Iodixanol and iohexol in cardioangiography. A comparative vectorcardiographic study.

PURPOSE: The non-ionic dimeric contrast medium (CM) iodixanol is isotonic with blood through the addition of electrolytes. In this study, we evaluated computerised dynamic vectorcardiography (VCG) as a tool in CM research by comparing the electrophysiological effects of iodixanol with those of the low-osmolar CM iohexol. MATERIAL AND METHODS: A total of 119 patients referred for cardioangiography were included in this double-blind, randomised, parallel comparison of iodixanol (320 mg I/ml) and iohexol (350 mg I/ml). VCG was recorded and different VCG parameters were analysed. General tolerability, safety and radiographic efficacy were also assessed. RESULTS: Iodixanol induced less changes than iohexol in all VCG parameters and the sensation of warmth was significantly milder after iodixanol, but both CM were well tolerated. VCG might be useful in future studies to analyse electrophysiological effects caused by CM.

Safety of the transpulmonary ultrasound contrast agent NC100100: a clinical and haemodynamic evaluation in patients with suspected or proved coronary artery disease.

OBJECTIVE: To evaluate the clinical and haemodynamic safety of NC100100, a new transpulmonary ultrasound contrast agent intended for vascular use. DESIGN: Pulmonary artery pressures and gas exchange, left ventricular and systemic blood pressure and ECG were measured at baseline, after saline injection, and after each of two increasing doses of NC100100 injected intravenously. PATIENTS: 30 patients who were evaluated for suspected coronary artery disease. RESULTS: No change was detected in any of the haemodynamic variables, or in haematological or clinical chemical parameters. Blood gases were unchanged, as were heart rhythm and arterial oxygen saturation. No serious adverse reactions were reported. CONCLUSIONS: NC100100 appeared to be haemodynamically inert and safe in patients with coronary artery disease.

Angiography with nonionic X-ray contrast media in severe chronic renal failure: renal function and contrast retention.

The effects of contrast media on renal function and the cortical retention of contrast media after abdominal angiography were investigated. Sixteen nondiabetic patients with predialytic chronic renal failure received either the nonionic dimeric contrast medium iodixanol or the monomeric contrast medium iohexol in a double-blind randomized study. All patients were well hydrated before, during and after angiography. Mean 99mTc-DTPA clearance was 14.0 ml/min/1.73 m2 in the iodixanol group, and 9.3 ml/min/1.73 m2 in the iohexol group at baseline. No statistically significant changes were seen after angiography. Serum creatinine increased significantly 48 and 72 h after angiography in both groups, and then normalized. Creatinine clearance was reduced only in the iohexol group, at 72-96 h. The urinary excretion of renal enzymes and of total protein did not change significantly. No patients developed oliguria or required dialysis during the 7-day observation period. Increased attenuation in the renal cortex, measured by computed tomography and probably reflecting intracellular retention of contrast medium, peaked at 24 h, and was observed in both groups during the follow-up period. Thus, although transient and minor changes in glomerular filtration rate were noted, both iodixanol and iohexol were safe for use in angiography in nondiabetic patients with severe chronic failure when the patients were well hydrated.

Determination of glomerular filtration rate with Visipaque in patients with severely reduced renal function.

Iodixanol (Visipaque, Nycomed Imaging AS, Oslo, Norway), and isotonic, dimeric and non-ionic contrast medium (CM), and iohexol (Omnipaque, Nycomed Imaging AS, Oslo, Norway), a low-osmolar, monomeric and non-ionic contrast medium, were used as glomerular filtration rate (GFR) markers in patients with severely impaired renal function. Different methods for determining GFR were compared. A total of 16 patients with s-creatinine > 400 mumol/l were enrolled in the study; 8 in each CM group. Serum-iodine was measured, and plasma CM clearance was determined using the Bröchner-Mortensen method, the single-sample method and conventional method. The ratios between the results obtained from the conventional method and each of the two other methods were calculated. These data were plotted against the mean of the pairs compared, and the upper and lower limits of agreement were calculated as the mean ratio +/- 2SD. The comparison showed a high degree of agreement between methods, and the two simpler methods seem to be good alternatives to the conventional method, which gave good estimates of GFR (vs that determined by means of renal 125I-iothalamate clearance) when 24-h blood samples were included. However, slight overestimations of GFR, due to extrarenal excretion of the CM, were observed. In summary, serum clearance of iodixanol, as determined by the Bröchner-Mortensen method or single-sample method seems to be a simple and accurate marker for GFR in patients with severely reduced renal function. The findings obtained with iodixanol were similar to those obtained with iohexol.

Iodixanol vs iopamidol in intravenous DSA of the abdominal aorta and lower extremity arteries: a comparative phase-III trial.

Iodixanol (Visipaque, 320 mgI/ml) was compared with iopamidol (Solutrast, 370 mgI/ml) in a double-blind, randomized, parallel group, intravenous DSA phase-III trial for evaluation of safety and efficacy. A total of 117 patients received iodixanol (n = 60) or iopamidol (n = 57). Diagnostic efficacy was evaluated using categoric and visual analogue scales. Discomfort and adverse events were recorded. A total of 39 patients collected urine up to 72 h after the examination for analysis. Diagnostic efficacy and radiographic density were similar in both groups. Discomfort was milder with iodixanol. The difference between the frequency of adverse events between both groups (iodixanol = 7, iopamidol = 2) was without statistical significance. Creatinine clearance was slightly more affected by iodixanol, whereas the increase in renal excretion of N-acetyl-beta-glucosaminidase (NAG) in the first 24-h collection period after the examination was significantly higher (p < 0.01) with iopamidol. Iodixanol was of equal diagnostic efficacy compared with iopamidol despite its reduced iodine content. Both contrast media are well suited for IV DSA.

Iodixanol in intra-arterial cerebral digital subtraction angiography: a comparison with iohexol.

We randomised 86 patients undergoing intra-arterial cerebral digital subtraction angiography (IADSA) to receive iodixanol (Visipaque; Nycomed, Oslo, Norway) 150 mgI/ml or iohexol (Omnipaque; Nycomed) 140 mgI/ml. The efficacy and safety of these two contrast media were compared: efficacy by evaluating the diagnostic information and radiographic density yielded by the angiograms, safety by recording all discomfort connected with the injections, and all adverse events up to 24 h after the investigation. Diagnostic information was optimal in all patients and the overall radiographic density optimal in all but one (iohexol) (P = 0.49). A feeling of warmth, the only discomfort reported, was experienced by 43% and 54% of patients receiving iodixanol and iohexol, respectively (P = 0.26). Two patients in the iodixanol group and five in the iohexol group reported one adverse event (nausea, dizziness, visual disturbance or paraesthesiae) (P = 0.30); all were of mild severity except for one moderate adverse event in each group. Iodixanol 150 mgI/ml and iohexol 140 mgI/ml were demonstrated to be suitable for IADSA, with no clinically or statistically significant differences in efficacy, discomfort or adverse events.

A comparison of iodixanol with iopamidol in aorto-femoral angiography.

This double-blind, randomized, parallel group clinical investigation in 140 consecutive patients undergoing aorto-femoral arteriography was carried out to compare iodixanol (Visipaque) 270 mgI ml-1 with iopamidol (Iopamiro) 300 mgI ml-1. The aims of the study were to compare adverse events and discomfort, clinical chemistry parameters in blood, haemodynamics and diagnostic information of the angiograms in the two groups. The main parameter for statistical analysis was the visual analogue scale (VAS) score for overall discomfort experienced by the patients during the examination. 134 patients, 69 and 65 receiving iodixanol and iopamidol, respectively, were examined according to the protocol and included in the evaluation. The two groups of patients were judged to be comparative. Statistically significant milder discomfort was felt with iodixanol than with iopamidol (p = 0.0001); mean VAS values 16 mm and 51 mm, respectively. Pain was reported far less frequently after iodixanol than after iopamidol (7.4% versus 50.8%) whereas sensation of warmth was less intense after iodixanol than after iopamidol. Four patients in the iodixanol group and two in the iopamidol group reported transient, non-serious adverse events. The difference was not statistically significant (p = 0.68). Systolic blood pressure was affected to a slightly greater degree after injection of iopamidol than after injection of iodixanol. Measurements of diastolic blood pressure, as well as clinical chemistry parameters in blood, revealed no changes of clinical importance, and all arteriograms performed were of diagnostic value. The conclusion is that iodixanol 270 mgI ml-1 is as efficacious as iopamidol 300 mgI ml-1, but produces less discomfort during arteriography. As such, iodixanol is a good alternative to iopamidol in aorto-femoral angiography.

Elimination of the non-ionic X-ray contrast media iodixanol and iohexol in patients with severely impaired renal function.

Iodixanol (Visipaque) and iohexol (Omnipaque) are dimeric and monomeric, respectively, non-ionic X-ray contrast media (CM), with well-characterized pharmacokinetics in healthy volunteers. This study was undertaken to study the pharmacokinetics of the contrast media in patients with severely impaired renal function. A total of 16 patients referred for preoperative abdominal angiography were randomized to form two groups of eight patients, receiving either iodixanol 320 mgI ml-1 or iohexol 350 mgI ml-1. Urine and faeces were sampled before the examination and collected quantitatively for five days afterwards, and blood samples were drawn frequently. The concentrations of iodine and contrast medium in urine and in serum, and the amount of iodine in faeces were determined. Mean baseline creatinine clearance was 13.6 and 9.9 ml min-1 1.73 m-2 in the iodixanol and iohexol groups, respectively. Patients in the iodixanol group received on average 0.34 gI per kg bodyweight (bw) and those in the iohexol group 0.39 gI per kg bw. The semilogarithmic plots of serum concentration of CM vs. time indicated elimination according to a two-compartment model. The mean elimination half-life was 23.0 h for iodixanol and 27.2 h for iohexol, and the mean apparent volume of distribution was similar for the two CM, ranging from 0.20 to 0.30 1 per kg bw. Mean plasma clearance of iodixanol was 10.4 ml min-1 1.73 m-2 and 6.9 ml min-1 1.73 m-2 for iohexol, whereas the mean renal clearances were 8.7 and 6.1 ml min-1 1.73 m-2, respectively. Mean faecal recovery was 8.2% for iodixanol and 6.1% for iohexol, and the respective figures for that in urine were 76.1 and 74.8%. Renal clearance of radiolabelled iothalamate, a marker of glomerular filtration rate (GFR), measured simultaneously, indicated that both CM were eliminated by the kidneys by glomerular filtration only. Thus, both media are suitable as GFR markers.

Main results of the first comparative clinical studies on Visipaque.

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.

Angiographic contrast media relax isolated rabbit aorta through an endothelium-independent mechanism that may not depend on the presence of the iodine atom.

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.

Renal tubular effects of diuretics and X-ray contrast media. A comparative study of equimolar doses in healthy volunteers.

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 in femoral arteriography (phase III): a comparative double-blind parallel trial between iodixanol and iopromide.

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.

Safety and tolerability of iodixanol in healthy volunteers with reference to two monomeric X-ray contrast media.

The low osmolar, non-ionic X-ray contrast media have shown a lower frequency of adverse events than the older ionic ones. In this study changes in routine clinical-chemical parameters in blood and urine, vital signs and adverse events were recorded in six groups of 10 healthy male volunteers receiving either iodixanol, a new non-ionic, dimeric X-ray contrast medium for general vascular use, or one of the two non-ionic, monomeric contrast media iopentol and iopamidol. Minor decreases were observed in the values for haemoglobin, haematocrit and erythrocytes 5 min and 3 days after injection of iodixanol. A minor increase was seen in platelets and total protein after 3 days. A transient increase in serum osmolality was seen 5 min after the injections of iopentol and iopamidol. This was not seen in any iodixanol group. The level of thyrotropin showed an increase in all groups at 3 days. It was back to normal within 21 days. No changes of clinical importance were seen regarding blood pressure, heart rate or ECG in any volunteer. No severe adverse events were reported. All events were of short duration, and of mild or moderate intensity. The results, however, may indicate a lower frequency of adverse events/discomfort after the administration of the dimeric iodixanol than the 2 monomeric contrast media iopentol and iopamidol.

[Iodixanol. A new isotonic x-ray contrast medium]. / Iodixanol. Et nytt isotont røntgenkontrastmiddel.

In this phase I study, safety, tolerance and pharmacokinetics of iodixanol 300 mg I/ml, were evaluated in 40 healthy male volunteers using four dose levels. No clinically important influences on renal function parameters, hemodynamics, ECG or clinical-chemical parameters in blood and urine were observed. 17 adverse events including discomfort were reported, but only three of them (sensation of warmth) were classified as related to iodixanol. CT-investigations revealed a dose-related, reversible increase in kidney cortex density. However, iodixanol caused no changes in glomerular function, and the increase in excretion of tubular enzymes was less than caused by other nonionic x-ray contrast media. Further investigations will focus on the safety and efficacy of iodixanol in patients.

Eicosapentaenoic acid reduces hepatic synthesis and secretion of triacylglycerol by decreasing the activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase.

The mechanism for the reduced hepatic production of triacylglycerol in the presence of eicosapentaenoic acid was explored in short-term experiments using cultured parenchymal cells and microsomes from rat liver. Oleic, palmitic, stearic, and linoleic acids were the most potent stimulators of triacyl[3H]glycerol synthesis and secretion by hepatocytes, whereas erucic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic, and eicosapentaenoic acids (in decreasing order) were less stimulatory. There was a linear correlation (r = 0.85, P less than 0.01) between synthesis and secretion of triacyl[3H]glycerol for the fatty acids examined. The extreme and opposite effects of eicosapentaenoic and oleic acids on triacylglycerol metabolism were studied in more detail. With increasing number of free fatty acid molecules bound per molecule of albumin, the rate of synthesis and secretion of triacyl[3H]glycerol increased, most markedly for oleic acid. Cellular uptake of the two fatty acids was similar, but more free eicosapentaenoic acid accumulated intracellularly. Eicosapentaenoic acid caused higher incorporation of [3H]water into phospholipid and lower incorporation into triacylglycerol and cholesteryl ester as compared to oleic acid. No difference was observed between the fatty acids on incorporation into cellular free fatty acids, monoacylglycerol and diacylglycerol. The amount of some 16- and 18-carbon fatty acids in triacylglycerol was significantly higher in the presence of oleic acid compared with eicosapentaenoic acid. Rat liver microsomes in the presence of added 1,2-dioleoyl-glycerol incorporated eicosapentaenoic acid and eicosapentaenoyl-CoA into triacylglycerol to a lesser extent than oleic acid and its CoA derivative. Decreased formation of triacylglycerol was also observed when eicosapentaenoyl-CoA was given together with oleoyl-CoA, whereas palmitoyl-CoA, stearoyl-CoA, linoleoyl-CoA, linolenoyl-CoA, and arachi-donoyl-CoA had no inhibitory effect. In conclusion, inhibition of acyl-CoA:1,2-diacylglycerol O-acyltransferase (EC 2.3.1.20) by eicosapentaenoic acid may be important for reduced synthesis and secretion of triacylglycerol from the liver.

Eicosapentaenoic acid inhibits cholesterol esterification in cultured parenchymal cells and isolated microsomes from rat liver.

The effects of eicosapentaenoic acid on synthesis and secretion of cholesterol and cholesterol ester by cultured rat hepatocytes were studied. In the presence of eicosapentaenoic acid cellular cholesterol esterification was decreased by 50-75% compared to oleic acid as measured by radioactive precursors and mass. Secretion of cholesterol ester was reduced by 50-60% in the presence of eicosapentaenoic acid as evaluated by radiolabeled fatty acids, mevalonolactone, and mass measurement. Oleic, palmitic, and stearic acid increased, whereas eicosapentaenoic and docosahexaenoic acid decreased synthesis and secretion of cholesterol ester as compared to a fatty acid-free control. Cellular and secreted free cholesterol were unaffected by eicosapentaenoic acid in comparison with oleic acid. The reduced cholesterol esterification was observed within 1 h and lasted for at least 20 h. Eicosapentaenoic acid caused lower cholesterol esterification than oleic acid in the concentration range 0.2-1.0 mM fatty acid and reduced the stimulatory effect of oleic acid on cholesterol ester formation. Cholesterol esterification and release of cholesterol ester were markedly increased by 25-hydroxycholesterol in the presence of eicosapentaenoic acid as well as oleic acid. Experiments with liver microsomes revealed that radioactive eicosapentaenoic acid and eicosapentaenoyl-CoA were poorer substrates (7-30%) for cholesterol esterification than oleic acid and oleoyl-CoA. Reduced formation of cholesterol ester was also observed when eicosapentaenoyl-CoA was given together with labeled oleoyl-CoA, whereas palmitoyl-CoA, stearoyl-CoA, linolenoyl-CoA, and arachidonoyl-CoA had no inhibitory effect. In conclusion, eicosapentaenoic acid reduced cellular cholesterol esterification by inhibiting the activity of acyl-CoA:cholesterol acyltransferase. The lowered cholesterol esterification caused by eicosapentaenoic acid secondly decreased secretion of very low density lipoprotein cholesterol ester.