Neurotoxicity of X-ray contrast media. Relation to lipid solubility and blood-brain barrier permeability.
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An allergic, immunologic mechanism for certain adverse reactions to radiocontrast agents has been postulated on the basis of clinical and theoretical considerations. One obstacle to the acceptance of this allergic theory has been the inability to demonstrate significant antibodies with specificity for these agents. In our studies, rabbits were immunized with 4 analogues of radiocontrast agents which induced IgG or IgE antibodies specific for the contrast media analogues. Then, to determine if antibodies to contrast agents were present in man a prospective, one-year surveillance of radiocontrast agent reactions was undertaken. Sera from 27 patients suffering severe reactions and 37 control subjects were analyzed by radioimmunoassay for antibodies reactive with radiocontrast media. Binding of radiolabeled contrast media was significantly elevated (p less than 0.01) by the serum globulin fraction of the patients suffering severe reactions. Demonstration of this antibody activity, although not proof of cause and effect between the presence of antibody activity and clinical symptoms, nonetheless adds support to the hypothesis that some adverse reactions to radiocontrast agents are due to antibodies.
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An abnormal filtration fraction or a significant divergence between a kidney's ability to extract Tc-99m dimercaptosuccinic acid (DMSA) and other function parameters, such as the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF), could lead to different estimates of relative or absolute renal function, depending on the radiopharmaceutical administered. To evaluate this possible divergence, we measured the relative GFR (I-125 iothalamate), ERPF (I-131 hippurate), and Tc-99m DMSA accumulation in adult male Sprague-Dawley rats with unilateral ureteral obstruction or unilateral ischemia at various times after renal injury. The relative ERPF of the obstructed kidney was significantly greater than the relative GFR at all time periods studied; significant but less dramatic differences were noted comparing DMSA with GFR in obstruction and DMSA and ERPF with GFR in ischemia. In evaluating renal disease, it is important to consider the functional parameter reflected by the administered radiopharmaceutical as well as the underlying disease state.
The pure methylglucamin salt of 5 acetamido-N-(2-hydroxy-ethyl). 2,4,6-trijodisophthalamic acid has been tested on 163 arterio- and venograms. Density of contrast and side effects proved favorable. Since it is easily injected, this substance is suitable for angiography.
It has been proposed that adenosine, derived from ATP and released into the renal interstitium, mediates a reduction in renal function in ischemic acute renal failure. Because no direct measurements of interstitial adenosine are available, we evaluated an in vivo microdialysis technique to assess the levels of adenosine and its metabolites in the cortex of the normal rat kidney (n = 6). Microdialysis probe implantation did not alter cortical renal blood flow, glomerular filtration rate, or fractional sodium excretion. The interstitial concentration of adenosine was 199 +/- 53 nM, and relative concentrations of inosine, hypoxanthine, xanthine, and uric acid were 99 +/- 47, 182 +/- 29, and 183 +/- 70 nM and 1.8 +/- 0.4 microM, respectively. Infusion of ATP-MgCl2 (n = 5) resulted in a significant increase in the dialysate levels of adenosine (67 +/- 11 to 378 +/- 97 nM), inosine (230 +/- 102 to 803 +/- 219 nM), and uric acid (3.5 +/- 1.3 to 6.9 +/- 1.7 microM). In conclusion, this study demonstrates that the microdialysis technique is suited to monitor metabolically important substances in the renal interstitium.
All current intravascular radiological contrast media are salts and produce solutions of very high osmolality--five to eight times that or tissue cells, plasma or tissue fluid (all of which have an osmolality of 300 mosmols per kg water). Erythrocytes and vascular endothelium are adversely affected by the high osmolality of intravascular contrast media, resulting in tissue anoxia and increased capillary permeability, the latter causing damage to the blood-brain barrier. Vasodilatation, systemic hypotension and osmotic hypervolaemia are generalized manifestations of the high osmolality of contrast media. New low osmolality contrast media have been synthesized, utilizing a non-ionizing radical (such as amide or amine) instead of the carboxyl group of a tri-iodinated substituted benzoic acid. Such examples are metrizamide (Amipaque) and Iopamidol (both non-ionic amides) and Hexabrix (salts of a mono-acid dimer). Early clinical evaluation suggests that these low osmolality solutions have major advantages in reducing pain, heat sensation and adverse reactions of angiography.
The influences of two water soluble contrast media, meglumine iothalamate and meglumine iocarmate, on the neuronal excitability and on the neuronal sensitivity to putative transmitters were examined in comparison with those of sucrose using two identifiable giant neurones of Achatina fulica Férussac (the TAN and the PON). A relatively low increase of osmotic pressure of the extracellular fluid, produced by the application of contrast media, reversed the Cl- dependent inhibition caused by a putative transmitter. The same increase of this osmotic pressure, however, did not influence the Cl- independent inhibition and the excitation of the neurone examined. The hyperpolarization of neuromembrane was caused by an increase of osmotic pressure of the extracellular fluid. Its relatively high increase was necessary to make spontaneous spike discharges disappear totally. All effects of the two contrast media, observed in this study, were due to the increase of osmotic pressure of the extracellular fluid ; no specific effect of the contrast media containing the iodine on the indicators used was observed.
For perioperative prophylaxis 200 mg ciprofloxacin were administered as a short intravenous infusion to 17 patients aged 57-84 years before transurethral resection (TUR-P) or transvesicular enucleation (TVP) of the prostate. 13 patients were injected simultaneously with 2.5 g ioxitalamic acid i.v. to determine the kidney function. In 11 patients the plasma concentrations were assayed and the pharmacokinetic parameters calculated. At the end of infusion the concentrations of ciprofloxacin in plasma reached 4.2 +/- 0.8 microgram/ml and decreased after a fast distribution period (plasma half-life 0.20 +/- 0.09 h) with a terminal half-life of 4.2 +/- 1.3 h to 0.2 +/- 0.09 microgram/ml after 10 h. The apparent volume of distribution in steady state was 183 +/- 45% of body weight, the plasma clearance 457 +/- 146 ml/min/70 kg. The average concentrations in prostatic adenoma tissue were at all sampling times higher (2fold) than in plasma. The mean concentrations in prostatic secretion were about half of the respective plasma concentrations. High concentrations of the concomitantly administered ioxitalamic acid in prostatic secretion are considered as an indicator of urinary contamination. In those patients high ciprofloxacin concentrations in prostatic secretion are not reliable.
Nephrotoxicity due to injection of uro-angiographic water soluble contrast media is a wellknown hazard in patients with renal failure, diabetes mellitus, cardiovascular disease, multiple myeloma and old age. Cases of nephrotoxicity in other patient populations are extremely rare. In order to document the influence of water soluble contrast media in patient undergoing intravenous urography diuresis, osmolar changes, creatinine clearance, absolute urinary creatinine excretion and uric acid metabolism were evaluated before and after contrast medium injection. No adverse reaction could be evidenced as far as the renal function is concerned, as creatinine clearance and absolute urinary creatinine output values showed no significant differences. The significant raise (p less than or equal to 0.001) of uric acid excretion (absolute urinary uric acid excretion values before and after contrast injection were respectively 5.22 micrograms/min.kg (IR: 3.24) and 10.68 micrograms/min.kg (IR: 4.03] can be co-responsible for adverse reactions when the renal function is not normal.
The inhibitory effect on platelet function induced by several radiographic contrast media is still poorly understood. In this study platelet abnormalities caused by in vitro addition of ioglicinic acid, a new ionic contrast medium, were evaluated. The appearance of several granules similar to dense bodies associated with shape change and internal reorganization were detected by electron microscopy techniques. A functional study revealed a marked decrease in the aggregating response of platelets to adenosine diphosphate and calcium ionophore A23187, while aggregation in response to collagen was completely normal. It is suggested that ioglicinic acid induces platelet abnormalities related to the effect on calcium movements and that studies with this contrast medium may help the understanding of some basic events of platelet activation.