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The expression of P-selectin was more upregulated following the exposure to nonionic low osmolar contrast agents than to ionic contrast agents. Exposure to nonionic contrast agents led to a marked adhesion of leukocytes to endothelial cells. Thrombomodulin activity of endothelial cells was decreased, and plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor (TNF) alpha in the supernatant were increased when leukocyte adhesion occurred after exposure to nonionic contrast agents. Results suggest that the adhesion of leukocytes to the endothelium increases procoagulant activity.

Angiographic contrast media (CM) may cause both vasodilatation and vasoconstriction, effects that can only be partly be explained by the media's hyperosmolality. The present study describes a CM-induced vasoconstriction of isolated rabbit coronary arteries that depends on chemotoxicity and ion content of the CM. Rings of arteries were mounted in tissue baths and the constrictions induced by different CM were measured. Iotrolan and iodixanol (non-ionic dimers) caused the most powerful constrictions followed by iohexol (non-ionic monomer) and mannitol. Ioxaglate (ionic dimer) and diatrizoate (ionic monomer) caused no or weak constrictions. By comparing these findings with previous studies, it is concluded that non-ionic media cause vasoconstriction due to depolarization of the smooth muscle cells, an effect that for iohexol can be counteracted by addition of 30 mM NaCl. The ionic media seem to cause hyperpolarization of the cells. This difference between non-ionic and ionic CM might be one of the reasons for the lower tendency of non-ionic CM to cause vasodilatation clinically.

The neural tolerance of the new non-ionic dimer iodixanol was compared with that of the clinically used monomer iohexol and the dimer iotrolan. Behaviour of non-anaesthetised rabbits was monitored for 3 hours after intracisternal injection, at a dose-volume of 1 ml/kg of iodixanol 150 mg I/ml, iodixanol 320 mg I/ml, iohexol 350 mg I/ml, or iotrolan 300 mg I/ml (10 rabbits in each group). Iotrolan induced generalized seizures in 5 rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits injected with iohexol, but compared with the dimeric contrast media the difference was not significant. Iohexol produced significantly more severe depressive changes than iodixanol 150 mg I/ml (p < 0.01), iodixanol 320 mg I/ml (p < 0.05), and iotrolan 300 mg I/ml (p < 0.05). The results indicate that the excitative neurotoxic potential of the dimer iodixanol is likely to be lower than that of the clinically used dimer iotrolan, but slightly higher than that of iohexol. It may be expected that both dimers will produce a lower frequency of minor neurological adverse reactions than iohexol.

Rationale and Objectives: The authors compared the effects of a nonionic monomeric, iohexol (Omnipaque, 300 mg I/ml), and a nonionic dimeric, iotrolan (Isovist, 300 mg I/ml), contrast medium in the spinal subarachnoid space of the pig., Methods: Lumbar and lateral C1-C2 punctures were performed in 10 pigs. Ten milliliters iohexol or iotrolan were injected via the lumbar needle. Blood pressure, electrocardiogram, intravesical pressure, and cerebrospinal fluid pressure were recorded during the injections and at intervals for 4 to 5 hours after the injections. Blood samples were taken at 30, 60, 120, 180, 240, and 300 minutes after the injections and analyzed for iodine concentration., Results: No changes were seen during the injections, and there were no differences in the blood pressure, cerebrospinal fluid pressure, electrocardiographic recordings, or in the plasma iodine concentrations during the first 4 to 5 hours after the injections. Short-lasting, rhythmic bladder contractions were seen during some injections with both iohexol and iotrolan., Conclusion: Both iohexol and iotrolan were well tolerated, and there was no significant difference between them. and there was no significant difference between them.

Rationale and Objectives: Bronchospasm is occasionally observed following iodinated X-ray contrast medium administration. We performed an in vivo study in guinea pigs to investigate the effects of a number of iodinated contrast media on pulmonary airway resistance and the mechanisms underlying the potential bronchoconstrictor effect., Methods: The contrast media studied were the pharmaceutical formulations of iomeprol (400 mg I/ml), iopamidol (370 mg I/ml), and iohexol (350 mg I/ml), which are nonionic, triiodinated contrast media; diatrizoate (370 mg I/ml), an ionic, triiodinated contrast medium; iotrolan (300 mg I/ml), a nonionic, hexaiodinated contrast medium; and iocarmate (280 mg I/ml) and ioxaglate (320 mg I/ml), which are both hexaiodinated and ionic contrast media. Each contrast medium was administered intravenously at 2 g I/kg. Changes in pulmonary airway resistance were evaluated by measuring intratracheal pressure at the moment of maximum insufflation, or maximal insufflation pressure (MIP), in anesthetized guinea pigs submitted to forced ventilation., Results: All contrast media except ioxaglate caused mean increases of MIP of no more than 20%. By contrast, ioxaglate caused a marked bronchoconstrictor effect, increasing MIP by 242% +/- 46%. Of the drugs tested for antagonistic action on this increase in MIP, salbutamol inhibited almost completely the increase in MIP for the first 40 min posttreatment. Similarly, lysine acetylsalicylate and indomethacin consistently reduced MIP after contrast media administration to levels only 30% and 14% above those of baseline precontrast media, respectively. Promethazine had only a minor inhibitory effect, and the response to prednisolone varied., Conclusion: There was no apparent relationship between the size of the increase in airway resistance and the charge or molecular weight of the contrast agent molecule or the pharmaceutical formulation. The increase induced by ioxaglate must be attributed to inherent molecular toxicity mediated through a direct action on the production of bradykinin and/or the prostanoid products of the cyclooxygenase pathway, rather than through a direct action on the release of histamine.

Purpose: To evaluate the platelet activation and aggregation produced by ionic high-osmolality contrast media (HOCM) and both ionic and nonionic low-osmolality contrast media (LOCM)., Materials and Methods: After each agent was mixed with heparinized blood, sequential platelet counts were used to monitor platelet aggregation, and flow cytometry was used to monitor both aggregation and activation. Aggregation was measured with CD41a-FITC (specific for glycoprotein IIb-IIIa) and activation was measured with CD62-PE (specific for P-selectin)., Results: High concentrations of the nonionic LOCM (> 31% by volume in whole blood) induced more than 90% platelet activation within 2 minutes of exposure to freshly drawn heparinized whole blood. Aggregation followed immediately after activation and was somewhat reversible. High concentrations of the ionic HOCM (> 31%) induced prominent activation, although it occurred at a much slower rate and to a lesser degree than with the nonionic media. There was approximately 70% activation after 45 minutes of exposure. Ionic HOCM inhibited platelet aggregation, however. The ionic LOCM ioxaglate produced minimal or no platelet aggregation or activation., Conclusion: There is likely to be an agent-related difference in the risk of platelet activation and aggregation in the catheter lumen and in the immediate environment of the catheter tip, where high concentrations of contrast media are known to exist.

In the present series of studies we investigated differences in vitro and in animal experiments between iopamidol (Iopamiron, CAS 60166-93-0) and ioversol (CAS 87771-40-2). The studies included the in vitro investigations partition coefficient, lysozyme inhibition, coagulation time and erythrocyte morphology as well as the in vivo paradigms acute toxicity, neural toxicity, general behavior/locomotor activity and angiography. Iopamidol was superior to ioversol in most of the tests. In spite of its higher hydrophilicity, ioversol did not show improved tolerance in comparison to iopamidol.

Even at its highest concentration, 320 mg I/ml, Visipaque - based on the nonionic dimer iodixanol - is isoosmotic 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 the solution is isoosmotic to plasma does not necessarily mean that it is isotonic to plasma. An isoosmotic 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.

Nineteen children received 99mTc-DTPA for renography. The next day they received a simultaneous injection of the non-ionic contrast medium iopentol for urography and another injection of 99mTc-DTPA. The glomerular filtration rate (GFR) was estimated from the plasma elimination of 99mTc-DTPA as well as iopentol. Serum concentrations of creatinine and beta 2-microglobulin, and urine concentrations of creatinine, beta 2-microglobulin, alkaline phosphatase, N-acetyl-glucosaminidase, and albumin were determined. A significant reduction (12 +/- 3%) of GFR was observed after the injection of iopentol, without a subsequent rise in serum creatinine or beta 2-microglobulin. The urinary excretion of albumin and beta 2-microglobulin remained unchanged, while the excretion of alkaline phosphatase and N-acetyl-glucosaminidase was significantly increased after the urography, indicating some tubular effects of iopentol. Iopentol caused few and mild adverse events, the diagnostic yield was high, and the small changes in the renal tubular function parameters are presumed to be without clinical importance. The observed depressive effect on the GFR demands further investigations before iopentol can be recommended as a GFR-marker in children.

Systemically administered iodinated angiographic contrast media evoke vasodilatation through mechanisms that are at present poorly understood. In the current investigation we have evaluated the role of the vascular endothelium in responses to an iso-osmolar formation of the non-ionic dimer iodixanol and a hyperosmolar formulation of the non-ionic monomer iopromide. Isolated rabbit aortic ring preparations with endothelium intact or removed by gentle abrasion were mounted in organ baths containing oxygenated Holman's solution, and cumulative concentration-response curves for relaxation to the contrast media were constructed after pre-constriction by phenylephrine (300 nM) in the presence of indomethacin to inhibit prostaglandin synthesis. Endothelial denudation did not influence the ability of either iodixanol or iopromide to relax the aortic ring preparations. Iopromide was significantly more potent than iodixanol when expressed in terms of iodine concentration (mg I ml-1), but both agents were equipotent when expressed in terms of molarity (mM). We conclude that relaxation of isolated rabbit aortic rings to iodixanol and iopromide under conditions where there is no fluid flow is endothelium-independent, and therefore not mediated by release of the potent endogeneous nitrovasodilator endothelium-derived relaxing factor (EDRF). Furthermore, their relaxant activity under the in vitro experimental conditions employed is attributable to a direct action on vascular smooth muscle by factors in addition to osmolality, and may depend on features that are not specifically associated with the presence of the iodine atom.

Rationale and Objectives: Iodixanol, a dimeric, nonionic X-ray contrast medium, has been formulated at 320 mg iodine per milliliter and supplemented with Na+, Ca2+, and Cl- to produce an osmolality that approximates that of plasma. We compared the effects of left main coronary artery injections of iodixanol, ioxaglate, and iopamidol on cardiac mechanical function in dogs., Methods: Six mixed-breed dogs were anesthetized and prepared for recordings for electrocardiogram, aortic and left ventricular pressures, and the first derivative of left ventricular pressure, dP/dt. The test solutions and saline were injected into the left coronary artery in a randomized order. The series of four injections were repeated three times in each animal for a total of 12 injections per dog., Results: Iodixanol caused significantly lower (p < .05) reduction in peak left ventricular pressure (-1.7 +/- 0.9% vs -0.7 +/- 2.0%), in diastolic aortic pressure (-1.3 +/- 1.1% vs -9 +/- 1.3%), and in left ventricular dP/dt (0.3 +/- 1.3% vs -13.2 +/- 2.4%) than did ioxaglate. Iodixanol also produced smaller cardiovascular effects than did iopamidol, but the differences were not statistically significant. Injections of both iopamidol and ioxaglate caused significant decreases from baseline parameter values; however, the changes with iodixanol were not significant., Conclusion: The isotonic formulation of iodixanol caused smaller cardiovascular hemodynamic effects than did iopamidol and ioxaglate and may offer increased safety in patients with severe cardiac disease.

Rationale and Objectives: Differences in leukocyte phagocytosis following exposure to different classes of radiographic contrast media (RCM) may help in the development of less toxic alternatives and be useful as a guide to contrast selection in certain patient groups. The effect of RCM on leukocyte phagocytosis of Escherichia coli was examined., Methods: Cell population phagocytosis and individual cell phagocytic activity were assessed in a control group and in samples exposed both to the ionic RCM diatrizoate and ioxaglate and to the nonionic RCM iohexol and iotrolan by using a flow cytometer., Results: The percentage of granulocytes undergoing phagocytosis was 88.4% in the control population. Following exposure to RCM, this value fell to 79.2% with iohexol, 77.6% with iotrolan, 70.5% with diatrizoate, and 68.7% with ioxaglate. The number of bacteria phagocytosed by active leukocytes was not affected by RCM., Conclusion: RCM adversely affect the percentage of granulocytes involved in phagocytosis but not the number of pathogenic bacteria that are phagocytosed by individual granulocytes.

Rationale and Objectives: In this study, the cardiac and hemodynamic effects of iopromide alone were compared with those of two combination preparations (iopromide plus sodium and iopromide plus the prostacyclin analog iloprost) and with ioversol after left ventricular bolus administration in rats., Methods: The tracheae of anesthetized male Wistar rats were cannulated to facilitate spontaneous respiration. The animals were set up to allow recording or calculation of the following parameters: femoral arterial blood pressure (systolic, mean, and diastolic), left ventricular end-diastolic pressure, heart rate, and contractility. Iopromide (330 mg iodine/mL; 2 g iodine/kg) with or without sodium chloride (20 mmol/L) or iloprost (approximately 50 ng/mL; dose: 300 ng/kg) was injected into the left ventricle within 30 seconds. Ioversol (320 mg iodine/mL) was used at the same dose and injection rate., Results: Iopromide and ioversol induced transient changes in blood pressure (decrease followed by an increase), left ventricular end-diastolic pressure (increase), heart rate (decrease), contractility (increase followed by decrease), and electrocardiogram (extrasystoles, ST depression). Ioversol exhibited more pronounced effects on contractility and ST depression. The differences were statistically significant. The addition of sodium to iopromide resulted in a slight, but not significant influence on cardiac or hemodynamic parameters. The addition of iloprost improved ST depression slightly and hemodynamics significantly resulting in less mean and end-diastolic blood pressure change and less heart rate decrease. Contractility was significantly increased compared with iopromide with or without sodium., Conclusions: The addition of sodium or iloprost to nonionic contrast media might be useful in the alleviation of cardiac and hemodynamic side-effects.

1. The involvement of endothelin in the renal responses to radiocontrast media was examined in the rat in vitro and in vivo using BQ123, a selective endothelin (ETA) receptor antagonist, and phosphoramidon, an endothelin-converting enzyme inhibitor. 2. For experiments in vitro, an isolated perfused rat kidney was employed perfusing in closed circuit with an albumin-based Krebs-Henseleit solution. The effects of BQ123 and phosphoramidon on the renal responses to iotrolan (iso-osmolar radiocontrast media) and diatrizoate (high-osmolar radiocontrast media) were examined. In vivo, renal conductance was measured using a Doppler flow probe in the anaesthetized rat pretreated with indomethacin, and the effects of BQ123 and phosphoramidon on the renal response to intravenous diatrizoate were examined. 3. In vitro, iotrolan and diatrizoate both produced a biphasic effect on the glomerular filtration rate, characterized by a transient increase followed by a sustained fall. Pretreatment with BQ123 (10 mumol/l), but not phosphoramidon (1 mmol/l), prevented both the increase and the sustained fall in glomerular filtration rate induced by radiocontrast media. 4. In vitro, iotrolan and diatrizoate both produced a sustained fall in renal perfusate flow. An initial increase in renal perfusate flow was only observed with diatrizoate. Pretreatment with BQ123 (10 mumol/l), but not with phosphoramidon (1 mmol/l), markedly inhibited the sustained fall in renal perfusate flow produced by both iotrolan and diatrizoate. BQ123 (10 mumol/l), however, markedly potentiated the renal vasodilatation produced by diatrizoate.(ABSTRACT TRUNCATED AT 250 WORDS)

The systemic and pulmonary haemodynamic effects of i.v. infusion (1 ml/s) of high doses (4 ml/kg) of 2 non-ionic, isoosmolar dimeric contrast media (CM) were investigated in 17 female pigs. The 2 CM were iodixanol and iotrolan. Both CM induced a significant increase of the following parameters: mean arterial, mean right atrial, mean pulmonary arterial, mean pulmonary arterial occlusion pressure, cardiac output, stroke volume, and diuresis. The plasma concentration of atrial natriuretic peptide was significantly increased following infusion of the 2 CM. A significant decrease was seen in the systemic and pulmonary vascular resistance.

Rationale and Objectives: Radiologic contrast media (CM) may influence processes of coagulation and fibrinolysis. In the current study, the effects of various CM on the formation of plasmin were examined in an in vitro buffer system., Methods: The effects of three clinically relevant concentrations of seven different iodine-containing CM and gadolinium-DTPA on streptokinase (SK) or recombinant tissue plasminogen activator (rt-PA)-induced plasmin formation was monitored using a plasmin-sensitive chromogenic substrate., Results: Contrast media generally had an inhibitory effect at the plasminogen activation step; this effect was particularly noticeable with the ionic CM., Conclusions: Contrast media influence plasminogen activation by SK and rt-PA in vitro. Ionic CM have a more pronounced inhibitory effect than the nonionic media. The ionic Gd-DTPA shows a less inhibitory effect than the ionic iodine-containing CM. However, they must be regarded separately because of the different chemical composition of the magnetic resonance imaging and x-ray CM.

Iodixanol, a new ratio 6 nonionic iodinated contrast agent with an osmolality equal to serum, was compared with iohexol in a randomized, double-blind, parallel study. Two hundred patients undergoing elective diagnostic cardiac angiography were randomized to iodixanol (n = 101) or iohexol (n = 99). There were no differences noted between the 2 agents in the mean changes in systolic or diastolic blood pressure or heart rate during or immediately after any angiography. However, significantly more patients had a decrease in diastolic blood pressure of > 20 mm Hg during left coronary angiography with iodixanol. The only significant differences in any electrophysiologic parameter were slightly more PR prolongation during left coronary angiography with iodixanol and more ST-segment depression with iohexol during coronary angiography. Neither was clinically significant. Injection-associated discomfort occurred with both agents, but more patients experienced moderate to severe discomfort with iohexol (52%) than with iodixanol (17%) (p < 0.001). Only 1 potentially serious adverse event, ventricular fibrillation with iohexol, was considered related to contrast, and there were no differences noted between the agents. Overall, angiographic quality was equal with all angiograms being assessed as good or excellent in both groups (p = 0.885). In this low-risk population undergoing cardiac angiography, iodixanol is safe and effective without clinically important differences from iohexol. Additional studies in patients at high risk for complications should help further define the role of iodixanol in cardiac angiography.

A prospective double-blind randomized cardioangiographic study with iopentol and iohexol was performed in 60 patients. Glomerular filtration rate (GFR) was assessed by serum values of creatinine and beta 2-microglobulin (beta 2-MG), estimated creatinine clearance (CCr) according to Cockroft & Gault's formula, and 24 hour CCr. The urinary excretion of albumin, beta 2-MG, and of the renal tubular enzymes alkaline phosphatase (ALP) and N-acetyl-beta-glucosaminidase (NAG) was also measured. Contrary to what has been found after i.v. injections, GFR was reduced by both nonionic contrast media. Serum creatinine (S-Cr) was increased by more than 25% in 6 patients, 3 in each group. CCr was more sensitive than S-Cr and S-beta 2-MG, but this method is less precise because of risk of urine sampling errors. Estimated CCr gave no additional information to S-Cr. The urinary excretion of NAG and ALP was increased. No clinically significant differences between iopentol and iohexol were detected. No correlation was found between the changes in tubular function parameters and changes in GFR. Twenty patients were on calcium channel blockers before the investigation, but this had no protective effect on the renal function parameters.

Rationale and Objectives: The purpose of this study is three-fold: 1) to quantify the cardiorespiratory responses to rapid right atrial injections of meglumine/sodium diatrizoate, ioxaglate, iotrolan, and iopamidol; 2) to compare the effects of each contrast medium to that of its corresponding vehicle and saline; and 3) to evaluate the role of the vagus nerve in the cardiorespiratory responses., Methods: Seventeen anesthetized dogs, breathing spontaneously, were used. Injections of 2.0 mL/kg were given into the right atrium in 2 seconds. Each contrast medium, along with its vehicle and saline, was tested on 4 dogs (5 dogs for diatrizoate). Blood pressure, air flow, tidal volume, upper airway pressure, esophageal pressure, mean arterial pressure and heart rate, breathing frequency, dynamic lung compliance, upper airway resistance, and total lung resistance were recorded or calculated., Results: Diatrizoate and its vehicle caused a significant increase in blood pressure, tidal volume, esophageal pressure, and a decrease in mean arterial pressure with an increase in heart rate. These responses were not mediated by vagal afferents. Ioxaglate and iotrolan, but not their vehicles, increased breathing frequency; this response was abolished by vagal block. Ioxaglate decreased mean arterial pressure and increased heart rate; the decrease in mean arterial pressure was still present during vagal block. Iopamidol and its vehicle did not alter respiratory parameters. Iopamidol, but not its vehicle, caused only a minimal and transient increase in mean arterial pressure before and during vagal block. None of the contrast media changed upper airway resistance, total lung resistance, and dynamic lung compliance., Conclusion: Both diatrizoate and its vehicle elicited the largest changes in respiratory and cardiovascular functions, not mediated by vagal afferents and caused by osmolality of the solution. Ioxaglate, iotrolan, and iopamidol induced smaller cardiorespiratory changes, mediated by vagal afferents. Their respective vehicles did not cause any effects, which suggests that the chemical structure plays a role. Nonionic contrast media elicited only minor and transient cardiorespiratory alterations.

Rationale and Objectives: Studies describing the effects of radiographic contrast media (RCM) in leukocyte chemotaxis have been contradictory. No studies have been performed after in-vivo exposure. The authors assess the effect of RCM on leukocytes following in-vivo exposure., Methods: Seventeen patients were studied after intraarterial bolus injection of 75 mL of iohexol (300 mg/mL) or iotrolan (300 mg/mL), 30 minutes and 24 hours postinjection; chemotaxis was assessed using an ex-vivo whole-blood under-agarose method., Results: With iohexol, there was a profound reduction in chemotaxis compared with the preinjection state (P = .001) at 30 minutes. No effect, however, was seen at 24 hours. With iotrolan, no significant reduction in chemotaxis was seen at 30 minutes or at 24 hours., Conclusions: Radiographic contrast media have differing effects on leukocyte chemotaxis. This may be of significance in the selection of appropriate RCM in certain patients.

Effects on circulating blood volume (CBV) of the intravenous injection of a nonionic contrast medium, ioversol, with various doses were assessed in order to find a way of injection with less effects on systemic circulation. Ioversol was injected as a bolus to 20 mongrel dogs at doses of A: 3.75 ml/kg (n = 8) or B: 2 ml/kg (n = 6) of a solution containing 320 mg iodine per ml, or C: 2 ml/kg (n = 6) of a 240 mgI/ml solution. Colloid oncotic pressure (COP) of the bloods drawn before and 1, 2, 3, 5 min after the injection of ioversol was measured by a needle type osmometer, and changes in CBV were calculated using the COP values. Upon injection of ioversol CBV increased rapidly and then gradually returned to the preinjection levels. The change in CBV induced by ioversol was significantly less than those reportedly induced by an ionic contrant medium, iothalamate, and a nonionic medium, iopamidol, and comparable to that by another nonionic medium, iohexol. The degree of increase in CBV and the blood concentration of ioversol were related to the amount, but not the volume, of ioversol injected. Thus, ioversol proved to be one of the low osmotic nonionic contrast media with less effects on CBV. Furthermore, it is suggested that the amount, rather than volume, of contrast medium should be taken into consideration when the angiography of the patients with reduced cardiac function, children or aged patients is performed in whom the contrast medium-induced CBV expansion needs to be as less as possible.

The recent need for selective bronchography during bronchoscopy in certain patients, together with paediatric indications for tracheo-bronchography, raises the question as to which contrast medium is both safe and efficient. The purpose of the present experimental study was to define the tissue reaction caused by iotrolan and iopamidol in the bronchi and lungs of rats. 60 animals used in this study were divided into five groups receiving iotrolan 300, iopamidol 370, iopamidol 150, physiological saline and anaesthetic only, the last two acting as control groups. Statistically there was no significant difference in the histological reaction between iotrolan 300, iopamidol 370 and iopamidol 150 compared with the control groups, although iotrolan 300 appeared to result in the least tissue reaction. With its adequately high iodine concentration, low osmolality and relatively high viscosity, iotrolan 300 would appear to be a suitable contrast medium for bronchography.

The effects of radiographic contrast media (RCM) on leucocyte orientation in vitro were studied using a Zigmond chamber. Leucocyte orientation was assessed following exposure of the leucocytes to iotrolan, iohexol, ioxaglate and diatrizoate. The RCM used were diluted to a concentration similar to that obtained in vivo during routine angiography. At this concentration there was a significant reduction in leucocyte orientation for all RCM investigated but the effect was more pronounced in the monomeric than the dimeric RCM. The results may have significance when deciding which radiographic contrast medium to use in selected patients, particularly those who are immunosuppressed or septicaemic.

Rationale and Objectives: The isotonic nonionic contrast medium iodixanol has been shown to increase urinary enzyme excretion less than the hypertonic contrast medium iopentol. The authors investigated whether this could be caused by different molar loads using enzyme excretion after diuretic administration as a model., Methods: Matching molar doses of mannitol were given to two groups of 10 healthy volunteers. Furosemide was administered perorally to a third group of 10 persons. Urinary enzyme excretion was sequentially measured, and the results were compared to our previous findings after contrast-media administration., Results: Equimolar doses of mannitol and contrast media (CM) induced similar changes in urine volume and free water clearance. Mannitol and furosemide increased the urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and alkaline phosphatase (ALP) in the period 0 to 4 hours after administration, i.e. during peak diuresis, whereas both CM increased ALP significantly more, their effects still evident at 24 to 48 hours. Iodixanol had no effect on urinary NAG excretion, but iopentol increased NAG more than did mannitol., Conclusions: The early effect of CM on urinary enzyme excretion can be related, in part, to the increased diuresis, but the late effect apparent at 24 to 48 hours cannot be explained by the osmotic load of the CM.

Iodixanol is a new non-ionic, dimeric contrast medium (CM) which is formulated to be isotonic with blood in all clinically relevant concentrations. This is a report of a parallel, double-blind study comparing the safety and efficacy of iodixanol with iopromide (Ultravist) in aortofemoral arteriography. One hundred consecutive, eligible patients scheduled to undergo peripheral arteriography were entered into the study and randomly allocated to receive one or other CM. Radiographic quality, discomfort, adverse events, femoral blood flow and renal function were examined. Ninety-five patients were successfully included in the study. Radiographic quality (efficacy) was found to be similar in both groups. Three patients (6%) in the iodixanol group and five patients (11%) in the iopromide group reported adverse events. In this respect there was no statistically significant difference between the two groups (P = 0.48), and all adverse events were mild and transient. Forty-six (97%) patients in the iodixanol group and 45 (100%) patients in the iopromide group experienced a sensation of warmth (discomfort) in connection with one or more of the injections. There was no statistically significant difference in the frequency of discomfort in the two groups. However, the intensity of warmth was significantly milder following iodixanol than after iopromide (P = 0.003, two-sided Mantel-Haenszel test). The mean percentage increase in femoral blood flow was found to be less with iodixanol (43.4%) than with iopromide (96.3%) (P < 0.05, Student's t-test). Renal function was affected slightly after administration of both CM. Serum creatinine and creatinine clearance were affected more by iodixanol than by iopromide, while the excretion of tubular enzymes was more affected by iopromide. In conclusion, this comparison between iodixanol and iopromide showed both contrast media to be safe, effective and well tolerated and the only major difference between them was in their effect on femoral blood flow.

The effect of i.v. injection of contrast media (CM, 1,600 mg I/kg b.w.) on proximal and distal tubular hydrostatic pressure (PTHP, DTHP) in the rat was investigated using a micropuncture technique. The PTHP and DTHP after injection of diatrizoate, iohexol, ioxaglate, or mannitol returned to control values within approximately 20 min. However, following iotrolan injection PTHP was still elevated above control levels after 35 min while DTHP remained elevated throughout the experiment (50 min). Iotrolan has a lower osmotic potential than the other CM when given in equivalent iodine doses. The concentration of iotrolan may thus increase more along the tubules than the other CM and consequently lead to a higher viscosity of urine, resulting in increases in PTHP and DTHP. The high intratubular pressure induced by iotrolan may explain our previous findings of reduced single nephron glomerular filtration rate caused by this CM.

The effects of slow (10 min) i.v. infusions of contrast media (CM, 1,600 mg I/kg b.w.) on single nephron glomerular filtration rate (SNGFR) in the rat kidney were investigated using a micropuncture technique. Diatrizoate, iohexol, or ioxaglate did not change SNGFR, although a tendency towards a transient suppression was seen during the infusion phase. Iotrolan infusion, however, decreased SNGFR (p < 0.05) and the value still remained below the control value 25 min after the start of infusion. Iotrolan is a nonionic dimeric CM and has a lower osmotic effect in the tubules than the ionic dimeric CM and the monomeric CM when given in iodine equivalent doses. These characteristics of iotrolan have probably some influence on the depression of SNGFR after iotrolan injection.

To study the mechanism of the pain produced by contrast media (CM) in peripheral arteriography, we examined the direct effects of low concentrations (1.85-100 mg I/ml) of CM (diatrizoate, iopamidol, ioxaglate, and iotrolan) on helically cut strips of canine blood vessels taken from six different regions. We found that: (a) low concentrations of CM induced vasoconstriction. (b) This occurred immediately after the application of CM and produced sustained constriction. (c) The constriction produced in arteries was dose-dependent. (d) The production and intensity of constriction in the arterial strips differed as follows: cranial mesenteric artery > renal artery > femoral artery > common carotid artery > thoracic aorta > coronary artery. The effects of the CM were, in order of magnitude: diatrizoate > iopamidol > ioxaglate > iotrolan. Differences between CM corresponded with the differences in osmolality of the CM solutions. (e) Low concentrations of meglumine and mannitol also produced vasoconstriction. (f) Constriction caused by all drug samples used was reversible, but the process of relaxation to the original tension was much slower in CM-treated arterial strips than in the other strips. From these results, we confirmed that the incidence and degree of vasoconstriction produced by all drug samples used in this experiment depended on solution osmolality, rather than on chemotoxicity or ionicity. We discuss the physiological mechanism of these results and stress the importance of CM hyperosmolality in vasoconstriction and vascular pain production.

The viscosity of 7 contrast media was measured using a rotational viscometer. When solutions with similar iodine concentrations were compared, the highest viscosities were found for the nonionic dimers iodixanol and iotrolan, the lowest for diatrizoate, iopamidol, and iopromide, and intermediate values for iohexol and ioxaglate. The viscosity of iohexol and ioxaglate was found to vary linearly with temperature and quadratically with concentration. Whole-blood viscosity was measured for 5 subjects at high and low shear rates before and after mixing with contrast media in various proportions. Low-shear viscosity was found to decrease and high-shear viscosity to increase with contrast medium concentration. It is concluded that the contrast media currently used may affect blood rheology less than previous agents, despite their higher viscosity.

The neutrophil granulocytes contain granules in which different proteins are present. When activated the neutrophils degranulate and thereby release some of these proteins to the surroundings. Some of these proteins are specific for this type of cell, e.g., lactoferrin and elastase. To investigate the influence of contrast media (CM) on this release, blood was incubated with diatrizoate, ioxaglate, iohexol, iodixanol, hyperosmolar saline, and hyperosmolar mannitol at different concentrations, and the amount of the neutrophil specific proteins lactoferrin and elastase were measured. Decreasing protein concentrations were observed for increased medium concentrations, suggesting that the degranulation process of the neutrophils was inhibited by the CM. The protein concentrations were lowest after incubation with the two ionic media diatrizoate and ioxaglate. Significantly decreased values of plasma lactoferrin were observed one min after i.v. injection of iohexol or ioxaglate in 82 patients undergoing urography. There was no significant difference between the two CM.

Different amounts of diatrizoate, ioxaglate, iohexol, iodixanol, NaCl 1,000 mOsm/kg, mannitol 1,098 mOsm/kg, and meglumine (meglumine concentrations corresponding to the content in the diatrizoate solutions) were added to either whole blood or a suspension of granulocytes in autologous plasma, and the adherence to nylon fibers was determined. At high concentrations all the investigated contrast media (CM) inhibited granulocyte adherence. The degree of inhibition was significantly greater when the ionic CM diatrizoate and ioxaglate were used, as compared with the nonionic media. Meglumine solutions at high concentrations also inhibited adherence but significantly less than diatrizoate solutions containing the same amount of meglumine. Diatrizoate showed the greatest inhibitory effect on granulocyte adherence, and significant inhibition could be detected even with a 1.25% solution.

Both ionic and non-ionic contrast media (CM) injected intra-arterially produce peripheral vasodilatation and a sensation of heat or even pain. This effect has been considered to be predominantly related to the osmolality of the CM used. Iodixanol is a non-ionic dimeric CM which can be made isotonic with blood at iodine concentrations up to 400 mg/ml. To assess the degree of peripheral vasodilatation following aortic injection of iodixanol, the change in femoral artery blood flow has been assessed non-invasively. Dupex ultrasound flow-velocity records were taken from the contralateral femoral artery in 10 patients undergoing transfemoral aortography. Volume flow, mean velocity, pulsatility index and peak systolic velocity were continuously recorded before and up to 2 min after injection of 60 ml of iodixanol at an iodine concentration of 320 mg/ml (iodixanol 320). Transient changes consistent with vasodilatation were observed in all patients. The greatest changes were observed during the time period 18-24 s after injection. Volume flow, mean velocity and pulsatility index all changed significantly from baseline (mean changes of 80.6%, 73% and -42.7% respectively). Peak systolic velocity did not change significantly. Intra-arterial injections of isotonic iodixanol 320 produces a significant increase in femoral blood flow in man. Factors other than hypertonicity must therefore be implicated in the vasodilatory effect of contrast media.

A new nonionic dimeric contrast medium (CM), iodixanol, was intravenously administered to 40 healthy male volunteers in doses of 0.3-1.2 g of iodine per kilogram of body weight, nonionic monomeric iopamidol and iopentol were administered to 20 others, and the renal effects were studied up to 120 hours after administration. Computed tomography of the kidneys was performed up to 80 hours after injection. Creatinine clearance as an index of the glomerular filtration rate was unchanged with all CM. Urine volume and osmolar clearance increased most with the monomeric CM. The proximal tubular brush border enzyme alkaline phosphatase increased with all CM. The lysosomal enzyme N-acetyl-beta-glucosaminidase increased more with the monomeric CM than with iodixanol. A persistent increased attenuation in the region of the cortex was observed with all CM. Attenuation returned to baseline within 80 hours, with the slowest decline with iodixanol. This delayed cortical enhancement did not correlate with the effects of the CM on the tubular enzyme excretion.

Iopentol (mean dose 0.42 g I kg-1) was administered for abdominal aortography and pelvic angiography in 10 patients with advanced non-diabetic chronic renal failure (S-creatinine 672 +/- 259 mumol l-1, mean +/- SD). Renal glomerular function measured as creatinine clearance and plasma clearance of [99Tcm]-diethyl-enetriaminepentaacetic acid (DTPA) was unchanged by iopentol, as also was urinary excretion of the renal tubular enzymes N-acetyl-beta-glucosaminidase (NAG) and alkaline phosphatase (ALP). The elimination of iopentol from serum and urine was delayed, and detectable serum and urine concentrations were found 5 days after administration of the contrast medium. Creatine clearance was 47% higher than the corresponding renal iopentol clearance. Plasma iopentol clearance, measured as the total area under the plasma concentration curve, was 40% higher than renal iopentol clearance because of extrarenal elimination of iopentol. We conclude that abdominal aortography with iopentol can be performed without effects on renal glomerular or tubular function parameters in patients with advanced renal failure. If iopentol is used for measurement of glomerular filtration rate (GFR) in this group of patients, one should measure renal clearance, as plasma clearance overestimates GFR.

The authors summarize the results of the main preclinical studies conducted to evaluate the tolerance of ioversol (Optiray), a new non ionic Low Osmolality Contrast Medium (LOCM). The various studies conducted by different routes of administration, in a number of animal species and at different dosages led to the conclusion that the product was equivalent or superior to the other non ionic agents used as references. This high inertia towards the biological systems particularly well evidenced in the neurologic tolerance studies has to be relied to the non ionic LOCM character of the agent but also to its highest hydrophilicity in its class and to the good distribution of this hydrophilicity around the molecule. These physiochemical characteristics which differentiate ioversol from the other products of its class make it a promising product for clinical use in humans.

This study was performed to assess the relative contributions of contrast medium osmolality and chemotoxicity to contrast-induced blood-brain barrier (BBB) damage. Experimental carotid angiography was carried out in rabbits with mannitol at an osmolality of 714 mOsm/kg, with the nonionic, monomeric contrast media iohexol and ioversol at similar osmolalities, and with the nonionic, dimeric contrast media iodixanol and iotrolan at osmolalities less than half that of the mannitol. The amount of damage caused by the procedure was assessed by determining the amount of intracerebral extravasation of intravascularly injected technetium-99m-pertechnetate. Mannitol caused no detectable BBB damage, but all four contrast media caused BBB damage that was significantly more severe than that caused by mannitol. The BBB damage caused by carotid angiography with iohexol, ioversol, iodixanol, and iotrolan was not attributable to their osmolalities, but due to some other physical and/or chemical effects of these media on the BBB.

Iodixanol is a new, nonionic, dimeric contrast medium which, in concentrations appropriate for radiographic use, is hypotonic with respect to plasma. The purpose of these in vivo and in vitro studies was to compare the effects of iopamidol, iodixanol formulated to isotonicity with sodium salts (sodium formulation), and iodixanol formulated to isotonicity with sodium, calcium, and magnesium salts (cationic formulation) on hemodynamic and electrophysiologic parameters. In vitro, the spontaneous rate of contraction by guinea pig right atrial and force development by right ventricular papillary muscles were evaluated in the presence of 1% to 100% (v/v) of the three contrast media. Iopamidol significantly (P less than .05) decreased the rate of atrial contraction to a greater extent than either formulation of iodixanol. Iopamidol decreased papillary muscle force development more than the sodium formulation of iodixanol (P less than .05). The cationic formulation of iodixanol had little effect (less than 30% change) on papillary muscle force development at concentrations up to 100%. The contrast media were also injected into the left coronary arteries of open-chest, anesthetized dogs at 0.8 mL/second for 5 to 30 seconds. All contrast media increased (P less than .05) systolic blood pressure (SBP), mean arterial pressure (MAP), and peak left ventricular pressure (LVP). Iopamidol increased LVP and LV end diastolic pressure to a greater extent (P less than .05) than the cationic formulation of iodixanol. We conclude that iopamidol affected cardiovascular parameters more than iodixanol.

The hemodynamic side effects of intracoronary injection of low osmolality contrast media were studied in anesthetised dogs, both with and without left ventricular (LV) failure. LV failure was induced by microembolization of the area supplied by the left main coronary artery. LV pressure and volume, aortic pressure, and cardiac output were recorded. 6 ml iodixanol 320 mg I/ml containing 20 mmol Na+/l, a new non-ionic dimer, was compared to iohexol and ioxaglate. Iodixanol induced small systolic alterations both before and after LV failure. Iohexol increased LV inotropy while ioxaglate depressed myocardial function. Before failure iodixanol and ioxaglate impaired isovolumic relaxation, but early diastolic filling was not reduced. After failure the relaxation process was not affected, but ioxaglate reduced early diastolic filling. Ioxaglate also increased LV end-diastolic pressure and volume more than the non-ionic contrast media. In conclusion, iodixanol induced only small changes in systolic and diastolic function. Iodixanol should therefore be hemodynamically well tolerated during coronary arteriography, and also in acute ischemic heart failure.

To investigate the effect of sodium on cardiac hemodynamics, sodium chloride was added to nonionic contrast media to a 0.9% concentration and was compared with the standard media iohexol, iopamidol, and ioversol. Left coronary angiography was performed in 10 closed-chest, atrial-paced dogs with 10 ml injections of each preparation in a randomized and blinded fashion. The maximum changes in left ventricular systolic pressure, mean aortic pressure, left ventricular and diastolic pressure, and maximal rise of left ventricular pressure were measured. The left ventricular systolic pressure and mean aortic pressure decreased by 17 +/- 7 mm Hg and by 12 +/- 5 mm Hg with iohexol plus 0.9% NaCl, but only by 5 +/- 4 mm Hg and by 4 +/- 3 mm Hg with iohexol alone (p less than 0.001). The left ventricular and end diastolic pressure increased by 2.2 +/- 0.6 mm Hg with iohexol plus 0.9% NaCl, but did not change with iohexol alone (p less than 0.001). Left ventricular dp/dt decreased by 204 +/- 161 mm Hg/sec with iohexol plus 0.9% NaCl but increased by 392 +/- 122 mm Hg/sec with iohexol alone (p less than 0.001). Similar results were obtained from experiments with iopamidol versus iopamidol plus 0.9% NaCl and ioversol versus ioversol plus 0.9% NaCl. Ioversol plus 5% dextrose or ioversol plus 2.1% choline chloride (isomolar to ioversol plus 0.9% NaCl) produced a significant increase in left ventricular systolic pressure and left ventricular dp/dt (versus ioversol plus 0.9% NaCl, p less than 0.001). Thus, sodium, but not the osmolality or chloride, contributed to the negative inotropic effect of the contrast media.(ABSTRACT TRUNCATED AT 250 WORDS)

With the availability of a newly developed, histamine-dependent allergy blood test, the authors studied the effect of ionic and nonionic radiocontrast media (RCM) on the in vitro release of histamine from whole blood obtained from 61 patients undergoing diagnostic arteriography. The ionic RCM, sodium meglumine diatrizoate (60 to 378 mmol/L), induced the release of a significantly (P less than .005) higher amount of histamine from blood compared with the nonionic agents, iopamidol and ioversol. Diatrizoate triggered significantly (P less than .05) more histamine release from the blood of eight patients with a history of adverse reactions to RCM than it did in 53 nonreactors; however, there was no appreciable difference in histamine release between reactive and nonreactive groups when stimulated with iopamidol and ioversol.

The systemic, pulmonary and renal haemodynamic effects following an intravenous infusion (1 ml/s, 4 ml/kg) of a non-ionic isoosmolar contrast medium (iodixanol) were investigated in 8 pigs. Histopathologic changes occurring after infusion of iodixanol were studied by repeated renal biopsies. Iodixanol caused a significant increase of cardiac output, mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary arterial occlusion pressure and mean arterial pressure. There was a decrease of the systemic and pulmonary vascular resistances. Most renal biopsies showed no pathologic findings after infusion of iodixanol but in 3 specimens proteinaceous content was observed 15 min after infusion.

The central, peripheral and renal haemodynamic effects after intravenous infusion (1 ml/s) of high doses (4 mg I/kg) of two low osmolar, chemically and physically similar non-ionic contrast media (iohexol and iopentol) were investigated in 16 pigs. Both contrast media induced a significant increase of mean arterial, mean right atrial, mean pulmonary arterial and mean pulmonary arterial occlusion pressure along with an increase in cardiac output. The systemic vascular and pulmonary vascular resistances were decreased. Renal venous blood flow and renal vascular resistance were not significantly changed after infusion of contrast media. There were no differences in haemodynamic effects between the two media studied.

The effect of three non-ionic contrast media (iosimide, iopamidol and iopromide) was investigated in rabbits and rats after single i.v. application up to high doses with regard to renal changes. Determinations of serum urea nitrogen and creatinine and urinary enzymes (lactate dehydrogenase, gamma-glutamyl-transpeptidase and N-acetyl-beta-D-glucosaminidase) as well as histological examinations of the kidneys were performed. The results obtained demonstrate that rabbit as an experimental animal was more sensitive than rat in exhibiting renal changes to contrast media. Furthermore, determinations of urinary enzymes demonstrated that gamma-GT in rabbits and LDH in rats were the most sensitive indicators for detection of early kidney damage. With regard to the high dose levels required, these kidney changes do not indicate any risk to humans at diagnostic dose levels.

The glucose metabolism effects of six hour exposures to subarachnoid injections of metrizamide, iohexol, iodixanol and control solutions were studied in vivo in 18 rabbits. The brain tissue uptake of intravenously injected 14C labelled deoxyglucose was measured using autoradiographic techniques. Metrizamide and iodixanol caused significant (p less than 0.05) decreases in deoxyglucose uptake in the outer cortical areas where the contrast medium concentrations were highest. Iohexol and the control CSF solution did not cause significant effects. The results appear to indicate that iohexol has less effect on brain tissue glucose metabolism than either metrizamide or the new non-ionic dimer iodixanol.

The four newly introduced contrast agents--iopamidol, iohexol, ioversol, and ioxaglate--are of much lower osmolality than conventional agents, and claims have been made that they are substantially safer. A chromogenic assay for thrombin was applied to 1:1 (50%), 2:1 (67%), and 4:1 (80%) contrast agent-whole blood mixtures, each containing enough contrast agent to render them unclottable. Thrombin generation occurred in the nonionic-whole blood mixtures and increased with time. No thrombin could be detected in any ioxaglate-whole blood mixtures. The authors conclude that this difference presents a novel hazard in that iopamidol, iohexol, and ioversol permit thrombin generation to occur while inhibiting the fibrin polymerization step of blood coagulation, thus posing a significant, albeit theoretical, threat to patient well-being.