Population pharmacokinetics and pharmacodynamics of eravacycline in patients with complicated intra-abdominal infections and community acquired bacterial pneumonia: support for a fixed-dose treatment regimen.

Eravacycline is a tetracycline used for the treatment of complicated intra-abdominal infections (cIAI) and has the potential to treat community-acquired bacterial pneumonia (CABP). The approved regimen for cIAI is 1mg/kg (Q12h). However, studies have reported the inconvenience of drug preparation based on body weight (BW) and wastage of the drug, because the specification is 50 mg per vial.

DDX54 drives ALKBH5-mediated demethylation of selected transcripts to suppress interferon antiviral response.

DEAD-box (DDX) proteins are currently reported to shape host innate immunity by regulation of N-methyladenosine (mA) modification of transcripts for host factors involved in antiviral signaling. However, which DDX proteins are involved in antiviral response remains incompletely understood. Here, we identified DDX54 as an inhibitor of type I interferon antiviral response by facilitating mA demethylation of selected transcripts.

Advances in Medical Devices for Augmented Acupuncture Therapy.

Acupuncture, as a traditional medicine applied worldwide, is considered an effective treatment for numerous chronic diseases. Many researches have explored the biological mechanisms of acupuncture, including the skin-neuro-immune axis and inflammation-immune modulation. However, traditional acupuncture faces several limitations, such as its complex operation, the wide variety of acupoint combinations, long treatment durations, and susceptibility to individual differences between the practitioner and the patient.

Crucian carp HERC7 is an RNA binding protein that selectively targets IRF7 mRNA to downregulate IFN response.

Crucian carp (Carassius auratus) HERC7 is a recently identified, fish-specific member of small HERC family that plays a pivotal role in negatively regulating the interferon (IFN) antiviral response by targeting three RLR signaling factors, STING, MAVS and IRF7. Mechanistically, crucian carp HERC7 facilitates proteasome-dependent protein degradation to downregulate STING- and MAVS-mediated IFN response. Although HERC7's role in degrading IRF7 protein is known, its potential regulation of IRF7 mRNA has not been clarified.

Long-acting IL-2 release from pressure-fused biomineral tablets promotes antitumor immune response.

Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO)(PO) (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2.

Microneedle Patch for In Situ Neutrophil Monitoring.

Monitoring neutrophil levels plays an essential role in diagnosing infections and various diseases, as well as for managing specific treatments such as chemotherapy and radiotherapy. However, the traditional complete blood count technique is invasive and challenging for quick and frequent monitoring of neutrophil. Herein, a button-like microneedle patch for rapid and convenient detection of neutrophil levels is reported without vascular invasion.

Biorhythm-mimicking growth hormone patch.

Timing dosing throughout the day impacts the therapeutic efficacy and side effects of medications. Thus, optimizing release profiles to synchronize drug concentrations with natural rhythms is critical for optimal therapeutic benefits. However, existing delivery systems are still inefficient in delivering drugs in a biorhythm-mimicking fashion.

A wearable osmotic microneedle patch provides high-capacity sustained drug delivery in animal models.

The maintenance of stable plasma drug concentrations within a therapeutic window can be critical for drug efficacy. Here, we developed a wearable osmotic microneedle (OMN) patch to support sustained drug dosing for at least 24 hours without the use of electronic components. The OMN patch uses an osmotic pressure driving force to deliver drug solution into the skin through three hollow microneedles with diameters of less than 200 micrometers.

Lefamulin dosing optimization using population pharmacokinetic and pharmacokinetic/pharmacodynamic assessment in Chinese patients with community-acquired bacterial pneumonia.

Purpose: Lefamulin is the first pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). However, the pharmacokinetic/pharmacodynamic (PK/PD) characteristics in Chinese CABP patients are not fully understood. This study aimed to evaluate its microbiological efficacy against and via PK/PD analysis.

Safety, tolerability, and pharmacokinetics of a novel anti-influenza agent ZX-7101A tablets in healthy chinese participants: A first-in-human phase I clinical study.

Background: We investigated the safety, tolerability, and pharmacokinetics of ZX-7101A tablets, a novel cap-dependent endonuclease inhibitor, in healthy participants in a first-in-human study.

Methods: The single ascending dose (SAD) part of the study included 40, 80, 160, 240, and 320 mg dose cohorts with10 participants in each dose cohort (8 participants received ZX-7101A tablets and 2 participants received placebo). The food effect (FE) part of the study was a randomised, 2-cycle, 2-way crossover design, which enrolled 16 participants to receive a single oral dose of 80 mg ZX-7101A tablets.

Pharmacokinetics and safety of colistin sulfate after single and multiple intravenous doses in healthy Chinese subjects.

Objective: Increasing antimicrobial resistance has led to the revival of the polymyxins as a last-resort therapeutic option for multidrug-resistant Gram-negative bacterial infections. A parenteral formulation of colistin sulfate is available solely in China. While the onset of action of IV colistin may occur faster than with its prodrug CMS, its pharmacokinetic (PK) profile remains unclear.

Glucose-Responsive Microneedle Patch with High Insulin Loading Capacity for Prolonged Glycemic Control in Mice and Minipigs.

Transdermal microneedle-mediated glucose-responsive insulin delivery systems can modulate insulin release based on fluctuations in blood glucose levels, thus maintaining normoglycemia effectively in a continuous, convenient, and minimally invasive manner. However, conventional microneedles are limited by the low drug loading capacity, making it challenging to be applied on human skin at a reasonable size for a lasting glucose-controlling effect, thus hindering their clinical translation. Here, we design a microneedle patch with a solid insulin powder core to achieve a high loading capacity of insulin (>70 wt %) as well as a glucose-sensitive polymeric shell to realize glucose-responsive insulin release.

Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes.

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status.

A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.

Background: Vupanorsen is a GalNAc-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia.

Objectives: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG).

Methods: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg.

Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process.

Recent Progress in Glucose-Responsive Insulin.

Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application.

Transdermal gene delivery.

Gene delivery has revolutionized conventional medical approaches to vaccination, cancer, and autoimmune diseases. However, current gene delivery methods are limited to either intravenous administration or direct local injections, failing to achieve well biosafety, tissue targeting, drug retention, and transfection efficiency for desired therapeutic outcomes. Transdermal drug delivery based on various delivery strategies can offer improved therapeutic potential and superior patient experiences.

Grooved Microneedle Patch Augments Adoptive T Cell Therapy Against Solid Tumors via Diverting Regulatory T Cells.

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, this work develops a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers.

Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown potency and efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the C ranged from 3.

Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality.

Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed.

Pharmacokinetic and safety profiles of mesalazine enema in healthy Chinese subjects: A single- and multiple-dose study.

Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine administered by an enema has not been clarified in Chinese population. We conducted an open-label study to assess the PK and safety profiles of mesalazine in 11 healthy Chinese subjects after receiving mesalazine enema (1 g/100 mL) once daily for 7 consecutive days.

A randomised, double-blind, placebo-controlled, first-in-human phase I study to characterise the safety, pharmacokinetics and immunogenicity of 9MW1411 in healthy Chinese subjects.

Introduction: 9MW1411 is a humanised monoclonal antibody against Staphylococcus aureus alpha-toxin. The safety, pharmacokinetics (PK) and immunogenicity of 9MW1411 should be characterised in humans before further clinical development.

Methods: A single-centre, randomised, double-blind, placebo-controlled phase I clinical study was conducted in humans for the first time.

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment.

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells' insufficient infiltration and rapid dysfunction.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion.

An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases.

Immune checkpoints play key roles in maintaining self-tolerance. Targeted potentiation of the checkpoint molecule PD-L1 through in situ manipulation offers clinical promise for patients with autoimmune diseases. However, the therapeutic effects of these approaches are often compromised by limited specificity and inadequate expression.