Nonionic Dimeric Contrast Medium Research Articles

Which iodinated contrast media is the least cytotoxic to human disc cells?

BackgroundIodinated contrast media (CM) is commonly used for various intradiscal injections such as in discography and endoscopic spinal surgery. However, CM has been shown to be toxic to renal tissue due to its ionic strength and osmolarity and as a result of iodine-induced cytotoxicity, which has raised concern over whether there are similar negative effects on disc cells. PurposeThis in vitro study was designed to identify the least cytotoxic iodinated CM to the human disc cell among four different physiochemical iodinated contrast dyes. Study designIn vitro laboratory study. MethodsIntervertebral disc tissue was obtained by discectomy from a total of 10 lumbar disc patients undergoing surgery and disc cells were isolated. The human disc cells were grown in 3D alginate bead culture with 0, 0.1, 10, and 100 mg/mL CM solutions (ionic dimer, ionic monomer, non-ionic dimer, and non-ionic monomer) and mannitol as a control for 2 days. The living cells were analyzed with trypan blue staining. Fluorescence-activated cell sorting analysis was performed using Annexin V and propidium iodide (PI) and 3D alginate bead immunostaining to identify live, apoptotic, and necrotic cells. ResultsHuman disc cell death was time- and dose-dependent in response to CM and more necrosis was observed than apoptosis. In addition, non-ionic dimeric CM (iodixanol) showed the least toxic effect on human disc cells, followed by non-ionic monomeric (iopromide), ionic dimeric (ioxaglate), and ionic monomeric CM (ioxithalamate). ConclusionsContrast media is cytotoxic to human disc cells in a dose- and time-dependent manner. This in vitro study revealed that, among four different CM preparations, non-ionic dimeric CM is the least detrimental to human disc cell viability. Careful attention should be paid to the type of CM chosen for discography and endoscopic spinal surgery. It is also necessary to investigate the detrimental effects of CM on disc cells and disc degeneration in further in vivo studies.

Development of a Physiologically Based Computational Kidney Model to Describe the Renal Excretion of Hydrophilic Agents in Rats

A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs. These data included the sodium and urea concentration gradient along the cortico-medullary axis, water reabsorption, urine flow, and sodium as well as urea urine concentrations for a normal hydration state. The model was evaluated by predicting the effects of mannitol and contrast media administration and comparing to experimental data on cortico-medullary concentration gradients, urine flow, urine viscosity, hydrostatic tubular pressures and single nephron glomerular filtration rate. Finally the model was used to analyze and compare typical examples of ionic and non-ionic monomeric as well as non-ionic dimeric contrast media with respect to their osmolality and viscosity. With the computational kidney model, urine flow depended mainly on osmolality, while osmolality and viscosity were important determinants for tubular hydrostatic pressure and kidney exposure. The low diuretic effect of dimeric contrast media in combination with their high intrinsic viscosity resulted in a high viscosity within the tubular fluid. In comparison to monomeric contrast media, this led to a higher increase in tubular pressure, to a reduction in glomerular filtration rate and tubular flow and to an increase in kidney exposure. The presented kidney model can be implemented into whole body physiologically based pharmacokinetic models and extended in order to simulate the renal excretion of lipophilic drugs which may also undergo active secretion and reabsorption.

Induction of Upregulation and Downregulation of the T-Cell Activation Marker CD98 in Patients Undergoing Contrast-Enhanced CT with Iodinated Non-Ionic Dimeric Contrast Medium

ObjectiveThis study was designed to determine prospectively the expression of the multifunctional CD98 protein in peripheral white blood cells in patients receiving iodinated contrast media (CM) for a computed tomography (CT) examination.Materials and MethodsIn 12 adult patients that received non-ionic dimeric CM (iosimenol or iodixanol), the expression of CD98 was analyzed from samples of peripheral white blood cells obtained prior to, one hour, and 24 hours after CM injection by the use of flow cytometry analysis and the use of the direct immunofluorescence technique.ResultsOverall, expression of CD98 was significantly downregulated 24 hours after CM injection (51.9%±10.8% vs. 38.8%±16.9%; p < 0.04). Patients that received iosimenol exhibited a more pronounced but not significant decrease of CD98 expression both one hour and 24 hours after CM injection. In an analysis of specific patient responses, CD98 downregulation occurred in eight patients. In two patients, CD98 was upregulated, and in the remaining two patients, expression remained unchanged. No patient acquired an adverse CM reaction.ConclusionThis is the first demonstration that CM may be a regulator of CD98 expression. To determine if upregulation is associated with an increased risk for the acquisition of an adverse CM-induced hypersensitivity reaction and if downregulation is associated without a risk for the acquisition of an adverse CM-induced hypersensitivity reaction, further studies with a larger population of patients are required.

Iosimenol, a new non-ionic dimeric contrast medium, does not induce immunoreactivity in the popliteal lymph node assay

Animal studies in mice were conducted to determine the potential immunoreactivity of the new non-ionic dimeric contrast medium (CM) iosimenol using the PLNA and flow cytometric analyses. Comparative studies were performed with iodixanol. The known immune-reactive substance strepozotocin (STZ) and vehicle injections served as positive and negative controls, respectively. Our experiments did not show any immunological effect of iosimenol, concluding that the new CM iosimenol may be beneficial for use in high-risk patients.

Nephrotoxic effects of X-ray contrast media.

The annual sale of x-ray contrast media (CM) now represents 60 million doses, and contrast nephropathy (CN) has been the third-leading cause of hospital-acquired acute renal failure. In this review article, physicochemical, pharmacokinetic, and pharmacodynamic properties of CM are surveyed. The definition of CN is presented, as well as the mechanisms involved in the pathogenesis. Low osmolar monomeric CM (LOCM) are less nephrotoxic than the older ionic high osmolar CM (HOCM), but in risk patients the incidence of CN is still high after intravascular administration of LOCM. Non-ionic dimeric CM are iso-osmolar to plasma (IOCM), and they have reduced the nephrotoxicity even more than LOCM. The most important risk factors for CN are diabetes mellitus and impaired renal function. Selection of patients, hydration, and type of CM are essential for prevention and prophylaxis of CN. We do not recommend routine prophylaxis with N-acetylcysteine (NAC) during CM investigations, but its use in high-risk patients should be considered.

Cytokine profiles after nonionic dimeric contrast medium injection.

Mediators of contrast media (CM)-induced allergic/pseudoallergic side effects are largely unknown. We evaluated the possibility of cytokines released as surrogate markers for allergic/pseudoallergic responses in patients who tolerated CM injection well. Interleukin-1beta (IL-1beta), -2, -4, -5, -6; tumor necrosis factor-alpha; plasma histamine level; and the anaphylatoxin C5a were measured by enzyme-linked immunosorbent assay technique in 9 patients who received the nonionic dimeric iodinated CM iotrolan under routine computed tomography examination conditions. Serum samples were collected before, 1 hour, 6 hours, and 24 hours after contrast medium injection. The cytokine values did not correlate with the hematocrit. Kinetic studies revealed a trend, although not statistically significant (P>0.05), for an early increase of IL-2 (1 hour after CM), followed by delayed increase of IL-4 and IL-6. Histamine significantly decreased after iotrolan injection and C5a increased 6 hours (P>0.05) after CM administration in parallel to IL-6. IL-1beta decreased (with the lowest value measured 6 hours after CM injection; P>0.05), and tumor necrosis factor-alpha did not show any tendency. Patients with late adverse reactions had a T helper 1 to T helper 2 shift and 24 hours after CM injection had the highest histamine values. The results suggest CM-related liberation of cytokines with a sequential T helper type 1 (IL-2 after 1 hour), and T helper type 2-like pattern (IL-4, -5, and -6).

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.

Effects of non-ionic monomeric and dimeric iodinated contrast media on renal and systemic haemodynamics in rats.

Non-ionic dimeric contrast media (CM) are a new class of CM which are iso-osmolar with plasma. The aim of this study was to investigate their effects on systemic and renal haemodynamics. The non-ionic dimeric CM iodixanol and the non-ionic monomeric agent iobitridol (both at a dose of 1,600 mgI/kg) were compared in terms of their effects on systemic blood pressure (BP) and renal blood flow (RBF) in two strains of rats (Wistar and Sprague Dawley). Iodixanol significantly lowered BP in Wistar rats (-33 +/- 9% of baseline, 10 min post-injection, P < 0.001 vs. saline and iobitridol). Iobitridol had virtually no effect on BP. Iobitridol and iodixanol significantly decreased RBF. This effect was more marked following injection of the dimer rather than the monomer (iodixanol: -32 +/- 13% iobitridol: -20 +/- 4 of baseline at 16 min, P < 0.05). For both agents, RBF was still decreased 50 min following injection (iodixanol: -30 +/- 11%, and iobitridol: -20 +/- 5% of baseline). Iodixanol also decreased RBF in Sprague Dawley rats, while BP remained unchanged. This suggests that changes in BP/RBF autoregulation do not account for the renal haemodynamic effects of this agent. When measured 2 h following injection, the iodixanol-induced renal hypoperfusion was still detectable (-29% vs. saline-treated rats), although not significant (P = 0.06). This effect was no longer observed 4 h following injection. Increasing the saline infusion rate (18 mL/h vs. 2 mL/h) during the experiment did not significantly decrease the effects of iodixanol on BP and RBF in Wistar rats. In spite of its iso-osmolality, iodixanol, a non-ionic dimeric CM, depressed RBF and BP significantly more than iobitridol, a monomeric non-ionic agent, in Wistar rats. This effect was long-lasting and was not alleviated by increasing the hydration rate.

Nephrotoxicity related to contrast media.

The numbers of contrast media (CM)-enhanced examinations are increasing. The annual sale of iodine for CM now represents 60 million CM doses a year world-wide. In spite of improvements in chemical structure, CM are still the third leading cause of hospital-acquired acute renal failure. The definition of contrast nephropathy (CN) is discussed, as well as the mechanisms involved in the pathogenesis. Low osmolar contrast media (LOCM) are less nephrotoxic than high osomolar contrast media (HOCM) and cause fewer osmotoxic side-effects such as pain and heat sensations. The non-ionic dimeric contrast media which are iso-osmolar to plasma (IOCM) cause even fewer haemodynamic side-effects and result in better opacification of the urinary tract than LOCM. The nephrotoxicity of IOCM is low. The risk factors for CN and methods for prevention of CN are discussed.

Urine viscosity after injections of iotrolan or iomeprol.

Previous observations in rats caused us to speculate whether the injection of iotrolan, a nonionic dimeric contrast medium (CM), would increase urine viscosity enough to obstruct urine outflow in the collecting duct. The urine viscosity in dogs was measured directly with a viscosimeter after injections of iotrolan or of iomeprol, a nonionic monomeric CM. The injection of iotrolan increased urine viscosity considerably whereas iomeprol had little effect on this variable. The osmolality-dependent adverse reactions of CM have previously been emphasized but viscosity-dependent adverse reactions must also be considered when the CM is a polymer with a low osmolality.

High-volume nonionic dimeric contrast medium: first experiences during complex coronary interventions.

Interventional cardiology is a rapidly developing field of medicine with annually increasing numbers of coronary interventions. Especially through the development of alternative techniques for coronary angioplasty, new indications have been found and more difficult lesions are tackled. Inevitably, such complex interventions are time-consuming and require high amounts of contrast medium. Newer, mostly nonionic agents have been developed with improved tolerability as well as fewer cardiac and renal side effects due to their nonionic, hydrophilic structure, and their osmolality isotonic to plasma. This study sought to investigate the effects of high-volume nonionic, dimeric contrast medium during coronary interventions with special emphasis on renal and hemodynamic side effects during routine hospital stays. Retrospectively, 25 consecutive patients (age 56 +/- 10 yr) with normal renal and cardiac function receiving > 500 ml of the nonionic dimeric contrast medium iodixanol during complex coronary interventions were analyzed. The analysis was based on serum creatinine levels 1 day before and 2 days after contrast medium administration for the monitoring of renal function. Additionally, heart rate and left ventricular pressures were evaluated before and after left ventricular angiography. Mean serum creatinine rose from 0.9 +/- 0.2 mg/dl to 1.1 +/- 0.2 mg/dl (P < 0.05) after 2 days of coronary intervention. Heart rate, left ventricular systolic pressure, and left ventricular end-diastolic pressure did not change significantly. No major side effects were encountered in the short follow-up period of 2 days. Based on this retrospective analysis, high-volume nonionic, dimeric contrast medium administration in patients without preexisting renal insufficiency is associated with little impairment of renal function, and has only minor hemodynamic and general side effects. Iodixanol 320 mg I/ml is well-tolerated and effective for the use of cardioangiography. Given the limitations of this retrospective analysis, future prospective studies should systematically address the effects of high-volume contrast medium administration in otherwise healthy patients as well as in high-risk patients undergoing coronary interventions.

High‐volume nonionic dimeric contrast medium: First experiences during complex coronary interventions

Interventional cardiology is a rapidly developing field of medicine with annually increasing numbers of coronary interventions. Especially through the development of alternative techniques for coronary angioplasty, new indications have been found and more difficult lesions are tackled. Inevitably, such complex interventions are time-consuming and require high amounts of contrast medium. Newer, mostly nonionic agents have been developed with improved tolerability as well as fewer cardiac and renal side effects due to their nonionic, hydrophilic structure, and their osmolality isotonic to plasma. This study sought to investigate the effects of high-volume nonionic, dimeric contrast medium during coronary interventions with special emphasis on renal and hemodynamic side effects during routine hospital stays. Retrospectively, 25 consecutive patients (age 56 ± 10 yr) with normal renal and cardiac function receiving >500 ml of the nonionic dimeric contrast medium iodixanol during complex coronary interventions were analyzed. The analysis was based on serum creatinine levels 1 day before and 2 days after contrast medium administration for the monitoring of renal function. Additionally, heart rate and left ventricular pressures were evaluated before and after left ventricular angiography. Mean serum creatinine rose from 0.9 ± 0.2 mg/dl to 1.1 ± 0.2 mg/dl (P < 0.05) after 2 days of coronary intervention. Heart rate, left ventricular systolic pressure, and left ventricular end-diastolic pressure did not change significantly. No major side effects were encountered in the short follow-up period of 2 days. Based on this retrospective analysis, high-volume nonionic, dimeric contrast medium administration in patients without preexisting renal insufficiency is associated with little impairment of renal function, and has only minor hemodynamic and general side effects. Iodixanol 320 mg l/ml is well-tolerated and effective for the use of cardioangiography. Given the limitations of this retrospective analysis, future prospective studies should systematically address the effects of high-volume contrast medium administration in otherwise healthy patients as well as in high-risk patients undergoing coronary interventions. Cathet. Cardiovasc. Diagn. 40:241–246, 1997. © 1997 Wiley-Liss, Inc.

Phase III clinical trial comparing iodixanol and iohexol in cerebral angiography

We report on our early clinical experience in the United States with the nonionic dimeric (6:1 ratio) contrast medium iodixanol in cerebral angiography. Iodixanol has an osmolality less than half that of monomeric, nonionic contrast media such as iohexol at equivalent iodine concentrations and is isosmotic to blood. Forty-nine adult patients undergoing elective cerebral angiography were studied in a phase III, double-blind, randomized, parallel-design clinical trial comparing the safety and diagnostic efficacy of iodixanol at 320 mg I/ml (IOD-320) and iohexol 300 mg I/ml (IOH-300). Diagnostically adequate cerebral angiograms were routinely obtained with both contrast agents. A total of 37% of the patients experienced adverse events (48% in the IOD-320 group and 25% in the IOH-300 group). No statistically significant differences were noted between the two groups studied in the proportion of patients with one or more adverse events or in the intensity of the adverse events. The most common adverse event was headache. There were no deaths or serious complications related to either contrast medium in this study. The results of this phase III trial support the conclusion that iodixanol at a concentration of 320 mg I/ml is comparable to iohexol at 300 mg I/ml in terms of efficacy (overall radiographic diagnostic visualization) and safety.

Effect of iodixanol on in vitro bleeding time

Both monomeric and dimeric ionic radio contrast media (CM) have been shown to be more anticoagulant than nonionic monomeric CM. Iodixanol is a relatively new nonionic dimeric contrast medium. We investigated whether the dimeric structure of iodixanol would produce the same level of anticoagulation that has been observed using nonionic monomeric CM. We used a global screening device that operates under physiologic flow conditions to monitor the effects of iodixanol on in vitro bleeding time (IVBT). This flow dynamic technique perfuses nonanticoagulated whole blood through a hollow fiber device. A leak in the fiber is created by a precision needle, and the resulting pressure fluctuations within the fiber are monitored to examine the ability of the hemostatic system to close the leak by forming a stable platelet plug. In 20 donors, iodixanol (25% CM/blood, v/v) was shown to lengthen the mean IVBT (18.74 min) compared with the normal blood mean IVBT (4.24 min). The addition of dimeric iodixanol to normal blood affects the IVBT in the same manner as nonionic monomeric CM (ioversol, iopamidol, and iohexol).

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Clinical experience of the use of a non-ionic dimeric contrast medium

Safety and Pharmacokinetics of Iotrolan in Hysterosalpingography

The authors compared the safety and pharmacokinetics of Iotrolan (water-soluble) in hysterosalpingography (HSG) with those of Lipiodol (oil-soluble). Iotrolan and Lipiodol were administered intraperitoneally at doses of 100 mg iodine/kg to female rabbits. Retention in the body was investigated by x-ray imaging, plasma kinetics, and urinary and fecal excretion. Irritability in the abdomen was investigated by histologic examination. Iotrolan was entirely excreted into the urine within 2 days after administration. Conversely, Lipiodol was excreted into the urine, had a half-life of 50 days, and was retained for more than 21 days in the abdomen. Iotrolan induced no inflammatory reaction in the abdomen, whereas Lipiodol induced a marked abdominal inflammatory reaction, including granuloma formation. Iotrolan had no effect on iodine concentration in the thyroid; Lipiodol increased iodine concentration significantly. Iotrolan, which is a water-soluble and nonionic dimeric contrast medium, has potential greater safety for use in HSG than Lipiodol.

The effect of iodixanol, anew isotonic contrast agent, on femoral blood flow in man

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.

Evaluation of renal function with delayed CT after injection of nonionic monomeric and dimeric contrast media in healthy volunteers.

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.

A comparison between iotrolan, a non-ionic dimer, and a hyperosmolar contrast medium, Urografin, in hysterosalpingography

For hysterosalpingography, there were no significant differences between the non-ionic dimeric contrast medium iotrolan (300 mgI/%) and Urografin (370 mgI/%) with regard to ease of application or radiographic quality, and both agents were equally suitable. There were no significant differences between two groups of patients with regard to pain due to instrumentation, pain at the time of injection and pain up to 2 h after the procedure. There was a significant difference (p = 0.04) between the two groups with respect to delayed pain, when iotrolan was associated with a lower incidence and decreased severity of delayed pain. There were no differences in the incidence of nausea, vomiting, headache and syncope. No allergic phenomena were seen in either group.