Publications by authors named "Jeff Kent"

5 Publications

  • Page 1 of 1

Reducing Immunogenicity of Pegloticase (RECIPE) with Concomitant Use of Mycophenolate Mofetil in Patients with Refractory Gout- a Phase II Double Blind Placebo Controlled Randomized Trial.

Arthritis Rheumatol 2021 Mar 22. Epub 2021 Mar 22.

University of Alabama at Birmingham, Birmingham, AL, United States.

Objectives: Pegloticase is used for treatment of severe gout patients but its use is limited by immunogenicity. We evaluated whether mycophenolate mofetil (MMF) would prolong the efficacy of pegloticase.

Methods: Participants were randomized 3:1 to 1000 mg MMF twice daily or placebo (PBO) for 14 weeks starting 2 weeks before and while receiving intravenous pegloticase 8 mg biweekly for 24 weeks. The primary endpoint was proportion of patients who sustained a serum urate (SU) level of ≤ 6 mg/dl at 12 weeks. Secondary endpoints included 24-week durability of SU ≤ 6 mg/dl and rate of adverse events (AEs). Fisher's exact test and Wilcoxon two-sample test were used for analyses along with Kaplan-Meier estimates and log-rank tests.

Results: 32 participants received at least one dose of pegloticase. Participants were predominantly men (88%), with mean age 55.2 years, gout duration of 13.4 years, and mean baseline SU of 9.2 mg/dL. At 12 weeks, 19 of 22 (86%) in the MMF arm achieved SU ≤ 6 mg/dl compared to 4 of 10 (40%) in PBO arm (p-value = 0.01). At week 24, the SU was ≤ 6 mg/dl in 68% of MMF arm vs. 30% in PBO (p-value = 0.06), and rates of AEs were similar between groups with the PBO arm having more infusion reactions (30% vs. 0%).

Conclusion: MMF therapy with pegloticase was well tolerated and showed a clinically meaningful improvement in targeted SU ≤6 mg/dL at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.
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http://dx.doi.org/10.1002/art.41731DOI Listing
March 2021

F-Labeled perfluorocarbon droplets for positron emission tomography imaging.

Nucl Med Biol 2017 Nov 12;54:27-33. Epub 2017 Jul 12.

Department of Medical Imaging, University of Toronto, Toronto, ON, Canada; Department of Materials Science and Engineering, University of Toronto, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address:

Introduction: Nanoscale perfluorocarbon (PFC) droplets have been used to create imaging agents and drug delivery vehicles. However, development and characterization of new formulations of PFC droplets are hindered because of the lack of simple methods for quantitative and sensitive assessment of whole body tissue distribution and pharmacokinetics of the droplets. To address this issue, a general-purpose method for radiolabeling the inner core of nanoscale perfluorocarbon droplets with a hydrophobic and lipophobic fluorine-18 compound was developed, so that positron emission tomography (PET) and quantitative biodistribution studies can be employed to evaluate PFC nanodroplets in vivo.

Methods: A robust method to produce [F]CF(CF)(CH)F from a tosylate precursor using [F]F was developed. The product's effectiveness as a general label for different PFCs and its ability to distinguish the in vivo behavior of different PFC droplet formulations was evaluated using two types of PFC nanodroplets: fluorosurfactant-stabilized perfluorohexane (PFH) nanodroplets and lipid-stabilized perfluorooctylbromide (PFOB) nanodroplets. In vivo assessment of the F-labeled PFH and PFOB nanodroplets were conducted in normal mice following intravenous injection using small animal PET imaging and gamma counting of tissues and fluids.

Results: [F]CF(CF)(CH)F was produced in modest yield and was stable with respect to loss of fluoride in vitro. The labeled fluorocarbon was successfully integrated into PFH nanodroplets (~175 nm) and PFOB nanodroplets (~260 nm) without altering their mean sizes, size distributions, or surface charges compared to their non-radioactive analogues. No leakage of the radiolabel from the nanodroplets was detected after droplet formation in vitro. PET imaging and biodistribution data for the two droplet types tested showed significantly different tissue uptake and clearance patterns.

Conclusion: A convenient method for producing F-labeled PFC droplets was developed. The results highlight the potential utility of the strategy for pre-clinical evaluation of different PFC droplet formulations through direct PFC core labeling using a fluorinated radiolabel.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.07.001DOI Listing
November 2017

A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives.

PLoS One 2016 9;11(12):e0167425. Epub 2016 Dec 9.

Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.

A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with 99mTc was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The 99mTc-labelled HYNIC-tetrazine was synthesized in 75% yield and exhibited high stability in vitro and in vivo. A trans-cyclooctene (TCO)-labelled bisphosphonate (TCO-BP) that binds to regions of active calcium metabolism was used to evaluate the utility of the labelled tetrazine for bioorthogonal chemistry. The pretargeting approach, with 99mTc-HYNIC-tetrazine administered to mice one hour after TCO-BP, showed significant uptake of radioactivity in regions of active bone metabolism (knees and shoulders) at 6 hours post-injection. For comparison, TCO-BP was reacted with 99mTc-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control 99mTc-HYNIC-tetrazine alone did not. A TCO-vancomycin derivative was similarly employed for targeting Staphylococcus aureus infection in vitro and in vivo. Pretargeting and active targeting strategies showed 2.5- and 3-fold uptake, respectively, at the sites of a calf-muscle infection in a murine model, compared to the contralateral control muscle. These results demonstrate the utility of the 99mTc-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167425PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147877PMC
July 2017

High yielding preparation of dicarba-closo-dodecaboranes using a silver(I) mediated dehydrogenative alkyne-insertion reaction.

Inorg Chem 2013 Aug 5;52(15):8743-9. Epub 2013 Jul 5.

Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada.

The synthesis of 1,2-dicarba-closo-dodecaboranes (ortho-carboranes) is often low yielding which is a critical issue given the increasing use of boron clusters in material science and medicinal chemistry. To address this barrier, a series of Cu, Ag, and Au salts were screened to identify compounds that would enhance the yields of ortho-caboranes produced when treating alkynes with B10H12(CH3CN)2. Using a variety of functionalized ligands including mono- and polyfunctional internal and terminal alkynes, significant increases in yield were observed when AgNO3 was used in catalytic amounts. AgNO3 appears to prevent unwanted reduction/hydroboration of the alkyne prior to carborane formation, and the process is compatible with aryl, halo, hydroxy, nitrile, carbamate, and carbonyl functionalized alkynes.
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http://dx.doi.org/10.1021/ic400928vDOI Listing
August 2013