A first in man study to evaluate the safety, pharmacokinetics and pharmacodynamics of RP7214, a dihydroorotate dehydrogenase inhibitor in healthy subjects.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double-blind, placebo-controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment-emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady-state concentrations were reached within about 3-6 days. The mean plasma half-life at steady-state was 12.8 hours (9.9-15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS-CoV-2 and acute myeloid leukaemia (NCT04680429).

Totally automatic definition of renal regions of interest from 99mTc-MAG3 renograms: validation in patients with normal kidneys and in patients with suspected renal obstruction.

INTRODUCTION: An image-processing algorithm (AUTOROI) has been developed to totally automatically (or with manual assistance) detect whole-kidney contours and generate renal regions of interest (ROI) for the extraction of the quantitative measurements used in the interpretation of Tc-mercaptoacetyltriglycine (Tc-MAG3) renograms. METHODS: The 18-20th min dynamic frames post-MAG3 injection were used to automatically define boxes surrounding each kidney, which were then transposed to an early composite image for interpolative and directional background subtraction. Sobel operator and unsharp masking were applied for edge enhancement, and the resulting image histograms were equalized to better define poorly functioning kidneys. AUTOROI searched radially from the center of mass to define each kidney's ROI coordinates. AUTOROI was validated using MAG3 studies from 79 patients referred for suspected obstruction (79 left, 77 right kidneys) and 19 kidney donors with normal kidney function and no obstruction. Renal ROIs were manually defined by a nuclear medicine technologist with 20+ years of experience (reference standard) and an American Board of Nuclear Medicine certified physician. AUTOROI and physician ROIs were automatically compared with the reference standard to determine the border definition error. RESULTS: AUTOROI totally automatically detected the renal borders in 89% (172 of 194) of the kidneys from the entire group of 98 patients. The 22 kidneys missed automatically were subsequently detected with the assistance of a single manually placed fiducial point demarcating the liver/kidney boundary. These 22 kidneys were shown to be associated with markedly reduced MAG3 clearance. The mean error of AUTOROI for all 194 kidneys was 6.66+/-3.77 and 7.31+/-4.52 mm for the left and right kidney, respectively. The physician's error was 6.78+/-2.42 and 6.65+/-2.05 mm for the left and right kidney, respectively. This error difference between AUTOROI and the physician was not statistically significant. CONCLUSION: AUTOROI provides an objective and promising approach to automated renal ROI detection.

Indium-111 diethylene-triamine-pentaacetic acid scintigraphy in the evaluation of function and patency of baclofen intrathecal infusion systems.

OBJECT: Baclofen pump infusion systems are used for the treatment of patients with severe spasticity. When symptoms do not respond to infusion rate increases, the cause may be pump malfunction or catheter obstruction. The purpose of this investigation was to review the authors' experience with indium-111 diethylene-triamine-pentaacetic acid (In-111 DTPA) scintigraphy for evaluation of baclofen infusion system function and patency and to correlate scintigraphic findings with patient treatment and outcome to determine optimal methodology and diagnostic criteria. METHODS: Ten scintigraphic studies acquired in eight patients (five adults, three adolescents) were retrospectively reviewed. Imaging was routinely performed at 4, 24, 48, and 72 hours after injection of In-111 DTPA into the pump reservoir. The results of the studies were interpreted by two nuclear medicine physicians who had no knowledge of the patients' clinical history or outcome. The scintigraphic findings (for example, radiotracer detected in the basal cisterns, cervical or thoracolumbar regions, infusion catheter, and pump) were recorded and correlated with neuroimaging findings, patient history, treatment, and clinical response to therapy. RESULTS: In cases in which the basal cistern could be visualized at any time and those in which radiotracer was visualized in the thoracolumbar intrathecal region within 48 hours, the pump systems were functional and symptoms responded to an increase in infusion rate. One patient in whom activity was visualized in the thoracolumbar intrathecal region by 72 hours also experienced clinical improvement with a flow rate increase. Visualization of the pump alone or only the pump and the subcutaneous catheter was consistent with catheter obstruction or pump malfunction. CONCLUSION: The use of In-111 DTPA scintigraphy of intrathecal baclofen infusion systems can play an important role in determining the functional status of these systems and guiding subsequent patient care.