Excretion of aqueous myelographic contrast media in animals undergoing a repeat myelogram.

The rate of elimination of contrast media may be a factor in side effects and complications of aqueous myelography. The authors studied the effect of a previous myelogram and arachnoiditis on the elimination of aqueous contrast media from the subarachnoid space. Serum and cisternal CSF iodine concentrations were measured after experimental myelography in subhuman primates. The transfer of the aqueous contrast media from CSF to serum was slowed and the circulation with the cerebrospinal fluid into the intracranial cisterns was increased by a previous myelogram or arachnoiditis.

Urographic excretion studies with metrizamide and "Dimer": a high dose comparison in dogs.

Metrizamide, a new non-ionic, triodinated contrast agent has been considerable for intravenous urography. Theory predicts that lower osmotic diuresis with this agent should lead to higher urinary iodine concentrations than with ionic agents, at equivalent iodine doses. However, a distinct advantage with metrizamide has not been observed with doses of 175 mgI/kg or less. In this study metrizamide and sodium locarmate were given intravenously to dehydrated dogs at a dose level of 600 mgI/kg. During the studies the concentrations and outputs of major urinary solutes were compared. Comparisons of urinary iodine concentrations and outputs showed that at this dose the predicted advantage with metrizamide can be observed.

Metrizamide in experimental urography. IV. Effects of bilateral ureteric stasis on urine iodine concentration after intravenous infection of an ionic and a non-ionic contrast medium.

The non-ionic contrast medium metrizamide was compared to the sodium salt of diatrizoate to investigate the potential usefulness of metrizamide in clinical urography when ureteric stasis is applied. After intravenous injection of the contrast media to rabbits at dose level 175 mg I/kg, the kidneys were subjected to temporary bilateral ureteric stasis. Urine was collected through ureteric catheters and analyzed for its concentration of iodine, sodium and potassium. After metrizamide injection the urine iodine concentration was twice as high as after sodium diatrizoate injection. This difference between one non-ionic and one ionic contrast medium was larger than what has been reported earlier during free flow of urine at the same dose. Furthermore, during the periods of ureteric stasis metrizamide was excreted faster than diatrizoate. When diatrizoate was given as its sodium salt, the sodium given was excreted at about the same rate as the diatrizoate given.

Metrizamide in urography. II. A comparison of 51Cr-EDTA clearance and metrizamide clearance in man.

In nine subjects undergoing urography with metrizamide measurements of total serum clearance of 51Cr-EDTA have been made before, during, and after the urography. During the urography both total serum clearances and renal clearances were determined for 51Cr-EDTA and metrizamide. The present study in man confirms the previous results from investigations in rabbits, that most of the intravenously injected metrizamide is excreted through the kidneys, that tubular reabsorption of metrizamide occurs and suggests that metrizamide might be used with advantage for urography.

Mechanism of renal excretion of various X-ray contrast materials in rabbits.

The excretory behavior of nine nephrotropic contrast agents with varying physicochemical properties such as charge, lipophilicity, and molecular size was investigated. Renal clearance in comparison with inulin was determined by means of the continuous infusion method. Each contrast agent was infused at three dose levels in four to six rabbits. The investigations show that tubular transportation in proportion to glomerular filtration decreases with increasing dosages of all the contrast agents. Thus, with the highest concentration in plasma all contrast agents are eliminated at more or less the glomerular filtration rate (GFR). After administration of the low dosages the following differences are found: 1) Net tubular secretion increases for the monomeric contrast agent acids with increasing lipophilicity, in the order diatrizoate congruent to iothalamate less than iodamide less than acetrizoate. 2) The clearance studies do not reveal any tubular secretion or reabsorption for a hydrophilic cationic contrast agent. 3) The nonionic contrast agents do not show net secretion. The more lipophilic they are, the more they are reabsorbed. 4) Two dimeric contrast agents also do not reveal any tubular secretion. They seem to be reabsorbed more than monomers with the same charge.

Metabolism of urographic contrast media.

The metabolism of ionic and nonionic contrast agents was examined in the rabbit and in humans by specific measurement of iodide present in urine at different time intervals after injection of high contrast medium doses. Interest was focused on the experimental model compound C-29, which was investigated using a 125I-labeled compound, permitting a study of iodide release and the appearance of other metabolites in serum, bile, and urine from rabbits. Large, quantitative, individual variations were found, but in most cases th urine collected from both rabbits and humans contained more iodide than had been injected. A mean of 0.07% of total injected iodine was found within three days after injection of the ionic contrast medium metrizoate. The results with rabbits indicated that this figure may increase to 1% using the nonionic media tested. Direct evidence of metabolism of C-29 was found in bile, where up to 35% of the total radioactivity present in the bile 4-6 hours after injection was identified as a metabolite.

Penetration of subarachnoid contrast medium into rabbit spinal cord. Comparison between metrizamide and iohexol.

The penetration into rabbit spinal cord of two nonionic contrast media, iohexol and metrizamide, and a reference tracer, technetium DTPA, were compared. The spinal subarachnoid space was perfused for 4 hours with a CSF solution to which technetium DTPA and either iohexol or metrizamide had been added. The contrast media and technetium DTPA concentrations reached a plateau level in CSF outflow within 80 minutes. The contrast media concentrations in CSF were higher than the technetium DTPA (P less than .001). In the cord tissue, technetium DTPA reached higher concentrations than the contrast media (P less than .001), and iohexol reached higher concentrations relative to technetium DTPA than metrizamide (P less than .001). The mean contrast media distribution volumes in the thoracic cord were 13% (iohexol) and 12% (metrizamide). The smaller distribution volume observed for metrizamide could be related to the larger effective size of "associated" metrizamide molecules or an interference with diffusion perhaps related to binding to glucose carriers.

Metrizamide in experimental urography. V. Renal excretion mechanism of a non-ionic contrast medium in rabbit and cat.

The excretion mechanisms of the non-ionic contrast medium, metrizamide, and the ionic, sodium diatrizoate, are compared to investigate the potential usefulness of metrizamide in clinical urography. A mixture of 125I-labeled metrizamide and 131I-labeled diatrizoate was injected intravenously to rabbits or cats. Urine, bile and blood were analyzed for their concentration of iodine. From these concentrations the renal and total clearance was calculated. In the rabbit the excretion of metrizamide was also compared with that of 3H-inulin with or without influence of p-aminohippurate or probenecid. The earlier reported relatively low urinary iodine concentrations after intravenous injection to rabbits of low doses were explained by the following findings: In the rabbit the volume of distribution, the renal clearance and the total clearance of metrizamide were smaller than those measured for diatrizoate and inulin. The biological half-life in serum measured 30-150 min after injection was the same for all three compounds. No indication of tubular secretion was found. The excretion mechanism of the contrast media exhibits species differences as no differences between metrizamide and diatrizoate in the parameters mentioned above could be measured in the cat.

Contrast enhancement pharmacokinetics of six ionic and nonionic contrast media.

The contrast enhancement of six contrast media (CM) was compared in 13 tissues of the rat after rapid intravenous bolus injection. The rats were sacrificed at 0 and 40 seconds and 2, 5, and 15 minutes after contrast injection. 125I labeled diatrizoate, metrizamide, ioxaglate, iohexol, iopamidol, and a nonionic dimer, iodecol, were each injected at a dose of 612 mg iodine per kg body weight, and iodine concentration (IC) and contrast enhancement were calculated from radioactivity measurements. Higher blood IC values were obtained with the nonionic CM; similar enhancement patterns were seen in the spleen, heart, lungs, and brain. Renal IC was directly related to the number of iodine atoms per ion or molecule of CM. In consequence, renal IC was inversely related to the CM osmolality, but no such correlation was seen with the blood IC. Metrizamide produced the greatest IC in the organs of the gastrointestinal tract. There was no apparent correlation of IC with molecular structure of physicochemical parameters of the CM in any of the other tissues studied.

Elimination of aqueous myelographic contrast media from the subarachnoid space.

Elimination of aqueous contrast media from the lumbar subarachnoid space was measured. Iodine concentrations in serum and cisterna magna cerebrospinal fluid were studied in animals undergoing myelography with metrizamide, iocarmate, Iopamidol, or P-297. We found that all four contrast media were eliminated rapidly into the serum and urine, and transported slowly into the basal cisterns.

Assessment of a non-ionic contrast medium (Amipaque) in the gastrointestinal tract.

Gastrografin and Amipaque with identical iodine content and flavoring were orally administered in 100 ml doses to 10 healthy volunteers in a double-blind crossover study. The nonionic Amipaque has only about one third of the osmolality of Gastrografin, and draws less fluid into the bowel lumen. Consequently there is less dilution with Amipaque, and a higher contrast density in the ileocecal region can be observed. Unlike the highly hypertonic Gastrografin, Amipaque causes less changes in hematocrit, and has only a very mild cathartic effect. No more than 0.4% of the iodine in Amipaque was excreted in the urine during one day, and no more than 0.8% during three days. This was less than the excretion found after ingestion of Gastrografin. Non-ionic media are recommended when there is an indication for use of water-soluble contrast media in the gastrointestinal tract.

Osmotic effect and solubility of amipaque (metrizamide) in the gastrointestinal tract.

Loops of small intestine in seven rabbits were resected with intact pedicle and ligated at both ends after instillation of 0.5 ml of Gastrografin, Urografin 76%, Amipaque 370 mg I/ml, Amipaque 170 mg I/ml or physiologic saline. After half an hour, the amount of fluid in the loops containing Gastrografin and Urografin 76% increases about twice as much as in the loops containing Amipague with the same iodine concentration because of their greater osmolality. The differences between the loops with isotonic Amipaque (170 mg I/ml) and physiologic saline are not significant. Precipitation occurs when sodium and meglumine salts of diatrizoate, metrizoate, iothalamate, iocarmate and ioglycamate are mixed with 0.05 N HCl. No precipitation occurs with Amipaque, not even when the HCl concentration is as high as 1.2 N. Precipitation occurs when Gastrografin is added to gastric juices with low pH, but is not seen with Amipaque should be a suitable contrast medium for gastrointestinal examinations because of its low osmolality and toxicity and good solubility in gastric juice.

Beta-endorphin suppression of acute morphine abstinence in morphine dependent monkeys: effective given intraventricularly but ineffective given intravenously.

Six female adult Macaca mulatta monkeys were made dependent upon morphine sulfate and were implanted with a chronic indwelling needle in the lateral ventricle of the brain for sterile intraventricular injections. Both beta-endorphin and morphine, in a dose dependent manner given intraventricularly suppressed the signs of 14 hour acute morphine abstinence. On a molar basis, beta-endorphin was more active than morphine in suppressing the signs of morphine abstinence. When given intravenously in much larger doses, beta-endorphin was ineffective in contrast to morphine which was effective in suppressing abstinence.

Elimination of metrizamide from the spinal subarachnoid space: a study of patients with abolished intracranial circulation.

Two absorptive pathways for contrast media injected into the lumbar subarachnoid space have been postulated: (1) through the intracranial parasagittal arachnoid granulations and (2) direct absorption through the spinal arachnoid villi into the blood. To study the capacity of the spinal absorptive pathway, serial measurements of metrizamide concentrations in blood serum and urine were obtained before and after lumbar intrathecal injection of contrast medium in four patients with arrested intracranial blood circulation ("brain death") and intracranial pressure exceeding systolic blood pressure who had no circulation of cerebrospinal fluid from the spinal subarachnoid space to the parasagittal arachnoid granulations. These measurements indicated a high capacity of the spinal absorptive pathway for metrizamide elimination.

Intramedullary penetrance of metrizamide in the dog spinal cord.

Metrizamide computed tomography (CT) myelography is clinically useful in the detection of syringohydromyelia. The mechanism by which intrathecally injected metrizamide migrates into the intramedullary cavity is unknown, although reflux into the central canal of the cord via the obex has been postulated. Since intrathecally injected metrizamide has been shown to penetrate normal brain, similar penetrance of the spinal cord might be expected. Five anesthetized mongrel dogs were examined with sequential CT scanning of the cervical spine for 24 hr after intrathecal introduction of metrizamide. The attenuation values of the specified subarachnoid space and the spinal cord at the level of the atlantoaxial joint were recorded. A significant and reproducible increase with time in attenuation values within the cervical spinal cord accompanied by a progressive decrease in attenuation values of the subarachnoid space was observed. The proposed mechanism of cord enhancement, the implication for cord imaging, and the analysis of patients with syringohydromyelia are discussed.

Brain parenchyma penetration by intrathecal ionic and nonionic contrast media.

Metrizamide, a nonionic water-soluble contrast medium, has been shown to penetrate normal brain when injected intrathecally. Recently it was suggested that the complications following intrathecal metrizamide are directly related to the cerebral concentration reached. Metrizamide, both in experimental animals and clinically, is regarded as less neurotoxic than equivalent iodine concentrations of ionic contrast media. In this study the degree and depth of brain penetration of intrathecal metrizamide and methylglucamine iothalamate (Conray 280), using a similar iodine concentration (280 mg l/ml), was compared at 1 hr in adult greyhound dogs. The depth of penetration and concentration reached in the cortical gray matter was determined by coronal computed tomographic scanning of the brain after removal. No significant difference was found between the two contrast media, suggesting that the rate of diffusion across the cerebrospinal fluid-brain interface is similar and that the difference in neurotoxicity is not explained by a reduced concentration of contrast medium in the case of nonionic metrizamide, when compared with ionic methylglucamine iothalamate. Using Evans blue as a qualitative marker, no evidence of gross blood-brain disruption was demonstrated in the area of maximum penetration with either contrast medium.

Concentration of intrathecal 3H-labeled metrizamide in normal dog brain: age-related differences.

Responses to intrathecal metrizamide in dogs were found to be age-related: Adult dogs had seizures; 7-week-old dogs appeared stuporous; 6-day-old dogs were clinically unaffected. The brain metrizamide concentrations 4, 6, and 20 hr after intrathecal injection correlated directly with the occurrence and severity of neurotoxic symptoms. Age-related differences in brain metrizamide concentration may be explained by two factors. The first is the failure of current clinical guidelines to adjust the recommended dosage of metrizamide to reflect differences among age groups in brain weight rather than body weight. This error resulted in lower doses/gram of brain weight being given to the puppies. However, the large differences in brain metrizamide concentrations among the three groups of dogs could not be explained solely by differences in the dose. A second factor, physiologic age-related differences in brain penetration, is believed to be operative. The precise nature of these differences is unclear.

Iotrol, a new myelographic agent: 1. Radiography, CT, CSF clearance, and brain penetration.

Four new myelographic agents, metrizamide, iopamidol, iohexol, and iotrol, were studied in the subarachnoid space of cynomolgus monkeys. Plain films and computed tomographic scans documented the transport of each material throughout the space and into the brain. At the concentration used (300 mg I/ml), all gave good radiopacity for myelography and delineation of the cerebral subarachnoid space. All four cleared similarly from the ventricular system. Metrizamide, however, penetrated the brain in greater degree and persisted longer than the other three agents. Next in persistence was iopamidol and least, and both statistically equal, iotrol and iohexol.

Pharmacochemical profile of iopromide.

Iopromide (Schering, Berlin) is a new nonionic, monomeric contrast medium containing three different substituents on the triiodinated benzene ring. Iopromide exhibits low osmolality and viscosity in aqueous solutions of high concentrations. It has been shown to have a remarkably low intravenous toxicity in mice and rats. Neural tolerance was found to be equal to or better than that of metrizamide when injected in rats intracisternally and intracerebrally, respectively. The effects of iopromide after selective peripheral and cerebral arterial injections in rats were demonstrated to be very moderate at high dosages. The interaction of iopromide with proteins and membranes was found to be considerably low due to its hydrophilicity. Excretion of iopromide is fast and predominantly by the renal route. On the basis of the preclinical profile iopromide is a very promising contrast agent, being most suitable for all angiographic indications, including digital subtraction angiography, urography, and computed tomography.

Absorption of metrizamide from cereb rospinal fluid to blood: pharmacokinetics in humans.

The rate of transfer of contrast agents from cerebrospinal fluid to blood is of clinical importance in radiological examinations of the subarachnoid space. Metrizamide, a potential contrast medium, was injected intrathecally to humans and serum levels at different times after injection were measured. A one-compartment open model was found to apply to the data. Considerable individual variations were found, but the mean absorption rate constant indicated that more than 50% of the absorbed dose had disappeared from the cerebrospinal fluid 0.75 hr after injection. TLC of the fraction excreted in the urine showed that metrizamide was not metabolized in the body.