Extracellular acidosis differentiates pancreatitis and pancreatic cancer in mouse models using acidoCEST MRI.

Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model treated with caerulein, which causes pancreatitis followed by development of pancreatic cancer. We also evaluated the KC model treated with PBS, and wild-type mice treated with caerulein or PBS as controls. The caerulein-treated KC cohort had lower pHe of 6.85-6.92 before and during the first 48 h after initiating treatment, relative to a pHe of 6.92 to 7.05 pHe units for the other cohorts. The pHe of the caerulein-treated KC cohort decreased to 6.79 units at 5 weeks when pancreatic tumors were detected with anatomical MRI, and sustained a pHe of 6.75 units at the 8-week time point. Histopathology was used to evaluate and validate the presence of tumors and inflammation in each cohort. These results showed that acidoCEST MRI can differentiate pancreatic cancer from pancreatitis in this mouse model, but does not appear to differentiate pancreatitis that progresses to pancreatic cancer vs. pancreatitis that does not progress to cancer.

A simple LC-MS method for the determination of iohexol and iothalamate in serum, using ioversol as an internal standard.

BACKGROUND: Chronic kidney disease (CKD) is diagnosed and explored through the determination of the glomerular filtration rate (GFR). Our goal was to develop a simple LC-MS method for the determination in serum of 2 popular GFR markers, contrast agents iohexol and iothalamate, for routine use and comparison studies between the two markers. A similar contrast agent, ioversol, was used as an internal standard and the method underwent a rigorous validation protocol based on ß-expectation tolerance intervals. METHODS: We adapted the HPLC-UV method from Cavalier et al. to our LC-MS system. Data treatment for the validation was performed using Multiquant 3.0 (Sciex, Framingham, MA, USA) and e.noval 3.0 software (Arlenda, Liège, Belgium). RESULTS: According to the validation results our method will give accurate and reliable results for concentrations ranging from 6.8 to 250µg/ml for iohexol and 6.15µg/ml to 250µg/ml for iothalamate. In our practice these intervals are sufficient to determine both compounds in most patient samples. Samples with higher detected concentrations can always be diluted into range. CONCLUSION: With its internal standard and extensive validation, our method is now ready for routine and clinical research use.

Do intravenous N-acetylcysteine and sodium bicarbonate prevent high osmolal contrast-induced acute kidney injury? A randomized controlled trial.

BACKGROUND: N-acetylcysteine (NAC) or sodium bicarbonate (NaHCO3), singly or combined, inconsistently prevent patients exposed to radiographic contrast media from developing contrast-induced acute kidney injury (CI-AKI). OBJECTIVE: We asked whether intravenous isotonic saline and either NaHCO3 in 5% dextrose or else a high dose of NAC in 5% dextrose prevent CI-AKI in outpatients exposed to high-osmolal iodinated contrast medium more than does saline alone. METHODS: This completed prospective, parallel, superiority, open-label, controlled, computer-randomized, single-center, Brazilian trial (NCT01612013) hydrated 500 adult outpatients (214 at high risk of developing CI-AKI) exposed to ioxitalamate during elective coronary angiography and ventriculography. From 1 hour before through 6 hours after exposure, 126 patients (group 1) received a high dose of NAC and saline, 125 (group 2) received NaHCO3 and saline, 124 (group 3) received both treatments, and 125 (group 4) received only saline. RESULTS: Groups were similar with respect to age, gender, weight, pre-existing renal dysfunction, hypertension, medication, and baseline serum creatinine and serum cystatin C, but diabetes mellitus was significantly less prevalent in group 1. CI-AKI incidence 72 hours after exposure to contrast medium was 51.4% (257/500), measured as serum creatinine > (baseline+0.3 mg/dL) and/or serum cystatin C > (1.1 · baseline), and 7.6% (38/500), measured as both serum creatinine and serum cystatin C > (baseline+0.3 mg/dL) or > (1.25 · baseline). CI-AKI incidence measured less sensitively was similar among groups. Measured more sensitively, incidence in group 1 was significantly (p<0.05) lower than in groups 2 and 3 but not group 4; adjustment for confounding by infused volume equalized incidence in groups 1 and 3. CONCLUSION: We found no evidence that intravenous isotonic saline and either NaHCO3 or else a high dose of NAC prevent CI-AKI in outpatients exposed to high osmolal iodinated contrast medium more than does saline alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01612013.

Formation of toxic iodinated disinfection by-products from compounds used in medical imaging.

Iodinated X-ray contrast media (ICM) were investigated as a source of iodine in the formation of iodo-trihalomethane (iodo-THM) and iodo-acid disinfection byproducts (DBPs), both of which are highly genotoxic and/or cytotoxic in mammalian cells. ICM are widely used at medical centers to enable imaging of soft tissues (e.g., organs, veins, blood vessels) and are designed to be inert substances, with 95% eliminated in urine and feces unmetabolized within 24 h. ICM are not well removed in wastewater treatment plants, such that they have been found at elevated concentrations in rivers and streams (up to 100 µg/L). Naturally occurring iodide in source waters is believed to be a primary source of iodine in the formation of iodo-DBPs, but a previous 23-city iodo-DBP occurrence study also revealed appreciable levels of iodo-DBPs in some drinking waters that had very low or no detectable iodide in their source waters. When 10 of the original 23 cities' source waters were resampled, four ICM were found--iopamidol, iopromide, iohexol, and diatrizoate--with iopamidol most frequently detected, in 6 of the 10 plants sampled, with concentrations up to 2700 ng/L. Subsequent controlled laboratory reactions of iopamidol with aqueous chlorine and monochloramine in the absence of natural organic matter (NOM) produced only trace levels of iodo-DBPs; however, when reacted in real source waters (containing NOM), chlorine and monochloramine produced significant levels of iodo-THMs and iodo-acids, up to 212 nM for dichloroiodomethane and 3.0 nM for iodoacetic acid, respectively, for chlorination. The pH behavior was different for chlorine and monochloramine, such that iodo-DBP concentrations maximized at higher pH (8.5) for chlorine, but at lower pH (6.5) for monochloramine. Extracts from chloraminated source waters with and without iopamidol, as well as from chlorinated source waters with iopamidol, were the most cytotoxic samples in mammalian cells. Source waters with iopamidol but no disinfectant added were the least cytotoxic. While extracts from chlorinated and chloraminated source waters were genotoxic, the addition of iopamidol enhanced their genotoxicity. Therefore, while ICM are not toxic in themselves, their presence in source waters may be a source of concern because of the formation of highly toxic iodo-DBPs in chlorinated and chloraminated drinking water.

Flow tracing microparticle sensors designed for enhanced X-ray contrast.

In applying the X-ray particle image velocimetry (PIV) technique to biofluid flows, the most pivotal prerequisite is suitable flow tracing sensors which should be detected effectively by the X-ray imaging system. In this study, to design those flow tracing sensors, X-ray contrast agent Iopamidol was encapsulated into the poly(vinyl alcohol) (PVA) microparticles crosslinked by glutaraldehyde (GA). The characteristics of the fabricated particle sensors were determined by optical microscopy, scanning electron microscopy, dynamic light scattering, laser Doppler electrophoresis and nuclear magnetic resonance spectroscopy ((1)H NMR). The amount of Iopamidol in the microparticles was measured using the energy dispersive X-ray spectroscopy (EDS) and (1)H NMR. The physical properties of the PVA microparticles are effectively controlled in terms of the average particle size, degree of crosslinking, degree of swelling and encapsulation efficiency of Iopamidol. By changing the amount of crosslinker, the degree of crosslinking and the efficiency of the Iopamidol encapsulation reached to the optimal. To some extent, the zeta-potential of the PVA microparticles is increased in less ionic media where the particles can effectively repel each other prohibiting aggregation. The X-ray absorption ability of the designed tracing sensors was examined by a synchrotron X-ray imaging technique. The X-ray absorption coefficients of the particle sensors were expressed by an exponential law assuming the spherical shape of the microparticles. The X-ray contrast agent, Iopamidol, was successfully encapsulated into the bio-compatible and bio-degradable PVA. With the controlled physical properties of the flow tracing sensors designed in this study, the particle sensors exhibit excellent X-ray absorption contrast fairly applicable in biological systems.

Sensitivity variation of doped Fricke gel irradiated with monochromatic synchrotron X rays between 33.5 and 80 keV.

An experimental binary radiotherapy proposes the concomitant use of a high-Z compound and synchrotron X rays for enhancing radiation dose selectively in tumours by a photoelectric effect. This study aimed at measuring the resulting dose enhancement in irradiated material. A doped Fricke gel dosemeter model was manufactured with 10 mg ml(-1) of iodine (Telebrix) or barium (Micropaque). Samples were irradiated with a monochromatic synchrotron beam at 33.5, 50, 65 and 80 keV. The ensuing enhancement of the sensitivity of the dosemeter was derived from the nuclear magnetic resonance relaxation rates measured at different X-ray doses. Our results demonstrate (1) the preservation of a linear relationship between relaxation rates and X-ray doses for dosemeters doped with high-Z atoms and (2) a clear energy-dependent sensitivity enhancement for barium-doped Fricke gels. This enhancement was neither reproducible with iodinated compounds nor clearly related to the expected dose enhancement factor. However 1% barium sulphate in the gel could significantly improve the gel's response when it was irradiated by low-energy X rays.

Studies on experimental iodine allergy: 2. Iodinated protein antigens and their generation from inorganic and organic iodine-containing chemicals.

We hypothesize that iodine allergy is an immune response to iodinated autologous proteins generated in vivo from iodine-containing organic and inorganic chemicals. In this report, effects of protein iodination on elicitogenic activity in guinea pig iodine allergy model and iodinated protein antigen generation in vitro from iodine-containing chemicals were investigated. Active cutaneous anaphylaxis (ACA) and delayed-type hypersensitivity (DTH) tests were performed in guinea pigs immunized with iodine. The amount of iodine (I2) reacted to proteins for giving them an eliciting activity of ACA was > or = 0.15 micromol for 1 mg of albumin. DTH reactions were provoked by intradermal injection of 10(6) PECs reacted with > or = 0.075 micromol of I2. I2 was generated from a potassium iodide (KI) solution or iodinated contrast media by UV light irradiation. X-ray irradiation of KI and iodinated contrast media in the presence of protein resulted in the generation of iodinated protein antigens. The generation of iodinated protein antigens was inhibited in the presence of reducing agents. Therefore, it is noteworthy that iodine allergy of the present hypothesis is dependent on reactive oxygens. By presenting these ex vivo and in vitro data, we discuss the possibilities for the generation of iodinated protein antigens in vivo.

Low- versus high-osmolality contrast media.

PURPOSE: To evaluate the effects of contrast media pharmokinetic differences on aortic enhancement at abdominal CT angiography and to determine whether these effects are of clinical relevance. MATERIAL AND METHODS: Two hundred and twelve patients referred for abdominal CT angiography were included in the study. All abdominal CT angiograms were performed with the same parameters (collimation 3 mm, pitch ratio 1.7, scan delay 30 s) after i.v. injection of 120 ml of contrast medium at 3 ml/s. After randomization, patients received either iobitridol 300 (low-osmolar, 300 mg I/ml), iobitridol 350 (low-osmolar, 350 mg I/ml) or ioxithalamate 350 (high-osmolar, 350 mg I/ml). The time attenuation curves obtained with the three contrast media were compared. RESULTS: The time attenuation curve obtained with ioxithalamate 350 was not parallel to those obtained with iobitridol 300 and iobitridol 350. Mean peak enhancements obtained with iobitridol 350 and ioxithalamate 350 were not significantly different but iobitridol 350 provided higher mean peak enhancement than iobitridol 300. Mean delays of the peak enhancements were the same with the three contrast media. After peak enhancement, the decrease of aortic opacification under a selected threshold of 200 HU was significantly slower with iobitridol 350 than with iobitridol 300 and ioxithalamate 350, whereas iobitridol 300 and ioxithalamate 350 showed no significant differences. CONCLUSION: For a given iodine concentration, low-osmolality contrast media provide longer aortic opacification and may be recommended for CT angiography when long acquisition times are needed.

Creation of radiopaque thrombi for in vivo experiments.

PURPOSE: A number of percutaneous thrombectomy devices are undergoing investigation for treatment of patients with venous thromboembolism. Use of radiopaque thrombus to monitor thrombus delivery and assess thrombectomy has been previously reported. The purpose of this project was to quantitatively test the effect of mixing different ratios of blood and contrast material to facilitate maximum thrombus formation and radiopacity. MATERIALS AND METHODS: The following ratios of blood and contrast material were mixed: 2 mL blood to 8 mL contrast material (ratio = 0.25), 4 mL blood to 6 mL contrast material (ratio = 0.67), 6 mL blood to 4 mL contrast material (ratio = 1.5), and 8 mL blood to 2 mL contrast material (ratio = 4). Contrast material was added at day 0, 3, or 6. Each sample received one of two ionic contrast agents to opacify the clots. At day 14, thrombus mass and opacity were determined. RESULTS: Three combinations of blood and contrast material produced maximum thrombus and radiopacity. These were sodium iothalamate 30% with a ratio of 4 with contrast material added on day 0 and sodium iothalamate 60% with a ratio of 1.5 with contrast material added on day 3 or 6. CONCLUSIONS: When forming radiopaque thrombi, significant differences can result from the ratio of blood to contrast material used. Contrast material type can also affect radiopacity and mass formed. The use of optimal ratios of blood to contrast material should maximize device evaluation with minimal wasting of valuable resources such as test subjects, physician time, and equipment.

Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their active metabolites.

The pharmacokinetics of benazepril, enalapril, and their active metabolites (benazeprilat and enalaprilat) were compared after a single administration of each product by the oral route at the recommended dosage (0.5 mg/kg for both drugs) in the dog before and after moderate experimental renal impairment. Ten dogs were randomly assigned to 2 groups of 5 animals in a 2-period crossover design for angiotensin-converting enzyme inhibitor administration. Renal failure was surgically induced by right nephrectomy and electrocoagulation of the remaining kidney. Renal mass reduction induced a significant decrease (P < .001) in glomerular filtration rate (GFR) (1.7 +/- 0.3 versus 3.3 +/- 0.7 mL/kg/minute). No significant differences before and after surgery were observed for enalapril and benazepril kinetics. The area under the curve (AUC) for enalaprilat increased after surgery from 23.6 +/- 14.7 to 42.4 +/- 20.9 micrograms.minute/mL (P < .01). Mean peak plasma concentration (Cmax) was increased in the impaired dogs (59.1 +/- 23.3 versus 43.9 +/- 32.9 ng/mL), but this variation was not significant (P > .05). Renal failure had no significant effect on AUC for benazeprilat (13.8 +/- 9.8 versus 14.9 +/- 5.0 micrograms.minute/mL) (P > .05), but Cmax decreased significantly (from 55.0 +/- 26.4 to 31.9 +/- 17.7 ng/mL) (P < .05). Multiple regression analysis showed that both GFR and AUC for enalapril were highly significant variables that explained the variation in AUC for enalaprilat (R2 = .86, P < .001) but not for benazeprilat (R2 = .12, P > .05). The results of this study indicate that exposure to enalaprilat, but not to benazeprilat, is increased in dogs with subclinical renal impairment.

Modified radioiodination and quality control methods for [125I]sodium iothalamate.

[125I]Sodium iothalamate can be prepared by the isotope-exchange method with the use of a contrast medium preparation (i.e. iothalamate sodium injection, USP, 80%). The initial isolation and purification of iothalamate from the contrast medium solution for radioiodination is tedious and time-consuming (i.e. 1 1/2 h for purification and overnight for drying). The new method uses iothalamic acid to replace iothalamate sodium injection as a starting material and reduces the heating time and multiple acid-washing steps during radioiodination to expedite the radiolabelling process. The radiochemical purity (RCP) of [125I]sodium iothalamate obtained from the new method was 98.9 +/- 1.3% (n = 30) versus RCP value of 99.2 +/- 1.0% (n = 25) from the old method with no significant differences between the two groups of RCP values. An RCP chromatographical system to separate and migrate the radiochemical species of [125I]sodium iothalamate from the origin is described in this paper.