM) and CaCl₂ (0.3 mM).

Changes in contractile function induced by modern roentgen contrast media (CM) were examined in isolated rat hearts. Four coronary perfusions were undertaken in each heart with increasing volumes of each CM in order to test a wider spectrum of potential side-effects. Left ventricular developed pressure (LVDP) and heart rate (HR) were recorded. Six commercially available or investigational CM were examined: A, Hexabrix (ioxaglate 320 mg I/ml, Na 146 mM); B, Isovist (iotrolan 300 mg I/ml, Na 6 mM); C, Visipaque (iodixanol 320 mg I/ml, Na 19 mM, Ca 0.3 mM); D, “Iodixanol high Ca-Mg” (iodixanol 320 mg I/ml, Na 19 mM, Ca 1.2 mM, Mg 0.6 mM); E, “Iohexol I 350” (iohexol 350 mg I/ml, Na 28 mM); and F, “Iohexol I 150” (iohexol 150 mg I/ml Na 28 mM). A, E and F were low-osmolal (400–940 mosm/kg H₂O) CM, whereas B, C and D were essentially isosmolal.

Contractile changes (transient LVDP depression) was volume-dependent. Maximal values for LVDP depression were: “Iohexol I 150” 11–22%< Isovist 13–45% and Visipaque 18–45%<“Iodixanol high Ca-Mg” 14–62%<“Iohexol I 350” 40–76%<Hexabrix 92–96%. No changes were observed in HR.

The study revealed that cardiac function was hardly affected by CM which had the following characteristics: a low to normal osmolality (<400 mosm/kg H₂O); a low concentration of contrast agent (150 mg I/ml); and an overall content of ions (Na 6-28 mM, Ca 0–0.3 mM) complying well with myocardial ratios of Na and Ca. Of the CM tested that may be in clinical use in coronary angiography (300–350 mg I/ml), Isovist and Visipaque induced the least changes in contractility.

This study was designed to compare the cardiac electrophysiological and mechanical effects of iodixanol to those of iotrolan, iopromide, ioxaglate and diatrizoate. Two consecutive injections of contrast media (CM) (0.3 g I/kg and 0.9 g I/kg b.w.) were given to spontaneously beating, Langendorff-perfused rat hearts. CM were given as a single, short-lasting bolus injection (i.e., over 2 and 5 s). Changes in aortic pressure, left ventricular pressures and ECG were continuously recorded during constant volume perfusion.

The nonionic CM had less pronounced effects on aortic pressure than had the ionic media. The peak rate of isovolumetric contraction (LV dP/dt_max) was slightly decreased by iodixanol and iotrolan, slightly more decreased by iopromide and markedly decreased by ioxaglate and diatrizoate. Similarly, the peak rate of pressure decline (LV dP/dt_min) was only slightly decreased by iodixanol and iotrolan. Also, the 2 nonionic dimers had the smallest effects on left ventricular enddiastolic pressure (LVEDP) and heart rate. Ioxaglate lengthened the PQ-interval, but less so than diatrizoate. The QT-interval was only slightly lengthened by iodixanol and iotrolan, as compared to the lenghtening caused by iopromide, ioxaglate and diatrizoate. Single ventricular extrasystoles were seen in all groups. Extrasystoles up to 3 coupled beats were registered after ioxaglate and diatrizoate. No episodes of ventricular fibrillation occurred with any CM.

In conclusion, the nonionic dimers, and in particular iodixanol, induce only minor changes in cardiac function, whereas the ionic dimer ioxaglate and the ionic monomer diatrizoate induce pronounced effects.

All types of clinically employed iodinated roentgen contrast media (CM) cause vasodilatation after i.a. and i.v. administration, regardless of precise molecular structure. It is now apparent, however, that at iodine concentrations which provide equivalent angiographic contrast, this effect is significantly less with the newer hexa-iodinated dimers, such as iodixanol and iotrolan, than older generations of compounds. The cellular mechanisms that underly the vasodilator effects of CM still remain to be fully elucidated but may include a) effects attributable to hyperosmolality; b) stimulation of the release of endogeneous vasoactive mediators; and c) direct relaxant effects upon vascular smooth muscle.

This review will discuss the possible contributions of these mechanisms to the vasodilatation observed in the clinical situation.

During angiography contrast media (CM) induce changes in vessel tone. The pathophysiological reasons for this are poorly understood. In this short review the anatomical structures and physiological factors involved in vessel tone are described, and previous and recent findings in vitro and in vivo concerning the effect of CM on vessel tone are discussed.

Although multifactorial, the main effect seems to result from a direct action of the CM on the vessel wall. For a particular CM formulation, the effect is due to a combination of its osmolality, molecular properties as well as electrolyte content. In vitro experiments performed in iso-osmolar solutions of pure CM suggest that CM interfere with the cellular mechanisms controlling intracellular calcium. When injected intravascularly, CM may cause either vasodilatation or vasoconstriction. Vasodilatation is the most frequent effect when a CM is injected into a vessel while vasoconstriction is relatively uncommon. Both vasodilatation and vasoconstriction can be caused by all types of CM.

This paper reviews the basic mechanisms of the thrombohemorrhagic balance, and ways in which contrast media (CM) influence these processes. Coagulation and platelet functions are strongly inhibited by ionic CM, but weakly so by nonionic CM, whereas the former are more detrimental to endothelium, and thus thrombogenic in this sense. Some observations indicate a lower rate of thromboembolic events with the ionic CM in percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), but this purported difference does not affect mortality or frequency of re-PTCA and emergency CABG. Thus, to challenge these events, strong acting antithrombotics, which also, unlike heparin, inactivate fibrin-bound thrombin, are necessary. Aggressive anti-atherogenic prophylaxis may hamper both thrombosis and reocclusion. The ideal antithrombotic in this setting is yet to be found.

We confirm that the phenomenon of platelet degranuation exists for both iohexol and diatrizoate, as reported earlier. In contrast to previous conclusions, however, we have determined that the degranulation is independent of the nonionic vs. ionic nature of the media per se, since degranulation was neither seen with nonionic iodixanol nor ionic ioxaglate. The degranulation, further, does not significantly augment platelet function, as measured by flowing whole blood platelet aggregometry.

A review of the literature on the influence of contrast media (CM) on fibrinolysis showed that information currently available is contradictory, inconclusive and fragmentary. Results of some in vivo studies suggest that both ionic and nonionic CM increase fibrinolytic activity, either by lowering plasma plasminogen activator inhibitor 1 levels, by releasing endogeneous tissue plasminogen activator and/or by altering the fibrin meshwork of thrombi. Most in vitro studies on the subject contain results that are contradictory to those from in vivo studies. The discrepancies are due to obvious differences between systems which are, at best, only comparable under conditions of stagnant flow. Thus, great care should be exercised when extrapolating or interchanging data obtained in vivo and in vitro.

Contrast medium- (CM) induced nephropathy may be evident from symptoms ranging from acute renal failure to minor changes in tubular function tests. While the incidence is usually low, it increases with the presence of risk factors and when arterial injections are made. The pathogenesis is not fully understood. No specific therapy exists, but in most cases it can be prevented by ensuring that the patient is well hydrated prior to injection of CM.

The extended phase I study with iodixanol (Visipaque) included detailed investigations on its renal effects. No changes in glomerular filtration rate (GFR) were found. Even though enzymuria was less pronounced after injection of iodixanol than after various monomeric CM, a somewhat higher degree of intrarenal retention of CM was observed on CT examination of the kidneys after iodixanol. In nondiabetic patients suffering from severe renal failure, angiography with either iodixanol or iohexol caused no changes in GFR, or in urinary excretion of protein and enzymes. However, a higher degree of contrast retention than that seen in healthy volunteers was found.

The intravenous use of roentgen contrast media (CM) is associated with a low incidence of renal impairment. This paper considers the intravascular handling and retention of CM in relation to effects on renal function – specifically the ability of the kidney to reabsorb and catabolise low molecular weight proteins.

Renal morphology following experimental administration of a high dose of an isotonic dimeric CM (iodixanol at 3 g I/kg) in rats showed numerous, large, protein-containing vacuoles or droplets in the cells of the proximal convoluted tubule. These were fully formed within 3.5 hours. The process of vacuole-formation involving the uptake of CM appears to be analogous to dextran uptake that occurs via fluid phase endocytosis. These vacuoles or CM droplets are abundant for 7 days but then slowly decline over several weeks. The quantitative recovery of ¹⁴C iodixanol (3 g I/kg) from the kidney between 3.5 hours to 7 days after administration was about 1% of the dose, with some 0.2% of the original dose still present at 28 days. Subcellular analysis to determine the site of the radiolabel showed that the ¹⁴C was associated with lysosomal marker enzymes.

The CM-induced vacuoles/droplets are most probably giant lysosomes, which contain the intracellularly retained CM. Co-administration of tracer doses of ¹²⁵I-labelled cytochrome C with iodixanol showed some impairment of low molecular weight protein reabsorption, but remarkably this process was not affected when the vacuoles were fully formed. The conspicuous morphology of the vacuoles, the CM retention and the transient proteinuria and enzymuria cannot presently be associated with any functionally significant impairment of tubular or cellular processes.

The effects of the new nonionic dimeric hexa-iodinated contrast medium (CM) iodixanol on renal function and morphology were investigated in 7 independent studies in rats, rabbits and monkeys and compared with other iodinated CM.

No significant effect on serum creatinine levels was seen at doses up to and including 5 g I/kg in rats and 10.5 g I/kg in rabbits. An immediate and transient increase in proteinuria was found in rabbits when 10.5 g I/kg was administered as a bolus, and when 12.5 g I/kg was administered as a slow infusion in a comparative study with several CM. Increased serum elimination half-life was shown by measuring serum iodine concentrations after the infusion of 12.5 g I/kg. The effect of a high dose of iodixanol on proteinuria and elimination half-life were in this study in the same range as those of the monomeric nonionic CM, but less pronounced than those of the monomeric ionic CM. Reduced renal capacity was induced in male rats by performing unilateral nephrectomy 4 weeks before i.v. injection of iodixanol or iopamidol (2 g I/kg). The administration of CM did not affect renal function monitored as serum concentrations of creatinine and urea. The vacuolation of renal proximal tubular cells and kidney iodine retention were investigated in rats 48 hours after administration of different doses of iodixanol or iotrolan. The no-effect level for vacuolation was 0.5 g I/kg for both CM. Iodine retention was higher in male than female rats, and was higher for iodixanol than iotrolan at the 2 highest dose levels (3 and 5 g I/kg). No difference in iodine retention was found at the other dose levels (0.25–1 g I/kg). The reversibility of renal proximal tubular vacuolation after administration of iodixanol was studied in male rats (1.2 g I/kg) and monkeys (1.2 and 3.6 g I/kg). The vacuolation was more pronounced in rats than in monkeys. Vacuolation was completely reversed in all rats 3 weeks after dosing, and in 2 of 3 monkeys 3 days after a dose of 1.2 g I/kg. The degree of vacuolation evident in renal percutaneous biopsy specimens from monkeys 14 days after i.v. administration of iodixanol at a dose of 3.6 g I/kg was not significantly different to that in control animals.

In conclusion, iodixanol affected renal function to the same degree as did the nonionic monomeric and dimeric comparative media, but to a lesser degree than the ionic monomers. The degree of renal proximal tubular cell vacuolation induced by iodixanol seems to be species-dependent, being less pronounced and more quickly reversed in monkeys than rats.

Proximal and distal tubular cells in culture have been exposed to various roentgen contrast media (CM) at concentrations of 0 to 100 mg I/ml for 22 hours to study cellular mechanisms that may be involved in CM-induced nephropathy. The effects on cell morphology were assessed by electron microscopy and cell viability was evaluated. Levels of brush border and lysosomal marker enzymes in the culture medium were assayed biochemically.

Morphological examination showed that CM induced a concentration-dependent formation of large cytoplasmic vacuoles in both cell lines. Cellular damage was observed more frequently after exposure to low-osmolal rather than the iso-osmolal CM iodixanol; the low-osmolal CM causing more cell death and inhibiting cellular growth to a greater degree than did iodixanol.

In cultures of both cell lines the CM produced a concentration-dependent increase in brush border marker enzyme activity. While an increase in lysosomal enzyme activity was seen at low concentrations, a decrease in activity occurred at high concentrations.

Earlier investigations have demonstrated that the nonionic CM have less pronounced effects on the cell lines studied than ionic CM. The results presented here indicate that the effects of the iso-osmolal nonionic CM (iodixanol) on both the investigated cell lines are less marked than those of the low-osmolal nonionic CM investigated.

A review is given of the development of the water-soluble contrast media (CM) with particular attention to the frequency of neurological complications. A remarkable improvement was achieved following the introduction of the nonionic agent metrizamide in 1974, and a further decrease in neurotoxicity was obtained with the newer nonionic monomers, which have multiple hydroxyl groups included at different sites of the molecule. Theoretical considerations and experimental studies suggest that the neurotoxicity of the new nonionic dimeric agents should be at least within the low range seen with the monomeric ones, but further experience is needed before definite conclusions can be drawn in this respect.

The mechanisms responsible for the neurological complications seen with CM are unknown but certain critical groups on the CM molecules are known. Several animal models have been developed, which may help predict the degree of neurotoxicity.

An attempt was made to assess the usefulness of using an animal model to predict the neural tolerability in man of iodinated contrast media (CM) in general, and of the new nonionic dimer iodixanol in particular. For this purpose, the results from 6 animal experiments evaluating excitative and depressive effects of subarachnoidally injected CM in nonanesthetized rabbits were compared with the results from 22 randomized double-blind clinical trials dealing with post-myelographic adverse reactions. Comparisons were made as regards the nonionic monomers metrizamide, iohexol, and iopamidol, and the dimer iotrolan.

The results seem to justify the conclusion that the convulsive effects of CM can be reliably predicted from animal experiments. The animal model cannot be used to predict specific types of nonconvulsive adverse reactions in man, but reflects well the differences in frequencies of minor reactions following clinical myelography with different nonionic CM. In general, the neural tolerability of iodixanol may be expected to be better than that of the nonionic monomers and approximately equal to that of iotrolan.

The neural tolerability of iodixanol has been assessed in studies in mice and dogs. The animals received up to 4 injections in the cisterna cerebellomedullaris while under light anesthesia. Iotrolan was included as a reference substance in 1 study. The observations comprised assessment of clinical behavior, cerebrospinal fluid analysis, hematology, clinical chemistry and/or macroscopic and microscopic examination at necropsy. In addition, the repeated-dose dog study, urinalysis and ophthalmoscopy were performed, electrocardiograms obtained, and respiratory rate, blood pressure and rectal temperature measured.

Clinical signs and minor pathological changes caused by the injection procedures were seen in all studies in some animals treated with iodixanol as well as in control animals. Single (2.0 g I/kg) and repeated (0.960 g I/kg) intracisternal administration of iodixanol to mice caused no significant toxicological effects. Two dogs treated with a high dose of iodixanol (0.256 g I/kg; 0.8 ml/kg) had pathological changes (meningeal inflammation and/or necrosis) that were more severe than those observed in control dogs. Single and repeated intracisternal administration of 0.128 g I/kg (0.4 ml/kg) of iodixanol to dogs, however, caused no significant toxicological effects. Apart from the findings in the 2 dogs, the neurological and neuropathological changes elicited by iodixanol were similar to those induced by control or reference substances.

The results from these intracisternal toxicity studies in mice and dogs indicate a significant margin of safety regarding the use of iodixanol in clinical intra-thecal indications.

The detection and quantification of altered intestinal barrier function (intestinal permeability) have been addressed frequently during the last years, but the tests available for determination of intestinal permeability are both flawed and have limitations.

The new water-soluble roentgen contrast media (CM) of low- and iso-osmolar type have been proposed as intestinal permeability probes. In this article this possible new application for water-soluble CM is discussed in terms of their inherent properties and the experimental and clinical results obtained so far. The 2 iso-osmolar dimers, iodixanol (Visipaque) and iotrolan (Isovist), seem to be as good as the well-documented radio-labeled permeability probe ⁵¹Cr-EDTA in detecting injury of the intestinal mucosal barrier. The CM offer the advantage of allowing direct control of bowel wall exposure with the aid of fluoroscopy. Current permeability probes lack this quality. Iodine-containing substances may be analyzed by the rapid, simple and reliable X-ray fluorescence technique, which is suitable for application in routine clinical practice.

We conclude that the new water-soluble roentgen CM have properties which may be of use in the diagnosis and quantification of altered intestinal barrier function.

Absorption and excretion of iodixanol 320 mg I/ml were investigated in rats after intragastric administration of 2.5 g I/kg b.w.

Animals were observed for up to 96 hours after treatment, and blood, urine and feces taken at several time-points throughout the experiment. Concentrations of iodixanol in serum and urine were measured by means of reversed-phase high-performance liquid chromatography. Fecal concentrations of iodixanol, based on iodine measurements, were determined by X-ray fluorescence spectrometry. Serial radiographs were obtained and histopathological examination was performed on selected tissues.

The results indicate that less than 1% of the intragastric dose of iodixanol is absorbed from the intestine into the blood stream. No adverse clinical signs were observed, and there were no treatment-related histomorphological findings.

Contrast media (CM) given orally for roentgen examination of the upper gastrointestinal tract may inadvertently enter the lungs. The present paper describes the local effects on the lungs of rats after a single intratracheal instillation of the nonionic, isoosmolar, dimeric CM iodixanol and iotrolan, and the ionic, hyperosmolar, monomeric CM diatrizoate. Hydrochloric acid (HCl) and saline were included as positive and negative controls, respectively. The test compounds were given by intratracheal instillation to anesthetized rats at dose volumes of 0.5 ml/kg b.w. The animals were killed 6 hours, 24 hours or 7 days after dosing, and the trachea and lungs subjected to histopathological examination. Acute signs of dyspnea were observed in 7 out of 15 animals that received HCl. No clinical signs could be related to treatment with any of the CM. Histomorphological assessment of the respiratory tract did not reveal any CM-related adverse effects, whereas animals treated with HCl showed marked histopathological changes.

The results indicate that accidental exposure of the respiratory system to iodixanol, iotrolan or diatrizoate is unlikely to cause any significant tissue damage or lead to respiratory complications.

The results are reviewed from 18 European clinical vascular studies in 1950 patients where iodixanol (Visipaque) – a new isotonic, dimeric, nonionic contrast medium (CM) – is compared to other CM.

Visipaque gave better patient comfort, i.e., less pain and heat sensation after vascular injections than the comparative CM. Adverse events reported after Visipaque were otherwise similar to nonionic CM but lower than after ioxaglate (Hexabrix) and other ionic CM. Human renal safety of Visipaque has been extensively studied. Only small changes in glomerular filtration rate and serum creatinine were measured with the monomeric nonionic CM as well as with Visipaque. The excretion of marker enzymes for renal tubular cell function was generally lowest for Visipaque. Thus Visipaque was highly tolerable in the kidneys. To study cardiac safety, electrophysiological and hemodynamic changes were recorded. Visipaque had generally no electrophysiological or hemodynamic effects, or less pronounced effects compared to the other CM. Radiograms revealed that Visipaque 320 mg I/ml yielded the same attenuation as 350 to 370 mg I/ml of the other CM and, similarly, 270 mg I/ml of Visipaque gave as good visualization as 300 mg I/ml of comparative CM.