Holde H. Muller

Preclinical Evaluation of Gadolinium (iii) Texaphyrin Complex: A New Paramagnetic Contrast Agent for Magnetic Resonance Imaging

RATIONALE AND OBJECTIVES.Gadolinium III texaphyrin (Gd[III] texaphyrin) complex, a new magnetic resonance imaging contrast (MRI) agent, was evaluated. METHODS.In vitro relaxivity (1.5 T) and stability studies (5% dextrose) were conducted. Subchronic toxicity (8 males, 8 females; 2-20 (µmol Gd(III) texaphyrin complex/kg body weight; 3 times per week for 3 weeks). Biodistribution and excretion studies were conducted in Sprague-Dawley rats; MRI studies were conducted in normal and tumor-bearing rats and rabbits. RESULTS.Relaxivity values were as follows:1=19 (µmol/ L · sec)-1and r2=22 (µmol/L · sec)-1The 21-day subchronic toxicity study revealed no abnormalities. The compound is stable. Biodistribution demonstrated liver uptake. Magnetic resonance imaging in normal (n=34) and tumorbearing (n=4) rats and normal (n=8) and tumor-bearing (n=19) rabbits revealed: significant (P<.05) contrast enhancement of liver and kidney after 1-17 µmol/kg of Gd(III) texaphyrin complex. Gadolinium (III) texaphyrin complex (2.5 (µmol/kg) produced significant contrast enhancement of liver carcinomas in rabbits (n=8). Thigh V2 carcinomas (n=22) had selective (P<.05) enhancement, 5 µmol/kg. In rat fibro-sarcomas (n=4), 17 (µmol Gd(III) texaphyrin complex produced significant enhancement up to 24 hours. CONCLUSIONS.Gadolinium (III) texaphyrin complex appears to be an effective and safe MRI contrast agent.

Detection of tumors with 19F magnetic resonance imaging

Previous 19F magnetic resonance imaging studies showed that the reticuloendothelial system can be imaged with an emulsion of perfluorooctyl bromide (PFOB). Similar techniques can be used to detect previously implanted RIF-1 tumors in mice after intravenous PFOB administration. Accumulation of PFOB within these neoplasms is due to egress of the emulsion through tumor capillary fenestrations. This is the first report in which 19F MRI and PFOB are used to detect tumors. This technique may allow clinical detection of cancer with 19F MRI.

Detection of hepatic malignancies using Mn-DPDP (manganese dipyridoxal diphosphate) hepatobiliary MRI contrast agent.

A new hepatobiliary contrast agent (Mn-DPDP) was used in the detection of liver metastases in six rabbits with seven hepatic V2 carcinomas. This contrast agent is derived from pyridoxyl-5-phosphate which is biomimetically designed to be secreted by the hepatocyte. After Mn-DPDP administration, a 105% increase in liver signal to noise was obtained using a 200/20 (TR/TE) pulsing sequence, and a 62% decrease in intensity was observed using a 1200/60 pulsing sequence. Liver V2 carcinoma contrast enhancement increased 427% using the 200/20 pulsing sequence and 176% using the 1200/60 pulsing sequence. Four of seven V2 carcinomas were not detectable prior to the administration of Mn-DPDP (50 mumol/kg). Two neoplasms were only detectable in retrospect (after Mn-DPDP) on the 1200/60 sequence. The smallest neoplasms detected in this study were 1-4 mm. Mn-DPDP appears to be a promising MRI contrast agent.

Blood pool and liver enhancement in CT with liposomal lodixanol: Comparison with lohexol

RATIONALE AND OBJECTIVES The authors compared the time course and blood pool and hepatic enhancement of three different doses of liposomal iodixanol with those of iohexol. MATERIALS AND METHODS A liposomal iodixanol formulation was prepared with 200 mg of iodine per milliliter total and 80 mg of iodine per milliliter encapsulated. Twelve normal New Zealand white rabbits divided into four groups received 75-, 100-, or 150-mg encapsulated iodine per kilogram doses of liposomal iodixanol or 2 mL/kg iohexol with 300 mg of iodine per milliliter. A liver section was scanned with serial computed tomography (CT) before the injection, immediately afterward, and at 1-minute intervals for 10 minutes. Region-of-interest measurements of the aorta and liver were plotted at each time point, and contrast enhancement was plotted as a function of time and iodine dose. RESULTS All liposomal iodixanol doses produced greater liver enhancement than iohexol. Results were significant (P < .05) for 100 mg and 150 mg iodine per kilogram dose groups at time points beyond 2 minutes. Peak hepatic enhancement (change in attenuation) was 54.9 HU +/- 7.6 with iohexol, compared with 59.6 HU +/- 6.1, 73.3 HU +/- 3.6, and 104.1 HU +/- 8.8 for 75, 100, and 150 mg encapsulated iodine per kilogram doses, respectively. Hepatic enhancement increased rapidly after injection of liposomal iodixanol, plateauing 2-3 minutes later. Blood pool enhancement decreased rapidly. Steady-state liver enhancement with liposomal iodixanol increased linearly with dose. Aortic enhancement was greater with iohexol. CONCLUSION Liposomal iodixanol yielded greater hepatic enhancement at lower total iodine doses than iohexol. Although liver enhancement occurred rapidly after injection, blood pool enhancement was brief.

Radiographic Blood Pool Contrast Agents for Vascular and Tumor Imaging with Projection Radiography and Computed Tomography

An emulsion of EthiodolR and PluronicR was evaluated as a vascular (blood pool) imaging agent with both the GE experimental scanned projection radiography system and conventional computed tomography (CT). 475 mg iodine/kg body weight of emulsion, was injected into 11 rabbits with thigh muscle V2 carcinomas. Both projection radiography scans and CT scans visualized aorta, vena cava, pulmonary, and femoral vessels, and distorted vessels around tumors for 20 min after infusion. This persistent vascular visualization allowed CT scanning at multiple contiguous levels, which could be followed by reformatting in the saggital and coronal planes. Following diatrizoate in identical iodine/kg doses, vascular visualization persisted for only I min after infusion. Blood pool agents are ideal for projection radiography systems and CT reformatting of vascular anatomy.

Interstitial MR and CT lymphography with Gd-DTPA-co-α, ω-diaminoPEG(1450) and Gd-DTPA-co-1,6-diaminohexane polymers: Preliminary experience

Rationale and Objectives. The authors assessed the efficacy of two gadolinium-based polymers used as lymphotrophic contrast media for computed tomography (CT) and magnetic resonance (MR) imaging. Materials and Methods. Two gadolinium-based polymers, gadolinium diethylenetriaminepentaacetic acid (DTPA)-co-1,6-diaminohexane (NC 22181) and Gd-DTPA-co-α, ω-diamino-polyethylene glycol(1450) (NC-66368), were formulated at a concentration of 80 mmol/L gadolinium. Doses of 0.1, 0.25, 1.0, or 2.0 mL per paw were administered subcutaneously into the hindpaws of normal rabbits. Spin-echo T1-weighted MR imaging (1.5 T) of rabbit popliteal and iliac nodes was performed before and immediately, 10 minutes, 2–3 hours, and 24 hours after injection. CT was performed 2–3 hours after injection of the high doses only. Results. MR imaging revealed prompt enhancement of the popliteal nodes with both polymers at doses of 0.25 mL and above. For doses of 1.0 mL or less per paw, nodal percentage enhancement was maximal at 2 hours and then declined at 24 hours. At the highest doses, however, a reservoir of subcutaneous contrast material remained at the injection site and resulted in peak enhancement at 24 hours. At CT, popliteal node enhancement was faintly visible 2–3 hours after the administration of NC 22181. At lower doses, no enhancement was appreciable at CT. Conclusion. At 80 mmol/L formulations, the two gadolinium-based polymers provide excellent popliteal nodal enhancement on MR images. In addition, high doses of one polymer (NC 22181) were sufficiently concentrated in popliteal nodes to be visible on CT scans. Thus, this agent may be useful for both CT and MR lymphography.

Manganese dipyridoxal diphosphate-enhanced magnetic resonance imaging in the evaluation of hepatocyte function.

RATIONALE AND OBJECTIVES.To determine whether contrast-enhanced magnetic resonance imaging can detect ethanol hepatotoxicity in rats. METHODS.Rats were treated with a single high dose of ethanol (acute) intraperitoneally or with a 36% ethanol diet (chronic) for up to 5.5 months. Magnetic resonance imaging was performed before and after intravenous administration of manganese dipyridoxal diphosphate (Mn-DPDP). RESULTS.Enhancement (acute group) was significantly lower in ethanol treated animals on T1-weighted scans (P < .02). Precontrast, a significant difference in intensity was seen on T2-weighted scans (P < .01). Electron microscopy revealed severe hepatocyte damage. In the chronic groups, there was no significant difference in intensity precontrast. Postcontrast, enhancement (ethanol group) was significantly lower on T1-weighted scans only at 2 weeks (P < .05). Electron microscopy demonstrated progressive ethanol hepatotoxicity. CONCLUSIONSMagnetic resonance imaging can distinguish between normal and certain types of ethanol damaged livers on T1-weighted scans. Enhancement, however, does not correlate with progressive microscopic chronic liver damage.

Optimization of an oral magnetic particle formulation as a gastrointestinal contrast agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVESMagnetically susceptible iron oxide (MSIO) contrast agents for magnetic resonance imaging (MRI) of the gastrointestinal (GI) tract are limited because they produce magnetic susceptibility artifacts. To determine whether oral magnetic particles (WIN 39996) can be an effective MRI contrast agent without producing induced image artifacts, we optimized a liquid formulation of WIN 39996. METHODSA range of concentrations (25–250 μg iron/mL) and viscosities (1–600 cP) was imaged in a phantom at 1.5 T using conventional spin- echo and gradient-recalled echo pulse sequences. Some formulations also contained titanium. RESULTSAll concentrations of WIN 39996 at 1 cP produced susceptibility artifacts. For formulations in the 150 to 600 cP range, the 125 to 150 μg/mL concentrations produced signal blackening and magnetic susceptibility image distortion comparable to an air control. Concentrations greater than 150 μg/mL were unacceptable because they produced significant susceptibility artifacts, while concentrations less than 125 μg/mL were undesirable because they produced insufficient signal blackening. CONCLUSIONSThese preliminary in-vitro studies suggest that an optimized liquid formulation of WIN 39996 can be produced that yields excellent negative contrast without producing image artifacts.

Methods for the systematic investigation of gastrointestinal contrast media for MRI: Evaluation of intestinal distribution by radiographic monitoring☆

Comparison of the effectiveness of various gastrointestinal (GI) contrast agents for magnetic resonance (MR) imaging is often complicated by varying amounts intraluminal filling with the orally administered agents. To achieve more uniform and reproducible imaging results with GI contrast agents for MR imaging (GICMR), we evaluated a radiographic method for monitoring intraluminal filling and distribution. Solutions of Mn-DPDP (2 mM), to which a small amount of barium sulfate (6 wt/vol%) was added, were administered orally to dogs. Gastric emptying and small bowel transit were monitored fluoroscopically. MR imaging was performed either 1) at a fixed time after administration of the contrast agent or 2) at a variable interval when the contrast agent was observed fluoroscopically to be in the terminal ileum. When initiation of MR imaging was guided by fluoroscopic monitoring of intestinal contrast distribution, uniform and reproducible intestinal contrast enhancement by GICMR was achieved. However, when MR imaging was performed at a fixed time interval after oral administration, non-uniform and variable GI visualization was obtained, and this corresponded to the variable intestinal distribution observed fluoroscopically. We conclude that reproducible intestinal filling with orally administered contrast agents can be accomplished with a radiographic monitoring technique, and this promotes more consistent GI visualization on MR images. Such standardized and reproducible methods are necessary for studies in which the effectiveness of GI contrast media for MR imaging is evaluated and compared.

Response of neoplastic and normal vasculature to acetylcholine

Intravascular acetylcholine causes vasodilation and an increase in normal tissue blood flow and could reasonably be expected to increase blood flow in malignant neoplasms. In this study using the microsphere reference sample technique, however, blood flow of V2 carcinoma, implanted in several organ sites in rabbits, was found to decrease after both an intra-arterial bolus and infusion of acetylcholine chloride. Cardiac output was not significantly changed. These observations may explain the recent report by Marincek et al. of a decrease in CT X-ray absorption in renal neoplasms after acetylcholine and previous reports of the lack of utility of vasodilators in improving the diagnosis of malignant neoplasms after arteriography.