Comparative Pharmacokinetic Analysis of Aflibercept and Brolucizumab in Human Aqueous Humor Using Nano-Surface and Molecular-Orientation Limited Proteolysis.

Aflibercept and brolucizumab, two anti-VEGF agents used as intravitreal injections in ophthalmology, differ significantly in molecular weight (aflibercept-115 kDa and brolucizumab-26 kDa). Using aqueous humor samples collected after drug administration, we measured and performed a comparative analysis of pharmacokinetics and half-lives of these drugs in the human eye. Since the quantification of monoclonal antibodies (mAbs) using antigen-antibody reactions, such as ELISA, is influenced by endogenous ligands or anti-drug antibodies, we employed nano-surface and molecular-orientation limited proteolysis (nSMOL), combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), for accurate measurements.

NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.

Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD ratio, reflecting the balance between NADH (reduced) and NADoxidized, is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD.

Targeted Plasma Bile Acid Metabolomic Analysis in Metabolic Dysfunction-Associated Steatohepatitis and Alcoholic Hepatitis.

Even though many metabolic liver diseases can now be diagnosed using blood tests and diagnostic imaging, early diagnosis remains difficult. Understanding mechanisms contributing to the progression from Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Alcoholic Hepatitis (AH) to cirrhosis is critical to reduce the burden of end-stage liver disease. Monitoring individual bile acids has been proposed as a way to distinguish various liver disorders.

Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD Depletion with Salvage Pathway Impairment.

Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism.

Arachidonic acid synergizes with aspirin preventing myocardial ischemia-reperfusion injury and mitigates bleeding risk.

Aims: The therapeutic efficacy of coronary revascularization is compromised by myocardial ischemia-reperfusion (MI/R) injury. Higher levels of circulating arachidonic acid (AA) are reportedly associated with lower risk of cardiovascular disease. The cyclooxygenase (COX) pathway metabolizes AA into prostaglandins (PGs) and the platelet-activating thromboxane A2 (TXA2), which is inhibited by aspirin.

Non-Targeted Metabolomics Reveal Apomorphine's Therapeutic Effects and Lysophospholipid Alterations in Steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas.

Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation.

Background: Abdominal aortic aneurysm (AAA) is a chronic vascular inflammatory disease without effective medications. PCSK9 (proprotein convertase subtilisin/kexin 9), a serine protease from the proprotein convertase family, has recently been associated with AAA in human genome-wide association studies. However, its role in AAA is unknown.

Complement factor B, not the membrane attack complex component C9, promotes neointima formation after arterial wire injury.

Background And Aims: Vascular restenosis due to neointima hyperplasia limits the long-term patency of stented arteries, resulting in angioplasty failure. The complement system has been implicated in restenosis. This study aimed to investigate the role of complement factor B (fB), an essential component of the alternative pathway of complement activation, in neointima formation.

Cadence-Based Pedometer App With Financial Incentives to Enhance Moderate-to-Vigorous Physical Activity: Development and Single-Arm Feasibility Study.

Background: High levels of physical activity are key to improving health outcomes, yet many people fail to take action. Using pedometers to target steps per day and providing financial incentives is a simple and scalable approach to promoting public health. However, conventional pedometers do not account for "intensity" and "duration," making it challenging to efficiently increase people's moderate-to-vigorous physical activity (MVPA), which is expected to improve health outcomes.

Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan.

Anti-drug antibodies (ADAs) generated in response to biopharmaceuticals can significantly impact pharmacokinetics (PK) and overall drug efficacy. Thus, the ICH M4 guidelines mandate summarizing immunogenicity data from clinical trials in drug approval applications. However, following the approval of the first antibody drug in Japan in 2001, no cross-sectional investigation has focused on immunogenicity during the regulatory review process.

Quantitatively analyzing the dissociation and release of disulfide-containing organic nanoparticles.

The disintegration of nanoparticles and drug release are important and imperative for nanoparticle formulations of therapeutic agents. However, quantitatively monitoring the drug release of nanomedicines is a major challenge. In this work, boron-dipyrromethene (BDP) was applied as a model drug to study the disassembly of nanoparticles and drug release.

Safety, tolerability, and pharmacokinetics of HRS9432(A) injection in healthy Chinese subjects: a phase-I randomized, double-blind, dose escalation, placebo-controlled study.

Unlabelled: HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered.

Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice.

Background And Purpose: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein-kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown.

Pharmacokinetics and Nephrotoxicity of Polymyxin MRX-8 in Rats: A Novel Agent against Resistant Gram-Negative Bacteria.

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments.

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies.

Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes.

A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed.

Polypharmacy-related Shock Symptoms and Complications Associated with Phenothiazine.

This report describes a case of shock symptoms in a 72-year-old woman with epilepsy who had been in a state of polypharmacy, taking multiple antipsychotic drugs. After receiving a normal dose of periciazine, she exhibited impaired consciousness, hypothermia, and hypotension and was admitted to hospital. Despite poor response to vasopressors, conservative treatment led to gradual improvement.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection.

Several genetic defects, including a mutation in myosin heavy chain 11 (), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation.

A biomarker framework for cardiac aging: the Aging Biomarker Consortium consensus statement.

Cardiac aging constitutes a significant risk factor for cardiovascular diseases prevalent among the elderly population. Urgent attention is required to prioritize preventive and management strategies for age-related cardiovascular conditions to safeguard the well-being of elderly individuals. In response to this critical challenge, the Aging Biomarker Consortium (ABC) of China has formulated an expert consensus on cardiac aging biomarkers.