Preliminary clinical experience with AMI 227.
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Adult↗
Biomedical subjects
S J McLachlan
Publications and source records attributed to S J McLachlan.
Characterization of reactive versus tumor-bearing lymph nodes with interstitial magnetic resonance lymphography in an animal model.
RATIONALE AND OBJECTIVES: To determine if magnetic resonance lymphography performed with subcutaneously administered AMI-227, a nanoparticulate iron oxide contrast agent, can distinguish reactive from tumor-bearing lymph nodes. MATERIALS AND METHODS: Mature male Copenhagen rats were inoculated with cell suspensions of R3327-MAT-LyLu rat prostate carcinoma (n = 21) or Freund's complete adjuvant (n = 15) in the left footpad to generate ipsilateral popliteal lymph node metastases or lymphadenitis. At 12 to 14 days after inoculation, T1-and T2-weighted magnetic resonance images of bilateral popliteal areas were obtained before and 24 hours after subcutaneous administration of AMI-227. Contrast-to-noise ratios were calculated in precontrast and postcontrast images. Bilateral popliteal nodes were excised for pathologic assessment. RESULTS: AMI-227 resulted in decreased contrast-to-noise ratios in reactive (T1-W = -7.01 +/- 1.13, T2- W = -31.64 +/- 5.35) and normal (T1 - W = -13.56 +/- 1.97, T2 - W = -21.62 +/- 2.51) nodes. Contrast-to-noise ratios were unchanged (T1 - W = -0.22 +/- 1.71, T2 - W = -2.20 +/- 4.19) in tumor-containing nodes. These differences in contrast-to-noise ratio changes between tumor-bearing versus nontumor-bearing nodes were statistically significant (P < 0.05). Histologic analysis showed similar distribution of AMI-227 within normal and reactive nodes, but not in tumor-bearing nodes. CONCLUSIONS: Differences in AMI-227-uptake between tumor- and nontumor-bearing nodes detected with magnetic resonance imaging are helpful for distinguishing the two entities.
Animals↗
Hydrogen isotope effects on the proton nuclear magnetic resonance spectrum of bovine ferricytochrome b5: axial hydrogen bonding involving the axial His-39 imidazole ligand.
The potential role of hydrogen bonding interactions in modulating the molecular and electronic structure of the active site of solubilized bovine ferricytochrome b5 has been investigated by monitoring solvent isotope effects on proton-NMR spectral parameters. It is observed that the hyperfine shifts of both the heme prosthetic group and one coordinated His are sensitive, while those for the other axial His and non-coordinated residues are insensitive, to 2H for 1H exchange. Two types of isotope influences are characterized; one whose chemical shift influence is time-resolved on the NMR time scale, and involves a single proton on one axial ligand, and a second effect which involves multiple protons, is not time resolved, and influences primarily the heme. A large isotope effect on the hyperfine shift is identified for the C beta H signals of His-39 but not His-63. The exchangeable ring NH of His-39 is assigned, and the pH influence on the exchange properties of heme pocket labile protons, when compared to the rate of base catalyzed averaging of the His-39 C beta H isotope effect, lead to the conclusion that the axial hydrogen bond which is responsible for this isotope effect is that between His-39 ring NH and Gly-42 carbonyl. The more rapid exchange of labile protons with solvent for His-63 than His-39 confirms a less solvent accessible and stronger hydrogen bonded His-39 than His-63. The stronger His-39-Gly-42 than His-63-Phe-58 hydrogen bond involving the ring NH leads to more extensive His-39 imidazolate character and hence a stronger iron-His-39 than iron-His-63 bond. The much larger hyperfine shifts for His-39 than His-63 imidazole ring non-labile protons support the stronger bonding of the former ligand, and account for the orientation of the rhombic magnetic axes by His-39 rather than His-63. The solvent isotope effect on the heme leads to rotation of the prosthetic group about the His-Fe-His bond by approximately 0.5 degrees so as to shorten the 7-propionate link to Ser-64. This suggests that the hydrogen bonds between the 7-propionate group and Ser-64 are responsible for the effect.
Animals↗
Initial clinical experience with dextran-coated superparamagnetic iron oxide for detection of lymph node metastases in patients with head and neck cancer.
PURPOSE: To investigate the efficacy of magnetic resonance (MR) imaging with dextran-coated superparamagnetic iron oxide in the differentiation of metastatic and benign nodes in patients with head and neck cancer. MATERIALS AND METHODS: MR imaging was performed before and after intravenous administration of iron oxide in 12 patients. Ninety-one pathologically proved nodes were visually analyzed, and 66 lymph nodes were quantitatively analyzed by measuring signal intensity in visually selected regions of interest. RESULTS: Forty of 42 histologically proved metastatic nodes and 41 of 49 benign nodes were detected, yielding 95% sensitivity and 84% specificity. The signal intensity ratio of benign nodes was substantially lower than that of metastatic nodes, indicating better differentiation of metastatic and benign nodes. Furthermore, 13 of 14 normal-sized nodes were detected. CONCLUSION: MR imaging with iron oxide can enable specific differentiation of metastatic and benign nodes in patients with head and neck cancer. This agent may potentially enhance the detection of metastatic lymph nodes and deserves further investigation.
Adult↗
AMI-227-enhanced MR lymphography: usefulness for differentiating reactive from tumor-bearing lymph nodes.
PURPOSE: To determine the value of magnetic resonance (MR) lymphography enhanced with AMI-227, a superparamagnetic reticuloendothelial-system-specific contrast agent, to distinguish normal and reactive from tumor-bearing lymph nodes. MATERIALS AND METHODS: Mature male Copenhagen rats were inoculated with cell suspensions of R3327-MATLyLu rat prostate carcinoma (n = 16) or Complete Freund Adjuvant (n = 15) to generate ipsilateral popliteal lymph node metastases or lymphadenitis. At 12-14 days after inoculation, T1- and T2-weighted MR images of bilateral popliteal areas were obtained before and 24 hours after administration of AMI-227 (dose, 30 mumol Fe/kg). The contralateral popliteal nodes served as controls. Contrast-to-noise ratios (C/Ns) between the nodes and adjacent muscle were calculated in pre- and postcontrast images. Subsequently, bilateral popliteal nodes were excised. RESULTS: AMI-227 resulted in decreased C/N in reactive nodes (T1-weighted, -186% +/- 90% [standard deviation]; T2-weighted, -205% +/- 96%) and normal nodes (n = 7) (T1-weighted, -306% +/- 82; T2-weighted, -350% +/- 96). C/N remained unchanged or increased (T1-weighted, 88% +/- 92; T2-weighted, 306% +/- 256) (P < .05). CONCLUSION: Differences in AMI-227 uptake at MR imaging may help differentiate tumor-bearing from nontumor-bearing nodes.
Animals↗
Pharmacokinetic behavior of gadoteridol injection.
RATIONALE AND OBJECTIVES: To assess the safety and pharmacokinetics of gadoteridol injection (0.5 M) in 18 healthy male volunteers in a phase I clinical trial. METHODS: Volunteers were assigned to one of six dosing groups: 0.05, 0.1, 0.15, 0.2, 0.25, and 0.3 mmol/kg gadoteridol (0.5 M), in an ascending dose study. Physical examination, vital signs, electrocardiogram, clinical laboratory tests, and serum and urine samples were obtained at selected time points before and after administration of gadoteridol. RESULTS AND CONCLUSIONS: No significant changes in vital signs, physical examination, clinical laboratory values, or electrocardiogram, that were believed by the principal investigator to be related to the administration of the contrast agent, were observed. A single adverse event (transient hive) believed to be related to contrast agent administration was observed in one volunteer. Pharmacokinetic data show that the elimination half-life and the distribution half-life were independent of the dose used. The mean distribution half-life was 0.20 +/- 0.04 hours, the mean elimination half-life was 1.57 +/- 0.08 hours, and greater than 94% of the drug was excreted in the urine in 24 hours.
Adolescent↗
One- and two-dimensional nuclear Overhauser effect studies of the electronic/molecular structure of the heme cavity of ferricytochrome b5.
A nuclear Overhauser effect, NOE, study of solubilized native bovine ferricytochrome b5 has provided the complete assignment of the heme resonances as well as those of the majority of the amino acid side-chains making contact with the prosthetic group. The resonances which could not be identified are those from positions very close to the iron (less than 5 A) for which paramagnetic relaxation is sufficiently strong to significantly decrease the NOEs. The observed 1H-1H dipolar contacts generally confirm a solution structure unchanged from that described in single crystals, except for the detailed orientation of the heme side-chains. The 2-vinyl group is found in both the cis and trans in-plane orientation as opposed to exclusively cis in the crystal, and the 7-propionate group is rotated by 30 degrees in solution towards the 6-propionate group. Identification of resonances for the individual axial histidine residues indicates non-equivalent interaction with the heme iron, and the patterns of meso-H, pyrrole substituent and amino acid dipolar shifts allow the location of the principal magnetic axes in the protein coordinate system. This identifies His-39 as the dominant influence in determining the electronic ground state that orients the molecular orbital for facile electron transfer via the exposed heme edge. The complete two-dimensional NOESY map for ferricytochrome b5 is presented that yields all the cross peaks expected on the basis of the one-dimensional NOE studies, and indicates that such two-dimensional methods should have profitable extension to strongly hyperfine-shifted resonances in paramagnetic proteins.
Animals↗
1H-NMR assignments and the dynamics of interconversion of the isomeric forms of cytochrome b5 in solution.
Cytochrome b5 reconstituted with specifically deuterated hemins has led to the assignment of the resolved 6,7 beta-propionate protons and heme meso protons. Freshly reconstituted cytochrome b5 contains a mixture of two isomers in an approx. 1:1 ratio. As time proceeds the minor isomer decreases in intensity until the equilibrium ratio, approx. 8:1, of the two isomers is reached. The rate of the heme disorder kinetics was investigated for cytochrome b5 as a function of pH, oxidation state and 2,4 heme substitutents. Comparison of the kinetic data for cytochrome b5 with that obtained for other b-type heme proteins supports the proposal that the heme disorder arises from a 180 degree rotation of the heme about the alpha, gamma-meso axis. Computer-difference methods allow the spectra of the two individual isomers to be generated. Comparison of the NMR spectral parameters for the two individual isomers indicates small structural differences for amino acid side-chain orientations.
Animals↗
Myoglobin: cytochrome b5 interactions and the kinetic mechanism of metmyoglobin reductase.
Metmyoglobin (metMb) reduction by metMb reductase from heart muscle requires cytochrome b5 as electron-transfer mediator. The existence of a metMb-ferrous cytochrome b5 complex is demonstrated by mutual perturbation of the proteins' respective electrophoretic titration curves between pH 4 and 7. The same technique shows a preferential binding of cytochrome b5 over metMb by the enzyme. The paramagnetic hyperfine shifts in the cytochrome b5 1H NMR spectrum are perturbed by metMb, indicating the formation of a specific bimolecular complex with a 1:1 stoichiometry and a binding constant estimated to be less than 10 microM. The resonances assigned to the cytochrome b5 heme 6-propionate methylene group exhibit the largest complexation shifts. Computer modeling implicates lysines 47, 50, and 98 of metMb as contact points with cytochrome b5 carboxylate residues 43, 44, 60, and heme 6-propionate. The mechanism of the enzymatic reduction establishes metMb reductase as an NADH-cytochrome b5 oxidoreductase. Cytochrome b5 is reduced at near diffusion-controlled rates by the enzyme with a turnover number of 1000 min-1 X Km for the cytochrome is 0.9 microM versus 100 microM reported for the erythrocyte enzyme. Ferrous cytochrome b5 then reduces metMb nonenzymatically with an apparent rate constant of 4.9 X 10(4) M-1 min-1 X Acetylation of metMb, which does not affect its oxygen affinity or chemical reduction, renders it a poor substrate for enzymatic reduction. This study suggests a function for the three exterior lysine residues conserved in all mammalian myoglobin sequences: they are contact points for complexation with cytochrome b5.
Acetylation↗
Spectroscopic studies on copper (II) complexes of human lactoferrin.
The interaction of Cu(II) with human lactoferrin has been studied as a function of pH, using electronic and electron spin resonance spectroscopy. Specific Cu(II) binding, with bicarbonate as the co-anion, occurs over the pH range 6 to 9. In the presence of a fiftyfold molar excess of oxalate, a monocopper(II) lactoferrin oxalate complex forms when the Cu(II) to protein is 1:1. If this ratio is increased to 2:1, a hybrid complex forms, in which the second copper utilizes bicarbonate as the co-anion, thus demonstrating, as for serum transferrin, a difference in the anion binding sites. The quenching of the intrinsic fluorescence of apolactoferrin is significantly less in the presence of oxalate than bicarbonate. The interaction of Cu(II) with apolactoferrin in the presence of the malonate, glycolate, thioglycolate, glycinate, and ethylenediaminetetraacetate ions has been examined.
Bicarbonates↗
Phase I clinical evaluation of a new iron oxide MR contrast agent.
The safety and magnetic resonance (MR) imaging potential of BMS 180549, a new superparamagnetic iron oxide contrast agent, were evaluated in a phase I, open-label, placebo-controlled study involving 41 healthy subjects. No clinically significant postdose changes in physical examination findings, vital signs, or electrocardiogram results were reported for any of the subjects evaluated. No clinically significant changes in clinical laboratory values were noted by the investigators. Fourteen adverse events considered not serious and considered possibly or definitely related to the drug were reported, three of which required minor treatment. Relaxation time measurements in plasma samples showed a strong, dose-dependent, and persistent decrease in T1 and T2 values. Significant changes in MR signal intensity of the blood pool and well-perfused organs (liver and spleen) were noted on both T1- and T2-weighted images. Changes in signal intensity of cervical lymph nodes were also observed at the higher doses and late postdose imaging times.
Adult↗
Efficacy evaluation of gadoteridol for MR angiography of intracranial vascular lesions.
A phase III multicenter study was conducted in 89 patients with known intracranial vascular lesions to evaluate an extracellular gadolinium contrast agent, gadoteridol, for intracranial magnetic resonance (MR) angiography. The pre- and postcontrast MR angiograms of 82 patients were evaluated by the unblinded investigators and by two blinded readers (A and B) for visualization of lesions; arterial and venous anatomy; extent, size, and number of lesions; and disease classification. The unblinded readers indicated that lesions were visualized better on postcontrast images in the following categories: venous anatomy, 87 (81%) of 107 lesions; arterial anatomy, 43 lesions (40%); and extent or size of lesions, 38 lesions (36%). In 29 (35%) of 82 patients, the unblinded readers determined that enhanced MR angiography provided more diagnostic information than unenhanced MR angiography. The blinded readers determined that enhanced MR angiography provided more information for visualization of vascular anatomy in more than 60% of cases. The additional information provided with gadoteridol would have changed the diagnosis in nine (8%) of 107 lesions seen by the unblinded readers, 11 (12%) of 90 lesions seen by reader A, and three (3%) of 93 lesions seen by reader B. The results confirm that the use of gadoteridol improves the visualization of intracranial vascular lesions with MR angiography. The authors conclude that development of new postprocessing algorithms will improve the utility of contrast-enhanced MR angiography.
Cerebral Arteries↗
MR angiography with an ultrasmall superparamagnetic iron oxide blood pool agent.
The purpose of the study was to investigate the use of a dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) as a blood pool contrast agent for thoracic and abdominal MR angiography. Abdominal and thoracic MR angiography was performed in six healthy volunteers using two-dimensional and three-dimensional spoiled gradient echo (SPGR) sequences before and after intravenous administration of USPIO. Doses ranged from 1.1 to 2.6 mg Fe/kg. Flip angle was varied from 20 to 60 degrees. Subjective image quality, analysis of signal-to-noise ratio (SNR), and blood T1 relaxation times were measured. USPIO significantly lowered the T1 of blood (from 1,210 ms precontrast to 159 ms postcontrast at a dose of 2.6 mg Fe/kg) (P < .01). Image quality on coronal fast three-dimensional breath-hold SPGR images of the abdomen increased with increasing dose and was maximum at the highest dose, producing an aortic SNR of 9.6 compared to 1.8 precontrast. Axial two-dimensional time-of-flight (TOF) aortic SNR was reduced significantly from 13 on precontrast to 6 on the postcontrast images at the highest dose (P < .05) due to T2* shortening effects. There was little flip angle dependence on image quality. Due to the T1 shortening effect and long intravascular half-life, USPIO improved visualization of vascular anatomy using three-dimensional fast SPGR imaging. The echo time must be minimized to minimize signal loss from T2* shortening effects. The blood pool distribution of USPIO is useful for equilibrium-phase MR angiography.
Abdomen↗
Diagnosis of carotid artery stenosis: comparison of 2DFT time-of-flight MR angiography with contrast angiography in 50 patients.
Fifty patients underwent 2DFT time-of-flight MR angiography and intraarterial contrast angiography for evaluation of possible carotid atherosclerotic disease. The MR angiography technique employed contiguous axial flow-sensitive (short TR/TE) slices that were reformatted and postprocessed by using a maximum-intensity projection algorithm to provide 16 angiographic views of the carotid arteries. Both studies were independently reviewed by two observers in a blinded manner. Carotid arteries were categorized as normal, mildly stenotic, moderately stenotic, severely stenotic, or occluded. For the 94 carotid arteries available for review, one observer reported a 70% agreement between the two techniques and the second observer reported a 56% agreement (p = .0001). The best correlation was in the severely stenotic category and the worst was in the occluded category. Agreement between observers was 67% for MR angiography and 72% for contrast angiography, which was similar to that between the two techniques. Although not all carotid atherosclerotic disease was visualized equally well, 2DFT time-of-flight MR angiography had a good overall correlation with the "gold standard" of intraarterial contrast angiography, supporting its use as a screening technique. While further improvements are needed, use of MR angiography as the primary diagnostic tool for many patients with suspected carotid stenosis should continue to increase.
Aged↗