Mallinckrodt (Ireland)

Hyperpolarized acetoacetate is a promising probe for detection of redox status inside mitochondria using 13C MRI. In this pilot study we used parahydrogen-induced polarization by means of side arm hydrogenation (PHIP-SAH) approach for hyperpolarization of [1,3-13C2]acetoacetate. The propargyl [1,3-13C2]acetoacetate precursor was synthesized and subjected to homogeneous hydrogenation with parahydrogen. After optimization, the observed 1H polarization was 25.5% while achieving 100% chemical conversion of propargyl moiety and 80% selectivity to allyl [1,3-13C2]acetoacetate product. After hydrogenation, linear magnetic field sweep was performed for 1H-to-13C polarization transfer in allyl [1,3-13C2]acetoacetate with maximum observed 13C polarizations: P(13C-1) = 4.1% and P(13C-3) = 2.7%. Next, we analyzed the products of allyl [1,3-13C2]acetoacetate hydrolysis under different conditions. Alkaline hydrolysis results in the formation of stereoisomeric enolates of allyl [1,3-13C2]acetoacetate, which can then be converted into hyperpolarized [1,3-13C2]acetoacetate under harsh alkaline conditions with subsequent decomposition to hyperpolarized [2-13C]acetone and [13C]carbonate. These results represent a step toward expanding the PHIP-SAH agent portfolio beyond pyruvate, here specifically towards establishing acetoacetate as a promising candidate for future redox and ROS-sensitive 13C MRI studies.

BackgroundA post-marketing surveillance (PMS) of INOflo® for Inhalation 800 ppm in Japan (N = 2,817) established its real-world safety and effectiveness in improving hemodynamic parameters during the perioperative period in patients undergoing cardiac surgery. However, the patient population was heterogeneous with respect to characteristics such as age and baseline hemodynamic parameters.ObjectiveThe objective of this study is to evaluate patient characteristics associated with the effectiveness of inhaled nitric oxide (iNO) for pulmonary hypertension following cardiac surgery in Japan.MethodsThis study was a retrospective analysis of the PMS data of INOflo. Adults aged ≥15 years with a mean pulmonary artery pressure (mPAP) ≥20 mmHg at baseline (i.e., prior to iNO initiation) who commenced iNO following cardiac surgery were included. The PMS prospectively monitored the safety and effectiveness of INOflo in Japan. The primary endpoint was the change in mPAP from baseline to 24 hours after iNO initiation. Multivariable regression analysis explored patient characteristics (age, BMI, sex, and prior pulmonary vasodilator medication) associated with the primary endpoint.ResultsA total of 427 Japanese patients were included (median (IQR) age: 71.0 (60.0-77.0) years). Significant improvements in hemodynamic parameters were observed, including mPAP at 24 and 48 hours from baseline. No patient characteristics were significantly associated with the change in mPAP from baseline to 24 hours after iNO initiation. However, patients aged 30 years or with a BMI of 35 did not show significant changes in mPAP, whereas other age and BMI categories demonstrated statistically significant improvements.ConclusionsiNO treatment was associated with improvements in hemodynamics in patients with pulmonary hypertension following cardiac surgery, irrespective of patient characteristics such as age, BMI, sex, or prior pulmonary vasodilator therapy in this analysis. Conversely, the models suggest that differences in age and BMI may influence the magnitude of iNO effectiveness on the change in mPAP.

Prostate-specific membrane antigen (PSMA)-targeted PET imaging plays a well-established role in staging, detecting recurrence, and selecting patients for PSMA-targeted radiopharmaceutical therapy in prostate cancer. We present a case of PSMA-expressing recurrent prostate cancer in the pelvis, involving the urinary bladder wall and pelvic lymph nodes that was not completely visualized on 18F-DCFPyL PET/CT, but clearly delineated on 18F-rhPSMA-7.3 PET/CT. This discrepancy is attributed to the significantly lower urinary excretion and consequent low urinary bladder activity with 18F-rhPSMA, yielding high target-to-background ratios in the pelvis, and highlighting its potential diagnostic advantage in evaluating pelvic lesions near the urinary bladder.

ABSTRACTBackgroundTreatments for hepatorenal syndrome with acute kidney injury (HRS‐AKI) that are not FDA‐approved have been widely used in the United States (US) with variable outcomes. This study describes the practice patterns, outcomes, and healthcare utilization around vasopressor use before terlipressin approval in 2022.MethodsA retrospective chart review study was conducted at 10 US medical centers, assessing adult patients diagnosed with HRS‐AKI between 2016 and 2019. The primary outcome was treatment response (change in serum creatinine [SCr] from the day of vasopressor treatment initiation to Day 14/vasopressor discontinuation). Secondary outcomes included overall and transplant‐free survival, treatment patterns, and healthcare resource use.ResultsOf the 198 eligible patients, 129 and 69 had mild/moderate (SCr < 5 mg/dL, acute‐on‐chronic liver failure [ACLF] ≤ 2) and severe disease (SCr ≥ 5 mg/dL, ACLF > 2), respectively. The mean age was 57 years; 52.5% were males, and 71.2% were White. Alcohol‐associated cirrhosis (53.5%) was the most common cause of cirrhosis. All 198 patients had a physician‐diagnosed HRS‐AKI, and only 30.3% met all International Club of Ascites (ICA)‐HRS criteria. Most patients (85.4%) initiated treatment with midodrine and octreotide for a median of 7 days. The overall response rate (n = 157) was 20.3%. Median (95% CI) overall and transplant‐free survival from vasopressor initiation was 48 (32–81) and 28 (19–36) days. Notably, 33.8% of patients died during hospitalization, and 31.3% required renal replacement therapy.ConclusionBefore 2022, hospitalized HRS‐AKI patients experienced suboptimal treatment response with off‐label treatments and poor survival. There remains an unmet need for safe and effective non‐transplant treatments for hospitalized HRS‐AKI patients in the United States.

Diagnostic agents capable of imaging β-amyloid (Aβ) plaques at prodromal stages could provide noninvasive tools to assess plaque burden and assist in determining efficacy of disease-modifying therapeutic interventions in vivo. To accomplish this goal, FDA approved 18F-incorporated tracers, such as Florbetapir, Flutemetamol, and Florbetaben may allow quantitative analysis of therapeutic efficacy of disease-modifying treatments that attenuate Aβ pathophysiology in vivo. Although promising, these tracers show high off-target binding. Importantly, current anti-amyloid therapy also targets diffuse amyloid plaques (included in revised NIAAA criteria for detecting AD) and other forms of amyloid plaques. Therefore, molecules capable of detecting both diffuse and fibrillar plaque pathology can potentially offer better quantitative tools for interrogating efficacy of anti-amyloid therapy. To achieve this goal, herein, we report synthesis and characterization of new small organic molecules: ((Z,E)-4-(2-(6-(2-Fluoroethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 4, ((Z)-4-(2-(6-(2-(2-(3-Fluoropropoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 5a and ((E)-4-(2-(6-(2-(2-(3-Fluoropropoxy)ethoxy)ethoxy)benzo[d]thiazol-2-yl)vinyl)-N,N-dimethylaniline) 5b. We also report preliminary investigations on binding affinity in vitro. While 4 demonstrated a relatively higher affinity, both 5a and 5b showed moderate affinity for Aβ1-42 aggregates in vitro. Furthermore, all 3 agents showed ability to detect Aβ fibrillar and diffuse plaque pathology in brain sections of APP/PS1 transgenic mice and post-mortem confirmed AD human brain tissue sections.