Preclinical Profile of Gadoquatrane: A Novel Tetrameric, Macrocyclic High Relaxivity Gadolinium-Based Contrast Agent

alexandrossfakianakis shared this article with you from Inoreader Preclinical Profile of Gadoquatrane: A Novel Tetrameric, Macrocyclic High Relaxivity Gadolinium-Based Contrast Agent via Investigative Radiology - Current Issue Objectives The aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability. Materials and Methods The r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model. Results The new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd (q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP −4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM−1·s−1 (corresponding to 47.2 mM−1·s−1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd3+ release in the presence of zinc in the transmetal lation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood. Conclusions The tetrameric gadoquatrane is a novel, highly effective mGBCA for use in MRI. Gadoquatrane provides favorable physicochemical properties (high relaxivity and stability, negligible protein binding) while showing essentially the same PK profile (fast extracellular distribution, fast elimination via the kidneys in an unchanged form) to established mGBCAs on the market. Overall, gadoquatrane is an excellent candidate for further clinical development. View on Web

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Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

alexandrossfakianakis shared this article with you from Inoreader Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218 via Investigative Radiology - Current Issue Objectives Preclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors. Materials and Methods Relaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218. Pharmacological effects on cardiovascular, respiratory, and central nervous systems were determined in rats and conscious beagle dogs. Pharmacokinetics were tested in rats and dogs. Biodistribution and excretion were studied in rats. Single and repeated dosing toxicity was evaluated in rats and dogs. In vitro and in vivo genotoxicity, in vitro hemolysis, and anaphylactic reactivity were also performed. Results At 1.4 T, the r1 and r2 relaxivities of MT218 were 5.43 and 7.40 mM−1 s−1 in pure water, 6.58 and 8.87 mM−1 s−1 in phosphate-buffered saline, and 6.54 and 8.70 mM−1 s−1 in aqueous solution of human serum albumin, respectively. The binding affinity of MT218 to extradomain B fragment is 3.45 μM. MT218 exhibited no dissociation of the Gd(III) chelates under physiological conditions. The peptide degradation half-life (t1/2) of MT218 was 1.63, 5.85, and 2.63 hours in rat, dog, and human plasma, respectively. It had little effect on CYP450 enzymes and transporters. MT218 produced up to 7-fold increase of contrast-to-noise ratios in the extradomain B fibronectin–rich tumors with a dose of 0.04 mmol/kg for at least 30 minutes. MT218 had little pharmacological effect on central nervous, cardiovascular, or respiratory systems. MT218 had a mean plasma elimination half-life (t1/2) of 0.31 and 0.89 hours in rats and dogs at 0.1 mmol/kg, respectively. No detectable Gd deposition was observed in the brain at 6 hours postinjection of MT218 at 0.1 mmol/kg in rats. MT218 was not mutagenic and had no mortality or morbidity in the rats or dogs up to 1.39 and 0.70 mmol/kg/d, respectively. The no observed adverse effect level of MT218 in Sprague-Dawley rats was 1.39 mmol/kg for single dosing and 0.46 mmol/kg/d for repeated dosing. The no observed adverse effect level in dogs was 0.07 mmol/kg/d. MT218 exhibited no genotoxicity, hemolysis, and anaphylactic reactivity. Conclusion The preclinical assessments showed that the targeted contrast agent MT218 has high r1 and r2 relaxivities, satisfactory physicochemical properties, pharmacokinetic, and safety profiles and produces effective tumor enhancement in multiple cancer types in rats and mice at reduced doses. View on Web

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Contrast Media Reduction in Computed Tomography With Deep Learning Using a Generative Adversarial Network in an Experimental Animal Study

alexandrossfakianakis shared this article with you from Inoreader Contrast Media Reduction in Computed Tomography With Deep Learning Using a Generative Adversarial Network in an Experimental Animal Study via Investigative Radiology - Current Issue Objective This feasibility study aimed to use optimized virtual contrast enhancement through generative adversarial networks (GAN) to reduce the dose of iodine-based contrast medium (CM) during abdominal computed tomography (CT) in a large animal model. Methods Multiphasic abdominal low-kilovolt CTs (90 kV) with low (low CM, 105 mgl/kg) and normal contrast media doses (normal CM, 350 mgl/kg) were performed with 20 healthy Göttingen minipigs on 3 separate occasions for a total of 120 examinations. These included an early arterial, late arterial, portal venous, and venous contrast phase. One animal had to be excluded because of incomplete examinations. Three of the 19 animals were randomly selected and withheld for validation (18 studies). Subsequently, the GAN was trained for image-to-image conversion from low CM to normal CM (virtual CM) with the remaining 16 animals (96 examinations). For validation, region of interest measurements were performed in the abdominal aorta, inferior vena cava, portal vein, liver parenchyma, and autochthonous back muscles, and the contrast-to-noise ratio (CNR) was calculated. In addition, the normal CM and virtual CM data were presented in a visual Turing test to 3 radiology consultants. On the one hand, they had to decide which images were derived from the normal CM examination. On the other hand, they had to evaluate whether both images are pathological consistent. Results Average vascular CNR (low CM 6.9 ± 7.0 vs virtual CM 28.7 ± 23.8, P View on Web

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The outbreak of SARS‐CoV‐2 Omicron lineages, immune escape and vaccine effectivity

alexandrossfakianakis shared this article with you from Inoreader The outbreak of SARS‐CoV‐2 Omicron lineages, immune escape and vaccine effectivity via Journal of Medical Virology ABSTRACT As of November 2021, several SARS-CoV-2 variants appeared and became dominant epidemic strains in many countries, including five VOCs (Alpha (1), Beta (2), Gamma (3), Delta (4) and Omicron (5) defined by the World Health Organization (WHO) during the COVID-19 pandemic. As of August 2022, Omicron is classified into five main lineages, BA.1, BA.2 (6), BA.3, BA.4, BA.5 (7) and some sub-lineages (BA.1.1, BA.2.12.1, BA.2.11, BA.2.75, BA.4.6) (https://www.gisaid.org/). Compared to the previous VOCs (Alpha, Beta, Gamma, and Delta), all the Omicron lineages have the most highly mutations in the spike protein, and with 50 mutations accumulated throughout the genome. Early data indicated that Omicron BA.2 sub-lineage had higher infectivity and more immune escape than the early wild-type (WT) strain, the previous VOCs, and BA.1 (8, 9, 10). Recently, global surveillance data suggest a higher transmissibility of BA.4/BA.5 than BA.1, BA.1.1 and BA.2, and BA.4/BA.5 is becoming dominant strain in many countries globally (7, 11). This article is protected by copyright. All rights reserved. View on Web

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Voriconazole‐induced severe skin allergy and neurological adverse event in a liver failure patient: A case report

alexandrossfakianakis shared this article with you from Inoreader Voriconazole‐induced severe skin allergy and neurological adverse event in a liver failure patient: A case report via Journal of Clinical Pharmacy and Therapeutics Severe allergy and neurological adverse events were appeared on the 19th day, which was the next day after voriconazole injection. The adverse events were alleviated after voriconazole withdraw for 1 week. VCZ: voriconazole, 0.4 g on the 18th day, followed by 0.2 g once daily, ALP: alprazolam, 0.2 g, per night, PT: piperacillin-tazobactam, 2.5 g every 12 h, IC: Imipenem cilastatin, 0.5 g every 8 hours, ENT: entecavir, 0.5 mg once daily, ADE: ademetionine, 0.25 g once daily, VAN: Vancomycin, 1 g every 12 h. Abstract What Is Known and Objective Triazole antifungal-associated severe skin allergy has received little attention. Here we report a case of an acute-on-chronic liver failure (ACLF) patient with diffused skin allergy pervading from the chest, abdomen, back, knees to perineum, with red colour and partially desquamation as well as a neurological adverse (insomnia) event after voriconazole treatment. Case Summary A 40-year-old man with liver failure in our hospital had received voriconazole for invasive fungal infection therapy, and while waiting for liver transplantation exhibited a severe diffuse rash and a neurological adverse event. What Is New and Conclusion To the best of our knowledge, this is the first report of a liver failure patient who suffered a severe allergy accompanied with a neurological adverse event after voriconazole administration. View on Web

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Impact of Ischemia Duration on Lower Limb Salvage in Combat Casualties

alexandrossfakianakis shared this article with you from Inoreader Impact of Ischemia Duration on Lower Limb Salvage in Combat Casualties via Annals of Surgery - Most Popular Articles Introduction: The 6-hour threshold to revascularization of an ischemic limb is ubiquitous in the trauma literature, however, contemporary evidence suggests that this threshold should be less. This study aims to characterize the relationship between the duration of limb ischemia and successful limb salvage following lower extremity arterial trauma. Methods: This is a cohort study of the United States and UK military service members injured while serving in Iraq or Afghanistan between 2003 and 2013. Consecutive patients who sustained iliac, femoral, or popliteal artery injuries, and underwent surgery to attempt revascularization, were included. The association between limb outcome and the duration of limb ischemia was assessed using the Kaplan-Meier method. Results: One hundred twenty-two patients (129 limbs) who sustained iliac (2.3%), femoral (56.6%), and popliteal (41.1%) arterial injuries were included. Overall, 87 limbs (67.4%) were successfully salvaged. The probability of limb salvage was 86.0% when ischemia was ≤1 hour; 68.3% when between 1 and 3 hours; 56.3% when between 3 and 6 hours; and 6.7% when >6 hours (P View on Web

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A Novel Nonantibiotic Gut-directed Strategy to Prevent Surgical Site Infections

alexandrossfakianakis shared this article with you from Inoreader A Novel Nonantibiotic Gut-directed Strategy to Prevent Surgical Site Infections via Annals of Surgery - Most Popular Articles Objective: To determine the efficacy of an orally delivered phosphate-rich polymer, Pi-PEG, to prevent surgical site infection (SSI) in a mouse model of spontaneous wound infection involving gut-derived pathogens. Background: Evidence suggests that pathogens originating from the gut microbiota can cause postoperative infection via a process by which they silently travel inside an immune cell and contaminate a remote operative site (Trojan Horse Hypothesis). Here, we hypothesize that Pi-PEG can prevent SSIs in a novel model of postoperative SSIs in mice. Methods: Mice were fed either a standard chow diet (high fiber/low fat, SD) or a western-type diet (low fiber/high fat, WD), and exposed to antibiotics (oral clindamycin/intraperitoneal cefoxitin). Groups of mice had Pi-PEG added to their drinking water and SSI incidence was determined. Gross clinical infections wound cultures and amplicon sequence variant analysis of the intestinal contents and wound were assessed to determine the incidence and source of the developing SSI. Results: In this model, consumption of a WD and exposure to antibiotics promoted the growth of SSI pathogens in the gut and their subsequent presence in the wound. Mice subjected to this model drinking water spiked with Pi-PEG were protected against SSIs via mechanisms involving modulation of the gut-wound microbiome. Conclusions: A nonantibiotic phosphate-rich polymer, Pi-PEG, added to the drinking water of mice prevents SSIs and may represent a more sustainable approach in lieu of the current trend of greater sterility and the use of more powerful and broader antibiotic coverage. View on Web

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Development and Implementation of the Cochlear Implant Quality of Life (CIQOL) Functional Staging System

alexandrossfakianakis shared this article with you from Inoreader Development and Implementation of the Cochlear Implant Quality of Life (CIQOL) Functional Staging System via The Laryngoscope The purpose of this study was to develop and implement a functional staging system using the Cochlear Implant Quality of Life (CIQOL) framework to improve the interpretation of real-world outcomes for adult cochlear implant users. Using a mixed-methods approach that engaged primary stakeholders (CI users) and clinicians, the CIQOL functional staging system was created and used to monitor improvement from pre-CI to 6-months post-CI activation. Results from this study can be used during discussions of expectation with potential CI users to provide enhanced insight regarding realistic outcomes and the anticipated timing for improvements. Objectives The purpose of this study is to develop and implement a functional staging system using the Cochlear Implant Quality of Life (CIQOL) framework. The CIQOL-35 Profile was developed and validated following a rigorous research design and found to be more comprehensive and psychometrically sound than previous patient-reported outcome measures (PROMs) applied to adult CI users. However, interpreting the CIQOL-35 Profile (and all PROMs) relative to real-world functioning remains difficult for patients and clinicians, which limits the capacity of PROMs to direct clinical care. To address this limitation, a functional staging system based on PROM scores was developed to provide detailed descriptions of patients' self-reported abilities (clinical vignettes) without sacrificing the inherent value of the psychometrically derived scores. The current study (1) creates an evidence-based CIQOL functional staging system using advanced psychometric techniques, (2) confirms the clarity and meaningfu lness of the staging system with patients, and (3) implements the staging system to measure CIQOL stage progression using data from a longitudinal study design. Methods Item response theory (IRT) analyses of CIQOL-35 Profile data from 705 experienced adult CI users and expert opinion were used to determine the cut-scores that separated adjacent stages for the six CIQOL-35 domains (communication, emotional, entertainment, environment, listening effort, and social). The research team then created clinical vignettes based on item response patterns for each stage. Semi-structured key informant interviews were conducted with 10 adult CI users to determine the clarity and meaningfulness of the CIQOL stages and associated clinical vignettes. Finally, we prospectively collected CIQOL-35 Profile scores from 42 CI users prior to cochlear implantation and then at 3- and 6-months post-CI activation to measure CIQOL stage progression. Results Psychometric analyses identified five statistically distinct stages for the communication domain and three stages for all other domains. Using IRT analysis results for guidance, research team members independently identified the cut-scores that represented transitions between the functional stages for each domain with excellent agreement (κ = 0.98 [95% confidence interval 0.96–0.99]). Next, the key informant interviews revealed that CI users found the clinical vignettes to be clear and only minor changes were required. Participants also agreed that stage progression represented meaningful improvements in functional abilities. Finally, 88.1% of 42 patients in the prospective cohort (n = 37) improved from pre-CI functional stage by at least one functional stage in one or more domains. The communication domain had the greatest number of patients improve by one or more stages (59.5%) and the social domain the fewest (25.6%). There was also a trend for les s improvement at 3- and 6-months post-CI activation for patients at higher pre-CI functional stages, even though higher stages were achievable. Conclusion The new CIQOL functional staging system provides an evidence-based understanding of the real-world functional abilities of adult CI users from pre-CI to 3- to 6-months post-CI activation across multiple domains. In addition, study results provide the proportion of CI users in each stage at each timepoint. Results can be used during discussions of expectations with potential CI users to provide enhanced insight regarding realistic outcomes and the anticipated timing for improvements. The use of the CIQOL functional staging system also presents an opportunity to develop individualized goal-based rehabilitation strategies that target barriers to stage advancement faced by CI users. Level of Evidence 2 Laryngoscope, 2022 View on Web

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Rapid Additive Manufacturing of a Superlight Obturator for Large Oronasal Fistula in Pediatric Patient

alexandrossfakianakis shared this article with you from Inoreader Rapid Additive Manufacturing of a Superlight Obturator for Large Oronasal Fistula in Pediatric Patient via The Laryngoscope This study developed a novel digital workflow to fabricate a 3D printed hollow obturator for the prosthetic reconstruction of palatal fistula. It will provide cleft surgeons and therapists a choice for treating children with large palatal fistula before the appropriate age for surgical reconstruction. Laryngoscope, 2022 View on Web

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