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Cholangiographic excretion studies: a comparison of iodipamide and iodoxamate in the dog.

Iodoxamic acid is a new hexaiodinated cholegraphic contrast agent. The methylglucamine salts of iodoxamate and iodipamide were administered to labrador dogs as an intravenous infusion. Bile salts were also infused. The biliary concentration and output of the two agents were compared. Bile flow rate, bile salt concentration and bile salt output with the two agents were also compared. The biliary output of iodoxamate (0.70-0.78 mumol/min/kg) was more than 50% higher than the iodipamide output (0.46 mumol/min/kg). Bile salt output and concentration with iodoxamate infusion were lower than with iodipamide infusion. The bile flow rate was higher with the new agent. The complementary effects of increased contrast output and decreased bile salt output with the new agent led to a significantly higher biliary iodine concentration compared with iodipamide. The results of this study support the suggestion that iodoxamate represents a significant advance in the cholegraphic contrast media field.

Animals↗

Saturation kinetics and choleretic effects of iodoxamate and iodipamide.

The biliary excretion and choleretic effects of iodoxamate (Cholevue) and iodipamide (Cholografin) were compared in unanesthetized dogs with biliary fistulas in order to assess the potential of the two contrast agents for use in intravenous cholangiography. For any equimolar infusion rate, more iodoxamate was secreted in the bile than iodipamide was the same. At the constant basal bile flow maintained in these studies, there was no difference in the maximum biliary concentration of the two compounds. With the presently recommended doses, it is unlikely that iodoxamate will offer a striking improvement over iodipamide for intravenous cholangiography in patients with normal liver function.

Animals↗

Elevation of serum lactate dehydrogenase-5 following methylglucamine iodipamide (Cholografin/Biligrafin) infusion for intravenous cholangiography.

Methylglucamine iodipamide (Cholografin-North America; Biligrafin-Europe, Squibb) is the only contrast medium in clinical usage for opacification of the biliary tree in intravenous cholangiography. We report two cases of elevation of serum lactate dehydrogenase-5 activity following infusion of 40 ml of Cholografin. This occurred without overt clinical signs of adverse reaction to contrast medium. This elevation was 65% of serum LD-5 activity in case one, 91% in case two. The elevation peaked at 12 h after administration of contrast medium in both cases and persisted for at least 24 h. These findings suggest that methylglucamine iodipamide causes transient hepatocellular toxicity, the mechanism of which is not known.

Adult↗

Biliary excretion of iodipamide and iodoxamate in normal and common bile duct-obstructed dogs.

Iodipamide and iodoxamate were compared at equimolar clinical dosages in dogs with normal, incompletely obstructed and completely obstructed common bile ducts. Forty-eight experiments were performed under general anesthesia in six cholecystomized chronic bile fistula dogs. The peak biliary iodoxamate excretion rate, but not the peak bile iodoxamate concentration, was significantly higher with normal and incompletely obstructed common bile ducts. In complete obstruction, both a significantly higher total biliary iodoxamate excretion and concentration were obtained, but this was still insufficient for radiographic opacification by conventional technique. Lesser toxicity of iodoxamate is suggested by its significantly lower serum levels, its higher bile: urine excretion ratio and its faster compensatory urinary excretion in complete common bile duct obstruction. Iodoxamate appears on this evidence to be a better cholangiographic contrast agent than iodipamide.

Animals↗

Biliary excretion of iodipamide and iodoxamate in dogs with hepatic dysfunction induced by oral administration of dimethylnitrosamine.

Iodipamide and iodoxamate were compared in equimolar clinical dosages in five cholecystectomized chronic bile fistula dogs in which hepatic dysfunction was produced by oral administration of a total dose of 480 and 960 microliters dimethylnitrosamine (DMNA), respectively. After both DMNA dosages, the peak biliary excretion rate for iodoxamate was significantly higher than for iodipamide (p less than 0.01). The peak bile iodine concentration was not significantly different for the two agents (480 microliter DMNA: p less than 0.1; 960 microliter DMNA: p = 0.07). On the basis of this investigation, it is suggested that iodoxamate should not significantly improve the opacification of the biliary system in patients with hepatic dysfunction.

Animals↗

Iotroxamide--a new intravenous cholangiographic agent. Comparison with iodipamide and the effect of bile salts.

The maximum biliary excretion rate of iotroxamide was found to be significantly greater than that of iodipamide in bile-fistula dogs. High bile salt excretion rates had no effect on the rate of biliary excretion of either compound, but the choleresis associated with greater bile salt excretion reduced the biliary concentration of both agents. Both are potent choleretics, stimulating about 23.5 ml of bile per mmole of contrast agent excreted in bile. This obligatory coupling of the contrast agents with water as they are excreted in bile imposes a limit on the maximum concentration that can be achieved in bile. Since iotroxamide is excreted more rapidly in bile than iodipamide for any equimolar plasma concentration, it may be a superior contrast agent for intravenous cholangiography.

Animals↗

Biliary iodipamide and iodoxamate excretion as function of basal bile flow in normal, common bile duct obstructed and liver-damaged dogs.

The investigation was performed in 6 cholecystectomized chronic bile fistula dogs in which, except in complete common bile duct obstruction, the bile was diverted and replaced with a constant taurocholate infusion of 0.3 mumoles per min. per kg. Iodipamide and iodoxamate were i.v. infused at a rate of 6.7 mumoles per minute per kg for 30 minutes. Different degrees of extrahepatic obstruction were simulated by producing different intrabiliary pressure conditions. Progressive hepatic parenchymal disease was induced by oral administration of dimethylnitrosamine. In both conditions basal (precontrast) bile flow, maximum biliary excretion rate and bile concentration of the contrast agents decreased with increasing hepatic dysfunction. This investigation suggests that, regardless of the underlying mechanism, the bile iodine concentration required for radiographic visualization of the biliary system is no longer attained in intravenous cholangiography when the basal bile flow decreases below 2 microliter per min per kg in the presence of a physiologic bile salt plasma pool. In hepatic dysfunction alkaline phosphatase correlated better with the maximum biliary excretion rate and concentration of the contrast agents than SGPT, SGOT, and serum bilirubin and therefore seems to be the best parameter to predict the chance of a successful intravenous cholangiography.

Animals↗

Biodistribution of a particulate hepatolienographic CT contrast agent: a study of iodipamide ethyl ester in the rat.

Particulate contrast agents have been shown to be efficacious in computerized tomographic detection of liver tumors. This article quantitatively defines the biodistribution of the experimental particulate agent iodipamide ethyl ester in the rat as a function of time after intravenous infusion. The contrast agent is actively accumulated in the liver and spleen with high selectivity compared to iodine concentrations in the blood or other organs. The contrast material remains at high concentration in the liver for more than 2 hours and then is slowly cleared from the organism in approximately two days. The high selectivity and retention of contrast in the liver are indicative of the value of particulate agents in contrast-enhanced computerized tomography.

Animals↗

Effect of intravenously administered iodipamide ethyl ester particles on rat liver morphology.

The effect of intravenously injected iodipamide ethyl ester (IDE) particles (150 mgI/kg) on the rat liver was studied by light and electron microscopy. IDE particles were phagocytized by Kupffer cells within a few minutes postinjection. After 4 hours particles began to dissolve in the Kupffer cells causing transient morphologic alterations resembling hydropic degeneration. The number of Kupffer cells seemed, however, to be unchanged and were ultrastructurally normal by 17 days postinjection. Hepatocytes contained large lipid droplets from one to four days after IDE injection. No changes were found in the hepatocytes from one week to one year after IDE injection. The fat-storing cells and endothelial cells remained ultrastructurally normal throughout the study.

Animals↗

Response of white blood cells to iodipamide ethyl ester particles.

The effect of intravenously injected iodipamide ethyl ester (IDE) particles (150 mgl/kg) on white blood cells was studied by light and electron microscopy. The clearance of IDE from rat plasma also was determined by analyzing free IDE particles in a counting chamber. The total white blood cell count remained essentially unchanged up to 40 minutes after the IDE injection, but the polymorphonuclear (PMN) neutrophil count decreased significantly. At 5 minutes postinjection, occasional PMNs contained ingested IDE particles, but by 40 minutes no intracellular particles could be found in the peripheral circulation. In vitro incubation experiments confirmed that human PMNs ingest IDE particles. In electron microscopy, the cells and particles seemed to be morphologically intact. Of the IDE particles counted at 5 minutes postinjection, only 4% remained in plasma at 30 minutes and none at 40 minutes. The decrease in PMN count apparently reflects sequestration of phagocytic cells from the circulation.

Animals↗

Computed tomographic enhancement of liver and spleen in the dog with iodipamide ethyl ester particulate suspensions.

Particulate suspensions have been developed for use as contrast agents to aid in the detection of hepatic lesions by CT. In several previous rodent studies, the toxicity and tissue concentrations of iodipamide ethyl ester (IDE) particles have been evaluated. The purpose of this study was to determine the pharmacokinetics of IDE in three dogs by evaluation of CT enhancement. Serum chemistry and hematologic parameters after intravenous administration were also followed. A dose of 75 mgI/kg IDE caused an increase of 40-60 Hounsfield units (HU) in liver attenuation, which persisted from 5 minutes to ten hours postinfusion. No enhancement of tissues other than liver and spleen was observed. IDE was completely eliminated from the liver within seven days. A mild transient elevation of liver enzymes may be attributable to the use of barbiturates rather than IDE. A transient depression of the white blood count was the only biochemical or hematologic change that was clearly in response to the infusion of IDE particulates.

Animals↗

Uptake and dissolution of particulate iodipamide ethyl ester in the spleen. A morphologic study.

Iodipamide ethyl ester (IDE) is an experimental particulate contrast agent being developed for CT image enhancement of the liver and spleen. IDE particles are phagocytized by the reticuloendothelial cells after an intravenous injection. The uptake and dissolution of IDE particles were studied in the spleen with light and electron microscopy. Two minutes after injection, intra- and extracellular IDE particles were found in the red pulp of the spleen. Highest concentration of IDE was seen in the marginal zone surrounding the white pulp. Particles also were seen elsewhere in the red pulp but only occasionally between the outermost cells of the white pulp. The extracellular particles disappeared within 4 hours postinjection. At one day postinjection, the amount of intracellular IDE particles had begun to decrease. Electron micrographs showed that the intracellular particles dissolved gradually in the phagocytes and caused transient degenerative morphologic changes. At three days postinjection, practically all IDE particles had disappeared from the spleen. Polystyrene latex particles were used as controls. They were phagocytized like the IDE particles, but they did not disappear from the phagocytes. IDE particles caused no morphologic injuries in nonphagocytic cells of the spleen.

Animals↗

Accumulation and elimination of particulate iodipamide ethyl ester in the lungs and kidneys of the rat. A morphological study.

Particulate iodipamide ethyl ester, a new hepatolienographic x-ray contrast agent, was intravenously injected into rats. Lung and kidney biopsies taken at various intervals after the injection were examined by light and electron microscopy. IDE particles could be found in the lung capillaries phagocytized by polymorphonuclear neutrophils (PMNs). There were also free particles in the alveolar capillaries in the samples taken 5 min to 4 hours after the injection. No aggregates or emboli were seen. Two days or more after the injection no intra- and extracellular particles were present. The PMNs underwent transient local hydropic degeneration; the lung cells were morphologically intact. In the kidneys, the particles first appeared in both cortical and medullary capillaries. No emboli were observed. The kidney cells did not ingest IDE, but polymorphonuclear neutrophils (PMNs) with ingested IDE were often seen loosely attached to the glomerular capillary walls. In addition, free particles were evident in the capillaries in the samples taken up to 1 hour after injection. All particles in subsequent kidney samples were located in PMNs in the glomeruli. After three or more days the renal tissue was totally devoid of particulate IDE. No morphological evidence of kidney cell injury was observed.

Animals↗

Renal tubular sludging of meglumine iodipamide (Biligrafin).

Linear densities which were thought to represent meglumine iodipamide were seen in the renal papillary tubules of three patients for respectively four, six and nine days following intravenous cholangiography (IVC). All three patients were children with hepato-biliary disease. Two patients had biliary roundworm infestation, and one patient had hepatic dysfunction and intestinal ascariasis with possible biliary involvement. Haematuria and renal enlargement were seen in one patient, but the cholangiogram was not conclusively implicated as a cause. This renal tubular "sludging" of biliary contrast medium is recorded because of its potential nephrotoxic significance. The possible causes are discussed.

Child↗

Double-blind comparison of meglumine lodoxamate (Cholovue) and meglumine iodipamide (Cholografin).

A double-blind comparison of two intravenous cholangiocholecystographic agents of similar molecular structure, meglumine iodoxamate and meglumine iodipamide, was carried out in 90 patients. Each produced a comparably high percentage of satisfactory examinations. A similar pattern of excretion speed and intensity was noted for each, though meglumine iodoxamate appeared to be slightly more effective in patients with elevated serum bilirubin. Less evidence of hepatic toxicity and fewer and less serious adverse side effects were observed in patients given the newer agent, meglumine iodoxamate.

Adult↗

Double-blind comparison of iodipamide and lodoxamate using direct and drip infusion intravenous cholangiography.

Biliary tract opacification was assessed in a double-blind clinical study that compared iodoxamate with iodipamide. Both drip infusion and direct (bolus) intravenous cholangiography were used to administer the contrast agents. The infusion method with either agent produced better opacification than bolus administration. Regardless of method used, iodoxamate produced greater biliary tract opacification, fewer unexplained failures, and fewer contrast reactions. Neither agent was successful in patients with elevated bilirubin levels, nor did either agent alter hepatic, renal, or hematologic function.

Alkaline Phosphatase↗

Meglumine iodipamide (Cholografin) hepatotoxicity.

Two cases of meglumine iodipamide (Cholografin) hepatotoxicity were confirmed by liver biopsy. The hepatic lesion was centrilobular in location and resolved within a short period of time. Nausea and vomiting commonly reported after intravenous cholangiography may be clinical manifestations of this entity.

Adult↗