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In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half‐life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug‐related exposure (DRE), while a direct N‐glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications. Proposed metabolic pathways for atuliflapon in humans. Asterisk (*) designates the site of 14C labelling.

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Fine fescues (Festuca spp.) are cool-season grasses used in low-maintenance turf areas. Mesotrione is a PRE and early-POST herbicide used during establishment of most cool-season turfgrasses, excluding fine fescues. Currently, efforts are being made to breed for increased tolerance to mesotrione in fine fescues to enhance weed control during establishment. This study was conducted to evaluate the association of foliar and root uptake of [14C]mesotrione with the tolerance of three lines each of Chewings fescue [Festuca rubra ssp. commutata Gaudin; syn. F. rubra ssp. fallax (Thuill.) Nyman], hard fescue [Festuca trachyphylla (Hack.) Hack.], and strong creeping red fescue (Festuca rubra L. ssp. rubra) lines. From a rate-titration experiment, the hierarchical rank of species for mesotrione tolerance from highest to lowest was: hard > Chewings > strong creeping red fescue. The hierarchical rank of species for foliar uptake from highest to lowest was: Chewings > strong creeping red > hard fescue. Translocation of foliar-absorbed 14C was not associated with differential tolerance levels of the three species. Root absorption was comparable among species, but differences between lines were detected within the species. The most susceptible lines of Chewings and strong creeping red fescue exhibited greater root uptake than lines with greater tolerance. Hard fescue translocated the least amount of root-absorbed radioactivity to shoots, while Chewings and strong creeping red fescues were comparable.

Breast cancer remains a pressing public health issue primarily affecting women. Recent research has spotlighted bioactive peptides derived from laminin-111, implicated in breast tumor development. Remarkably, the sequences IKVAV, YIGSR, and KAFDITYVRLKF from the α1, β1, and γ1 chains, respectively, have garnered significant attention. This study aims to assess the potential of these radiolabeled peptides as targeting agents for breast cancer. The three peptides were synthesized using the Fmoc strategy, purified via reversed-phase high-performance liquid chromatography (RP-HPLC), and characterized through mass spectrometry. Iodine-131 (131I) radiolabeling was performed using the chloramine T method, exhibiting high radiochemical yield and stability for [131I]I-YIKVAV and [131I]I-YIGSR. Conversely, [131I]I-KAFDITYVRLKF demonstrated low radiochemical yield and stability and was excluded from the biological studies. The lipophilicity of the compounds ranged from − 2.12 to − 1.10. Serum protein binding assay for [131I]I-YIKVAV and [131I]I-YIGSR reached ≅ 48% and ≅ 25%, respectively. Affinity for breast cancer cells was evaluated using MDA-MB-231 and MCF-7 tumor cell lines, indicating the affinity of the radiopeptides with these tumor cells. Ex vivo biodistribution profiles of the radiopeptides were assessed in the MDA-MB-231 breast tumor animal model, revealing tumor tissue accumulation, supported by a high tumor-to-contralateral muscle ratio and autoradiography. These results signify the effective penetration of YIKVAV and YIGSR into tumor tissue. Therefore, the synthesized α1 and β1 peptide fragments exhibit favorable characteristics as potential breast cancer-targeting agents, promising future exploration as radiopharmaceuticals for breast cancer.

Infective endocarditis (IE) is a life-threatening disease, establishing a diagnosis is often challenging. The aim of this prospective study was to evaluate and compare the diagnostic performance of the combined use of single photon emission tomography and computed tomography with technetium99m-hexamethylpropyleneamineoxime—labeled leukocytes (99mTc-HMPAO-SPECT/CT) with transthoracic echocardiography (TTE) in patients with suspected IE. We enrolled 40 consecutive patients (12 females, 28 males, mean age: 58.6 ± 18) with suspected IE in the years 2015–2016. All patients underwent clinical evaluation, TTE and 99mTc-HMPAO-SPECT/CT for the assessment of lesions typical for IE. Scans were evaluated for the presence and location of increased radioactivity foci, corresponding to the accumulation of radiolabeled leukocytes in inflammatory lesions. After 6 months, the patients were re-evaluated clinically and with TTE. Final IE diagnosis was established in 14 (35%) patients. Lesions typical for IE were shown in 28 (70%) TTEs and 16 (40%) 99mTc-HMPAO-SPECT/CTs. The latter tests were characterized by 90% accuracy, 93% sensitivity, 88% specificity, 96% negative predictive value (NPV), 81% positive predictive value (PPV). TTE demonstrated 60% accuracy, 93% sensitivity, 42% specificity, 92% NPV, and 46% PPV. 99mTc-HMPAO-SPECT/CT was characterized by a lower number of false-positive results compared to TTE (3 vs. 15). In patients with suspected IE, 99mTc-HMPAO-SPECT/CT yields a smaller number of false-positive results, significantly higher diagnostic accuracy, specificity and PPV than TTE. It helps to differentiate IE infectious and sterile echocardiographic lesions and reduces by 27% the number of misdiagnosed IE classified in the ‘possible IE’ category by modified Duke Criteria.

The coronavirus disease 2019 (COVID-19) has become a substantial threat to the international health sector and the global economy. As of 26 December 2021, the number of mortalities resulting from COVID-19 exceeded 5.3 million worldwide. The absence of an effective non-vaccine treatment has prompted the quest for prophylactic agents that can be used to combat COVID-19. This study presents the feasibility of chicken egg yolk antibody (IgY) anti-receptor-binding domain (RBD) spike SARS-CoV-2 as a strong candidate to neutralize the virus for application in passive immunization. For the purpose of preclinical studies, we radiolabeled IgY anti-RBD spike SARS-CoV-2 with radionuclide iodine-131. This allowed us to evaluate several biological characteristics of IgY in vitro, in vivo, and ex vivo. The preclinical data suggest that IgY anti-RBD spike SARS-CoV-2 could specifically bind to the SARS-CoV-2 antigens; however, little uptake was observed in normal cells (MRC-5) (<2%). Furthermore, the ex vivo biodistribution study revealed that IgY predominantly accumulated in the trachea of normal mice compared to other organs. We also found that IgY possessed a good safety profile when used as an intranasal agent. Taken together, we propose that IgY anti-RBD spike SARS-CoV-2 has the potential for application in passive immunization against COVID-19.

The rapid development and translation of targeted molecular imaging agents from bench to bedside is currently a slow process, with a clear bottleneck between the discovery of new compounds and the development of an appropriate molecular imaging agent. The ability to identify promising new molecular imaging agents, as well as failures, much earlier in the development process using high-throughput screening techniques could save significant time and money. This work combines the advantages of combinatorial chemistry, site-specific solid-phase radiolabeling, and in vivo imaging for the rapid screening of molecular imaging agents. A one-bead-one-compound library was prepared and evaluated in vitro, leading to the identification of 42 promising lead peptides. Over 11 consecutive days, these peptides, along with a control peptide, were successfully radiolabeled with 4-[¹⁸F]fluorobenzoic acid and evaluated in vivo using microPET. Four peptides were radiolabeled per day, followed by simultaneous injection of each individual peptide into 2 animals. As a result, 4 promising new molecular imaging agents were identified that otherwise would not have been selected based solely on in vitro data. This study is the first example of the practical application of a high-throughput screening approach using microPET imaging of [¹⁸F]-labeled peptides for the rapid in vivo identification of potential new molecular imaging agents.

Diacylglycerol acyltransferase (DGAT) is considered as a rate-limiting enzyme of triacylglycerol (TAG) biosynthesis in many organisms including algae. Many algae have multiple DGAT genes in their genomes. It is crucial to clarify substrate specificity and activity of different DGATs for understanding their biological roles. The current in vitro DGAT assays involve predominantly the use of radiolabeled substrates, either acyl-CoA or diacylglycerol (DAG). The availability of limited radiolabeled substrates and technical difficulties to conduct radiolabeled experiments have limited the use of these assays. Therefore, an assay without the involvement of radiolabeled substrates is needed. In the present study, we developed a novel in vitro DGAT assay using non-radiolabeled substrates and optimized its conditions including buffer pH and concentration, Mg 2+ concentration, microsomal protein amount, acyl-CoA concentration, and incubation time. CrDGTT1, a type 2 DGAT from Chlamydomonas reinhardtii , was used to assess the feasibility of our non-radiolabeled in vitro assay toward different acyl-CoAs and DAGs. In addition, the substrate preference and activity of ScDGA1, a yeast-derived type 2 DGAT, were evaluated with our assay method, and the results obtained were consistent with those from a previous radiolabeled assay. We also demonstrated the suitability of this assay for the activity of phospholipid:diacylglycerol acyltransferase, an enzyme responsible for the acyl-CoA-independent TAG biosynthesis. Taken together, the in vitro acyltransferase assay developed here eliminates the use of radiolabeled substrates, is simple and reproducible, and allows the investigation of enzyme specificity and activity over a wide range of substrates.

High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a 55Co-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with 57Co and 55Co, stability, binding specificity, and in vitro and in vivo characteristics of 57Co-NOTA-PEG2-RM26 were studied. NOTA-PEG2-RM26 was successfully radiolabeled with 57Co and 55Co with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. 57Co-NOTA-PEG2-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG2-RM26 translated into high contrast preclinical PET/CT (using 55Co) and SPECT/CT (using 57Co) images of PC-3 xenografts. The initial biological results suggest that 55Co-NOTA-PEG2-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa’s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.