ジアトリゾ酸ナトリウム

/HUMAN EXPOSURE STUDIES/ The electrocardiographic changes induced during a rapid bolus intravenous injection of both a conventional ionic agent (sodium iothalamate) and a new, low-osmolality non-ionic agent (iohexol) have been studied. Multiple abnormalities were observed but in every category significantly less frequently, or not at all, with iohexol. The most common abnormality was an increase in sinus rate of 15 beats/min over the rate during needle insertion. Other abnormalities observed included T-wave flattening and premature atrial and ventricular contractions. Contrary to some previous studies, we did not find that age, known heart disease or an abnormal base-line ECG were statistically significant determinants of subsequent ECG changes on contrast administration. There was, however, a significant correlation between ECG changes and more severe subjective side-effects experienced after the contrast injection. This offers support for the theories suggesting a psychogenic basis for some contrast reactions, since low-osmolality contrast media are known to produce less marked subjective side-effects. The new agents are known to be less cardiotoxic and to produce less profound hemodynamic changes. These factors may also play a part in the observed reduction in ECG disturbance.

/HUMAN EXPOSURE STUDIES/ As part of a general safety study of iopamidol, a nonionic iodinated contrast agent, urine N-acetyl-beta-glucosaminidase enzyme assays were done to compare the renal toxicity of iopamidol with that of iothalamate and diatrizoate. In a randomized study of 30 patients for computed body tomography and another 30 patients for angiography, 10 in each group were injected with iopamidol, 10 with iothalamate, and 10 with diatrizoate. After computed tomography or angiography with the three agents, there was no significant difference in urinary enzyme levels among the groups. The nephrotoxicity of iopamidol appears equivalent to that of diatrizoate and iothalamate.

/CASE REPORTS/ A case of ventricular tachycardia occurring after intravenous injection of sodium iothalamate (Conray 420) into a patient taking prenylamine is described. Both of these drugs may cause prolongation of the corrected QT interval and the mechanisms of this potentially fatal drug interaction are discussed.

/OTHER TOXICITY INFORMATION/ The newest addition to a group of contrast media utilized in excretory urography is iothalamate (Conray). Its basic chemical structure, 2,4,6- triiodobenzoic acid, is shared with acetrizoate (Urokon), diatrizoate (Hypaque and Renografin ), and diprotrizoate (Miokon ). The structural differences between these organic iodides are determined by the nature of the radicals at positions three and five. lothalamate differs from diatrizoate by the substitution of -CONHCH., for -NHCOCH., in position three. Conray-60-60%, is the methylglucamine salt. Whereas, Conray-400 - 66.8% and Angio-Conray - 80% are the Na salts of iothalamate. The Na salts, although more likely to produce tissue irritability, are less viscous than the methylglucamine preparations in solutions of the same concentration. In a previous study, the renal clearance of (131)I labeled Na iothalamate was found to approximate that of inulin. However, no inferences could be made as to clearances at both high and low plasma concentra tions, because the carrier utilized in this study was the methylglucamine instead of the Na salt of iothalamate. The purpose of this study is to investigate the use of a radioactive form of this contrast medium for the measurement of glomerular filtration rate (GFR ) in man.The average inulin-to-iothalamate (131)I clearance ratio obtained from 100 renal clearance studies in 16 subjects was 1.005. lothalamate (131)I provides an accurate measurement of glomerular filtration rate in man.

/OTHER TOXICITY INFORMATION/ The renal clearance of iothalamate sodium (125)I, identical to that of inulin, permits measurement of glomerular filtration rate with a single injection in varying degrees of renal failure.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Diatrizoate sodium

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/ALTERNATIVE and IN VITRO TESTS/ Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. Effects of ioversol were compared with equi-iodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided.These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

/ALTERNATIVE and IN VITRO TESTS/ The direct effects of sodium iothalamate on renal vascular resistance (RVR) were examined using the isolated perfused rat kidney experimental model. A concentration-dependent biphasic change in RVR was produced with the hyperosmolar solution of sodium iothalamate [(Conray 420), 420 mgI/mL, 2500 mOsmol/kg/H2O]. The response characterized by an initial fall followed by a prolonged increase in RVR on discontinuation of the iothalamate infusion. No significant change in RVR was observed when iothalamate was infused as an iso-osmotic solution (60 mgI/mL, 280 mOsmol/kg/H2O) at a rate of 0.525 mL/min. to produce a concentration of 4.2 mgI/mL in the renal perfusate. We conclude that sodium iothalamate can exert direct biphasic effects on RVR which are mediated by its hyperosmolality rather than its chemical content.

/OTHER TOXICITY INFORMATION/ The authors compared the renal toxicity of the low osmolality radiocontrast agents, iohexol and ioxaglate, and the ionic agent, iothalamate, at equivalent iodine dose, using experimental models in vitro and in vivo. In isolated perfused rat kidneys, all agents induced comparable biphasic hemodynamic changes, associated with similar declines in glomerular filtration rate (GFR) and tubular necrosis. In two different in vivo models (using multiple insults combined with the administration of radiocontrast), iothalamate appeared to induce more severe morphologic injury. Despite similar nephrotoxic potential in vitro, the newer radiocontrast agents, iohexol and ioxaglate, cause in vivo less renal injury than iothalamate in the experimental models.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 22,494 workers (15,852 of these were female) were potentially exposed to iothalamate in the US(1). Occupational exposure to iothalamate may occur through dermal contact with this compound at workplaces where iothalamate is produced or used. Monitoring data indicate that the general population may be exposed to iothalamate via dermal contact contaminated drinking water. Exposure to iothalamate among the general population may be limited to those administered the drug as a contrast agent(SRC).

DRINKING WATER: It has been suggested that in all countries with an advanced medical care system, x-ray contrast media can be expected to be present in sewage effluent which, therefore, leads to potential contamination of receiving waters(1).

SURFACE WATER: Iothalamate has been detected in German surface waters at a median concentration of 0.23 ug/L with isolated maximum values exceeding 100 ug/L(1).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Rat intravenous 14,700 mg/kg

LD50 Mouse intramuscular 20,349 mg/kg

LD50 Mouse intravenous 1400 mg/kg

LD50 Cat intravenous 11,300 mg/kg

LD50 Dog intravenous 13,200 mg/kg

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