Ioxaglic Acid

Intravenous injection of ioxaglate (4 g iodine kg(-1)), an iodinated radiographic contrast medium, caused a marked protein extravasation, pulmonary edema and a decrease in the arterial partial oxygen pressure in rats. All of these reactions to ioxaglate were reversed by the pretreatment with gabexate mesilate (10 and 50 mg kg(-1), 5 min prior to injection) or nafamostat mesilate (3 and 10 mg kg(-1)), in which the inhibition was complete after injection of nafamostat mesilate (10 mg kg(-1)). Both gabexate mesilate and nafamostat mesilate inhibited the activity of purified human lung tryptase, although the latter compound was far more potent than the former. Ioxaglate enhanced the nafamostat-sensitive protease activity in the extracellular fluid of rat peritoneal mast cell suspensions. Tryptase enhanced the permeability of protein through the monolayer of cultured human pulmonary arterial endothelial cells. Ioxaglate, when applied in combination with rat peritoneal mast cells, also produced the endothelial barrier dysfunction. These effects of tryptase and ioxaglate were reversed by nafamostat mesilate. Consistent with these findings, immunofluorescence morphological analysis revealed that tryptase or ioxaglate in combination with mast cells increased actin stress fiber formation while decreasing VE-cadherin immunoreactivity. Both of these actions of tryptase and ioxaglate were reversed by nafamostat mesilate. These findings suggest that tryptase liberated from mast cells plays a crucial role in the ioxaglate-induced pulmonary dysfunction. In this respect, nafamostat mesilate may become a useful agent for the cure or prevention of severe adverse reactions to radiographic contrast media.

Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that ioxaglate is expected to have very high mobility in soil(SRC). The estimated pKa of ioxaglate is 0.99(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Ioxaglate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-39 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Iodinated X-ray contrast agents are considered non-biodegradable by microorganisms(6).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that ioxaglate is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 0.99(3) indicates ioxaglate will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of 2.51(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Iodinated X-ray contrast agents are considered non-biodegradable by microorganisms(7).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ioxaglate, which has an estimated vapor pressure of 1.8X10-39 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ioxaglate may be removed from the air by wet or dry deposition(SRC). Ioxaglate contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of ioxaglate can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that ioxaglate is expected to have very high mobility in soil. The estimated pKa of ioxaglate is 0.99(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ ...Ioxaglate was administered intra-arterially to 20 consecutive patients ... ...The intra-arterially administered contrast medium elicited a marked increase of /fibrinopeptide A (FpA) and thrombin-antithrombin III complexes (TAT)/, together with an anticoagulant effect. /The authors conclude that ioxaglate is/ able to interfere with the clotting/fibrinolytic system in the general circulation when /it is/ administered to patients at the usual dosages. ... The procedure (ie, arterial catheter versus intravenous infusion) seems to be more important than the category of contrast medium in conditioning the magnitude of these effects.

/HUMAN EXPOSURE STUDIES/ ... In a multicenter study, 20 patients with mild to severe reactions to iodinated contrast material and 20 control subjects without reactions were evaluated. Ionic contrast material was associated with 18 (90%) of 20 reactions. Concentrations of plasma histamine, tryptase, urinary methylhistamine, specific immunoglobulin E (IgE) against ioxitalamate or ioxaglate, and the anaphylatoxins C3a and C4a were measured with radioimmunoassays; complement C3 and C4 levels were measured with nephelometry. Histamine levels were increased in 14 patients; tryptase levels, in 16; and methylhistamine levels, in six. Histamine and tryptase values correlated with the severity of the reaction (P < 0.02 and P < 0.004, respectively). Significantly higher levels of specific IgE against ioxaglate (P < 0.005) and ioxitalamate (P = 0.045) were found in patients. No differences were found for complement fractions. Skin test results in two patients with life-threatening reactions were positive for the administered contrast material. /Investigators concluded that/ histamine release and mast cell triggering are related to severe reactions. An IgE-related mechanism is strongly suspected. ...

/HUMAN EXPOSURE STUDIES/ ... Twenty-one patients undergoing either intravenous pyelography or arteriography with Ioxaglate were studied. Renal clearance studies were carried out 1 day before and 1 day after administration of Ioxaglate (173 +/- 37 mL) injected into each patient. None experienced any adverse reaction. Mean serum creatinine, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and urinary NAG excretion were unaltered by ioxaglate. No patient suffered a nephrotoxic reaction or acute oliguria that required dialysis as a result of the administration of contrast material. In the subset of seven patients receiving cyclosporine the same results were observed. In the subset of 10 patients with a GFR lower than 60 mL/min before injection of Ioxaglate were also observed no significant change in mean GFR, ERPF and urinary NAG excretion. Only two patients had a transient decrease of GFR of between 10 and 20%. The results of this study show that the ionic, low osmolar contrast medium ioxaglate may be used safely in patients with a renal transplant thus extending previous data obtained in patients with chronic renal failure.

An estimated BCF of 3 was calculated in fish for ioxaglate(SRC), using an estimated log Kow of 2.51(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The estimated pKa of ioxaglate is 0.99(1), indicating that this compound will primarily exist as an anion in the aqueous environment and anions do not volatilize from water or moist soil surfaces. Ioxaglate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-39 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Acute Exposure/ This study aimed to examine both the role of apoptosis in low-osmolar contrast media-induced kidney injury in normal and diabetic rats and the difference in the induced kidney injury between ionic and nonionic contrast media. Normal and streptozotocin-induced diabetic Wistar rats were administered with ionic low-osmolar ioxaglate, nonionic low-osmolar iopromide or normal saline injection. Apoptosis in kidney tubular cells was determined by the presence of positive terminal deoxynucleotidyl transferase-mediated dUTP in situ nick end-labeling (TUNEL) stain. At 24 hours after administration, both ioxaglate and iopromide injections induced more apoptosis in diabetic (49.7% vs. 25.3% for ioxaglate; 37.7% vs. 25.3% for iopromide; both p<0.001) and normal (36.2% vs. 27.4%, p=0.002, for ioxaglate; 33.6% vs. 27.4%, p=0.029, for iopromide) kidney tubular cells than normal saline injections. Additionally, ioxaglate induced more apoptotic tubular cells in diabetic kidneys than in normal kidneys (p<0.001). Moreover, ioxaglate significantly induced more apoptotic cells than iopromide in diabetic kidneys, but not in normal kidneys (p<0.001, for diabetic rats; p=0.345, for normal rats). Ionic low-osmolar contrast media induced more apoptosis in tubular cells in diabetic kidneys than in normal kidneys. Notably, ionic contrast media induced more apoptosis than nonionic contrast media in diabetic kidneys.

/LABORATORY ANIMALS: Acute Exposure/ ... Nonionic (iohexol) and ionic (ioxaglate) contrast media were intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye uptake as a quantitative marker of albumin extravasation in lung tissue. Intravenous injections of contrast media at doses of 4 and 6 g I/kg induced a dose-dependent increase in pulmonary vascular permeability. L-Arginine (an NO synthase substrate) and N(G)-nitro-L-arginine (L-NNA) (an NO synthase inhibitor) prevented and aggravated, respectively, the increase in pulmonary vascular permeability induced by the contrast medium. An aggravating action of L-NNA was confirmed by morphological and histological observations, this action being blocked by L-arginine (300 mg/kg) but not by D-arginine. Isosorbide dinitrate (1-20 mg/kg), an NO donor, had a dose-dependent protective effect on ioxaglate-increased vascular permeability. /The investigators'/ experimental findings suggest that contrast media at high doses produce pulmonary edema by inhibiting endothelial NO production, and nitrovasodilators protect against this adverse effect in rats.

/LABORATORY ANIMALS: Acute Exposure/ Using two different models, the effect on the blood-brain barrier of intracarotid injections of sodium/meglumine ioxaglate at similar iodine concentrations (280 mgI/mL) was investigated. In both models the degree of blood-brain barrier damage was assessed visually using Evans' Blue stain. Quantitative assessment of blood-brain barrier disruption was made by contrast enhancement as measured by CT of the dog brain, and by 99mTc-pertechnetate uptake by the brain in the rabbit model. No Evans' Blue staining was observed in any study using the canine/CT model. Slight staining was observed in two studies with ioxaglate using the rabbit/pertechnetate model. Statistical analysis of results from the canine/CT model did not detect any damage to the blood-brain barrier with either ioxaglate or saline control studies (P greater than 0.1). However, in the rabbit/pertechnetate model a slight increase in disruption of the blood-brain barrier was observed with ioxaglate compared with control studies, but this was only significant at the 0.1 level. The results suggest that the rabbit/pertechnetate model is a more sensitive measure of blood-brain barrier disruption than the canine/CT model. This study also demonstrates that blood-brain barrier disruption following intracarotid injection of ioxaglate is minimal.

In patients with advanced renal disease, iodinated contrast media should be used with caution and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure and recent renal transplant recipients present an additional risk. Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment.

Since intravascular administration of contrast media may promote sickling in individuals who are homozygous for sickle cell disease, fluid restriction is not advised.

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available.

Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

For more Populations at Special Risk (Complete) data for Ioxaglate (9 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ioxaglate sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ioxaglate sodium/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ioxaglate meglumine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ioxaglate meglumine/

MEDICATION

THERAPEUTIC CATEGORY: Diagnostic aid (radiopaque medium)

Use (kg; approx.) in Germany (2009): >50

Each milliliter /of HEXABRIX/ contains 393 mg of ioxaglate meglumine, 196 mg of ioxaglate sodium and 0.10 mg edetate calcium disodium as a stabilizer. The solution contains 3.48 mg (0.15 mEq) sodium in each milliliter and provides 32% (320 mg/mL) organically bound iodine.

/Available as:/ HEXABRIX Glass Vials/Bottles 25x50 mL vials; 12x100 mL fill/150 mL bottles; 12x200 mL fill/250 mL bottles.