Jeffrey P. Norenberg

Performance Evaluation of the LabPET APD-Based Digital PET Scanner

The LabPETTM is a fully digital avalanche photodiode (APD) based PET scanner designed for state-of-the- art molecular and genomic imaging of small animals. Two versions of the scanner were evaluated, having 3.75 (LabPET4) and 7.5 cm axial FOV (LabPET8). The detectors are made of 2x2x10/12 mm3 LYSO and LGSO crystals assembled in phoswich pairs read out by an APD. After digital crystal identification, the average energy resolution is 24 plusmn 6% for LYSO and 25 plusmn 6% for LGSO. The scanner overall timing resolution is 6.6 ns for LYSO/LYSO and 10.7 ns for LGSO/LGSO coincidences after coarse timing alignment. The FBP reconstructed tangential/radial resolution is 1.3/1.4 mm FWHM (2.5/2.4 mm FWTM) at the FOV center and remains below 2.1 mm FWHM (3.6 mm FWTM) within the central 4-cm diameter FOV. MLEM reconstruction of a micro resolution phantom provided clear separation of the 1.35 mm spots and fair identification of 1 mm spots. With an energy window of 250-650 keV, the sensitivity is 1.1% for LabPET4 and 2.1% for LabPET8. The imaging capabilities of the scanner are demonstrated with in vivo images of rats and mice.

Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin

ABSTRACT The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [125I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (±standard deviation) body mass index was 46.2 ± 5.5 kg/m2 or 21.8 ± 1.9 kg/m2 for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.

Comparison of Oxidative Stress Markers After Intravenous Administration of Iron Dextran, Sodium Ferric Gluconate, and Iron Sucrose in Patients Undergoing Hemodialysis

Study Objective. To compare non–transferrin‐bound iron and markers of oxidative stress after single intravenous doses of iron dextran, sodium ferric gluconate, and iron sucrose.

213Bi-[DOTA0, Tyr3]Octreotide Peptide Receptor Radionuclide Therapy of Pancreatic Tumors in a Preclinical Animal Model

Purpose: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) β-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET α-emitter, 213Bi, was evaluated. Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/μg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model. Results: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield ≥99.9%. Biodistribution data showed specific binding to somatostatin receptor–expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 ± 1.40% injected dose/g (ID/g) tissue versus 11.15 ± 0.46%, P < 0.0001] and bone marrow (0.31 ± 0.01% ID/g versus 0.06 ± 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02). Conclusions:213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

Regional particle size dependent deposition of inhaled aerosols in rats and mice

Context: The current data analysis tools in nuclear medicine have not been used to evaluate intra organ regional deposition patterns of pharmaceutical aerosols in preclinical species. Objective: This study evaluates aerosol deposition patterns as a function of particle size in rats and mice using novel image analysis techniques. Materials and Method: Mice and rats were exposed to radiolabeled polydisperse aerosols at 0.5, 1.0, 3.0, and 5.0 µm MMAD followed by SPECT/CT imaging for deposition analysis. Images were quantified for both macro deposition patterns and regional deposition analysis using the LRRI-developed Onion Model. Results: The deposition fraction in both rats and mice was shown to increase as the particle size decreased, with greater lung deposition in rats at all particle sizes. The Onion Model indicated that the smaller particle sizes resulted in increased peripheral deposition. Discussion: These data contrast the commonly used 10% deposition fraction for all aerosols between 1.0 and 5.0 µm and indicate that lung deposition fraction in this range does change with particle size. When compared to historical data, the 1.0, 3.0, and 5.0 µm particles result in similar lung deposition fractions; however, the 0.5 µm lung deposition fraction is markedly different. This is probably caused by the current aerosols that were polydisperse to reflect current pharmaceutical aerosols, while the historical data were generated with monodisperse aerosols. Conclusion: The deposition patterns of aerosols between 0.5 and 5.0 µm showed an increase in both overall and peripheral deposition as the particle size decreased. The Onion Model allows a more complex analysis of regional deposition in preclinical models.

Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients

BACKGROUND Fixed combination fluticasone-salmeterol is the most used anti-inflammatory asthma treatment in North America, yet no studies report the actual respiratory tract dose or the distribution of drug within the lungs. Inflammation due to asthma affects all airways of the lungs, both large and small. Inhaled steroid delivery to airways results from a range of drug particle sizes, with emphasis on smaller drug particles capable of reaching the peripheral airways. Previous studies suggested that smaller drug particles increase pulmonary deposition and decrease oropharyngeal deposition. OBJECTIVES To characterize the dose of fluticasone-salmeterol hydrofluoroalkane-134a (HFA) (particle size, 2.7 μm) delivered to asthmatic patients and examine the drug distribution within the lungs. The results were compared with the inhalation delivery of HFA beclomethasone (particle size, 0.7 μm). METHODS A crossover study was conducted in asthmatic patients with commercial formulations of fluticasone-salmeterol and HFA beclomethasone radiolabeled with technetium Tc 99m. Deposition was measured using single-photon emission computed tomography/computed tomography gamma scintigraphy. RESULTS Two-dimensional planar image analysis indicated that 58% of the HFA beclomethasone and 16% of the fluticasone-salmeterol HFA were deposited in the patients lungs. The oropharyngeal cavity and gut analyses indicated that 77% of the fluticasone-salmeterol HFA was deposited in the oropharynx compared with 35% of the HFA beclomethasone. CONCLUSIONS The decreased peripheral airway deposition and increased oropharyngeal deposition of fluticasone-salmeterol HFA was a result of its larger particle size. The smaller particle size of HFA beclomethasone allowed a greater proportion of lung deposition with a concomitant decrease in oropharyngeal deposition.

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate 99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

Breast and endometrial cancers are the most common invasive malignancies in women, with more than 217,000 new diagnoses per year in the United States. These cancers are often classified into 2 subtypes based on the expression of the classical estrogen receptor. In this study, we describe a new structural class of neutral tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivatives for potential use in breast and endometrial cancer imaging. Methods: The 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative was synthesized via the Sonogashira cross-coupling reaction and radiolabeled via the tricarbonyl approach. Radiochemical purity was assessed by high-performance liquid chromatography. Cell-binding studies were performed with human breast adenocarcinoma MCF-7 cells. The in vivo biodistribution of the 99mTc(I) derivative was evaluated in virgin female C57BL/6 mice in defined phases of the estrous cycle. Biodistribution and SPECT/CT studies were performed with mice bearing MCF-7 and primary human endometrial tumors. Results: Radiochemical analysis demonstrated that the postpurification purity of the 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative was ≥95%, with a specific activity of 99mTc of 47.5 TBq/mmol. Cell-binding studies yielded a dissociation constant (mean ± SEM) of 11 ± 1.5 nM. In vivo studies revealed that receptor-mediated uptake was present in all phases of the estrous cycle in reproductive organs and mammary glands but was highest during the diestrous phase of the estrous cycle. Despite high nonspecific uptake in the liver, significant receptor-mediated uptake was observed in target tissues and estrogen receptor–expressing tumors (0.67% for MCF-7 tumors and 0.77% for endometrial tumors). Tumor uptake was reduced by approximately 50% on coinjection with 17β-estradiol. Conclusion: We have characterized a novel neutral tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative for potential use in breast and endometrial cancer imaging. This study represents the first step on a path toward the design of estrogen-based Tc-labeled tracers with improved targeting and SPECT imaging characteristics.

Microglial priming through the lung–brain axis: the role of air pollution–induced circulating factors

Air pollution is implicated in neurodegenerative disease risk and progression and in microglial activation, but the mechanisms are unknown. In this study, microglia remained activated 24 h after ozone (O3) exposure in rats, suggesting a persistent signal from lung to brain. Ex vivo analysis of serum from O3‐treated rats revealed an augmented microglial proinflammatory response and β‐amyloid 42 (Aβ42) neurotoxicity independent of traditional circulating cytokines, where macrophage‐1 antigen‐mediated microglia proinflammatory priming. Aged mice exhibited reduced pulmonary immune profiles and the most pronounced neuroinflammation and microglial activation in response to mixed vehicle emissions. Consistent with this premise, cluster of differentiation 36 (CD36)–/– mice exhibited impaired pulmonary immune responses concurrent with augmented neuroinflammation and microglial activation in response to O3. Further, aging glia were more sensitive to the proinflammatory effects of O3 serum. Together, these findings outline the lung‐brain axis, where air pollutant exposures result in circulating, cytokine‐independent signals present in serum that elevate the brain proinflammatory milieu, which is linked to the pulmonary response and is further augmented with age.—Mumaw, C. L., Levesque, S., McGraw, C., Robertson, S., Lucas, S., Stafflinger, J. E., Campen, M. J., Hall, P., Norenberg, J. P., Anderson, T., Lund, A. K., McDonald, J. D., Ottens, A. K., Block, M. L. Microglial priming through the lung‐brain axis: the role of air pollution‐induced circulating factors. FASEB J. 30, 1880–1891 (2016). www.fasebj.org

Iodinated NanoClusters as an Inhaled Computed Tomography Contrast Agent for Lung Visualization

Improvements to contrast media formulations may be an effective way to increase the accuracy and effectiveness of thoracic computed tomography (CT) imaging in disease evaluation. To achieve contrast enhancement in the lungs, a relatively large localized concentration of contrast media must be delivered. Inhalation offers a noninvasive alternative to intrapleural injections for local lung delivery, but effective aerosolization may deter successful imaging strategies. Here, NanoCluster technology was applied to N1177, a diatrizoic acid derivative, to formulate low density nanoparticle agglomerates with aerodynamic diameters <or=5 microm. Excipient-free N1177 NanoCluster powders were delivered to rats by insufflation or inhalation and scanned using CT up to 1 h post dose. CT images after inhalation showed a approximately 120 (HU) Hounsfield units contrast increase in the lungs, which was more than sufficient contrast for thoracic CT imaging. Lung tissue histology demonstrated that N1177 NanoClusters did not damage the lungs. NanoCluster particle engineering technology offers a novel approach to safely and efficiently disseminate high concentrations of contrast agents to the lung periphery.

Assessment of Effective Renal Plasma Flow, Enzymuria, and Cytokine Release in Healthy Volunteers Receiving a Single Dose of Amphotericin B Desoxycholate

ABSTRACT The present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for α and π glutathione-S-transferases (GSTα and GSTπ, respectively) and N-acetyl-β-d-glucosaminidase (NAG). Six men and six women with mean ± standard deviation (SD) ages of 24.8 ± 5.3 and 28.0 ± 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean ± SD decrease in ERPF after administration of AmB was significant (P < 0.05) in males (15.7 ± 8.1%) but not females (9.5 ± 14.0%). The GSTπ and GSTα indices increased significantly (P < 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-α (P < 0.05) but not IL-1β (P = 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-α as subclinical markers of polyene-induced toxicity.