Utilising Endogenous Biomarkers in Drug Development to Streamline the Assessment of Drug-Drug Interactions Mediated by Renal Transporters: A Pharmaceutical Industry Perspective.

The renal secretion of many drugs is facilitated by membrane transporters, including organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K and organic anion transporters 1 and 3. Inhibition of these transporters can reduce renal excretion of drugs and thereby pose a safety risk. Assessing the risk of inhibition of these membrane transporters by investigational drugs remains a key focus in the evaluation of drug-drug interactions (DDIs).

Association between urinary arsenic species and vitamin D deficiency: a cross-sectional study in Chinese pregnant women.

Background: An increasing number of studies suggest that environmental pollution may increase the risk of vitamin D deficiency (VDD). However, less is known about arsenic (As) exposure and VDD, particularly in Chinese pregnant women.

Objectives: This study examines the correlations of different urinary As species with serum 25 (OH) D and VDD prevalence.

Detonation Performance of Insensitive Nitrogen-Rich Nitroenamine Energetic Materials Predicted from First-Principles Reactive Molecular Dynamics Simulations.

Because of the excellent combination of high detonation and low sensitivity properties of the 1,1-diamino-2,2-dinitroethylene (FOX-7) energetic material (EM), it is useful to explore new energetic derivatives that start with the FOX-7 structure. However, most such derivatives are highly sensitive, making them unsuitable for EM applications. An exception is the new nitroenamine EM, 1,1-diamino-2-tetrazole-2-nitroethene (FOX-7-T) (synthesized by replacing a nitro group with a tetrazole ring), which exhibits good stability.

Serum Folate and Vitamin B Modify the Associations of Genetic Variants with Gestational Diabetes Mellitus: A Cross-Sectional Study in Chinese Pregnant Women.

Purpose: This study aimed to explore the association between N-6 adenine-specific DNA methyltransferase 1 () single nucleotide polymorphisms (SNPs) and gestational diabetes mellitus (GDM) and the modification of the relationship by folate and vitamin B.

Methods: A cross-sectional study involving 1303 pregnant women (262 GDM and 1041 non-GDM) was performed in Tianjin, China. Nine SNPs in were genotyped, and serum folate, vitamin B, and homocysteine (Hcy) levels were measured.

The Effect of BI 730357 (Retinoic Acid-Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open-Label, Non-randomized, 2-Period Fixed-Sequence Trial in Healthy Subjects.

Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail.

A semi-empirical formula based on a modified general penetration resistance for predicting the motion of the rigid projectile.

The semi-empirical formula is an effective method for predicting the motion of rigid projectiles in practical applications due to the simplicity of its theory and the convenience of parameter calibration. The commonly used semi-empirical formula is Forrestal's form, combining several specific experimental cases that have been published, we find it exists deficiencies in predicting deceleration histories and the penetration depths of high velocities. To solve this problem, the general penetration resistance is employed to formulate the semi-empirical formula due to the 'general' characteristic of the general penetration resistance, and also make an assessment of this semi-empirical through experimental data.

Can Mechanistic Static Models for Drug-Drug Interactions Support Regulatory Filing for Study Waivers and Label Recommendations?

Background And Objective: Mechanistic static and dynamic physiologically based pharmacokinetic models are used in clinical drug development to assess the risk of drug-drug interactions (DDIs). Currently, the use of mechanistic static models is restricted to screening DDI risk for an investigational drug, while dynamic physiologically based pharmacokinetic models are used for quantitative predictions of DDIs to support regulatory filing. As physiologically based pharmacokinetic model development by sponsors as well as a review of models by regulators require considerable resources, we explored the possibility of using mechanistic static models to support regulatory filing, using representative cases of successful physiologically based pharmacokinetic submissions to the US Food and Drug Administration under different classes of applications.

Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials.

Background:  Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children.

Objectives:  This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]).

Methods:  Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ = 358]; dTT 2,348 [ = 324]; ECT 2,929 [ = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements;  = 1,978).

Efficacy and Safety Differences between Domestic Paclitaxel Drug-Coated Balloons and Metal Bare Stents in the Treatment of ASO of Femoral-Popliteal Arteries Type IIA-C.

The aim in this study was to investigate the efficacy and safety of domestic paclitaxel-coated balloon (DCB) and bare metal stent (BMS) in the treatment of Transatlantic Cooperative Organization Consensus II (ASC II) types A-C femoral-popliteal arteriosclerosis obliterans (ASO). A total of 103 patients with ASC II A-C femoropopliteal ASO, who received treatment in our hospital from March 2020 to March 2021, were retrospectively selected and divided into the DCB group ( = 56) and BMS group ( = 47), according to treatment methods. The general clinical data and surgical results were compared between the two groups.

Dynamic Mechanical Properties of TC11 Titanium Alloys Fabricated by Wire Arc Additive Manufacturing.

To study the compressive mechanical properties and failure modes of TC11 titanium alloy fabricated by wire arc additive manufacturing (WAAM) technology in a large strain rate range at room temperature, the quasi-static and dynamic compression tests were carried out. In addition, optical microscopy (OM) and scanning electron microscopy (SEM) were employed to observe the metallographic structure and fracture morphology, respectively. The stress-strain curves in the range of 0.

Ballistic Performance of Polyurea-Reinforced Ceramic/Metal Armor Subjected to Projectile Impact.

Although polyurea has attracted extensive attention in impact mitigation due to its protective characteristics during intensive loading, the ballistic performance of polyurea-reinforced ceramic/metal armor remains unclear. In the present study, polyurea-reinforced ceramic/metal armor with different structures was designed, including three types of coating positions of the polyurea. The ballistic tests were conducted with a ballistic gun; the samples were subjected to a tungsten projectile formed into a cylinder 8 mm in diameter and 30 mm in length, and the deformation process of the tested targets was recorded with a high-speed camera.

Study on Intrinsic Influence Law of Specimen Size and Loading Speed on Charpy Impact Test.

Charpy impact energy/impact toughness is closely related to external factors such as specimen size. However, when the sample size is small, the linear conversion relationship between the Charpy impact energy of the sub-size and full-size Charpy specimens does not hold; the Charpy impact toughness varies with the size of the specimen and other factors. This indicates that studying the internal influence of external factors on impact energy or impact toughness is the key to accurately understanding and evaluating the toughness and brittleness of materials.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

Background: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules.

Objectives: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm.

Patients/methods: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling.

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

Background: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism.

Methods: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries.

Safety, pharmacokinetics and pharmacodynamics of BI 655064 in phase 1 clinical trials in healthy Chinese and Japanese subjects.

Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80-240 mg and multiple dosing of 240 mg once weekly over 4 weeks.

Methods: Two phase 1, double-blind, placebo-controlled studies were conducted (single-rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved.

The Ubiquitiformal Characterization of the Mesostructures of Polymer-Bonded Explosives.

A nesting ubiquitiform (NU) approach was developed to characterize the mesostructural features of polymer-bonded explosives (PBXs), and then used to predicate some equivalent physical properties of PBXs, which can also be expected to be extended to other composites with complicated internal mesostructures. To verify the availability, two NU models for two kinds of PBX with different compositions are presented, which are PBX 9501 and LX-17, based on which, the equivalent thermal conductivities were calculated. Particularly, it is so encouraging that an analytical expression of the equivalent thermal conductivity was obtained only under a simply assumption of homogeneity.

Investigation of the agglomeration reduction mechanism of the aluminized HTPB propellant containing ferric perfluorooctanoate [Fe(PFO)].

In this study, ferric perfluorooctanoate [Fe(PFO)] was used in the aluminized HTPB propellant to reduce Al agglomeration during solid propellant combustion, and the agglomeration reduction mechanism was experimentally demonstrated the burning rate measurement, heat of explosion and Al agglomeration analysis. The behavior of the burning particles on the burning surface as well as the morphology and composition of the quenched burning particles were characterized by microscopic high-speed photography and X-ray photoelectron spectroscopy, respectively; the thermal decomposition properties and gaseous decomposition products of Fe(PFO) were investigated by thermal gravimetry-differential scanning calorimetry joint analysis (TG-DSC), Fourier transform infrared spectroscopy (FTIR) and mass spectrometry (MS). The results show that Fe(PFO) can significantly increase the burning rate of the aluminized HTPB propellant and reduce Al agglomeration.

Computational analysis of mesoscale thermomechanical ignition behavior of impacted LLM-105 based explosives.

LLM-105 (2,6-diamino-3,5-dinitropyrazine-1-oxide) is an insensitive high explosive crystal which has performance between that of HMX and TATB. An elastoviscoplastic dislocation model is developed for LLM-105 crystal, which accounts for the dislocation evolutions at the crystal interior and crystal wall and strain-rate dependent work hardening. Three different crystal morphology (cubic, icosahedral, rodlike) of LLM-105 based explosive computational models were constructed and subjected to an impact velocity of 200 m s and 500 m s.

Shock initiation of multi-component insensitive PBX explosives: Experiments and MC-DZK mesoscopic reaction rate model.

To facilitate the pre-estimation and optimization of the prescription design of a multi-component polymer bonded explosive (PBX), a multicomponent mesoscopic reaction rate model (MC-DZK model) is developed to predicate preferably the influence of both the explosive components and the particle size of on the shock initiation. All the parameters in the model are determined directly by the parameters in the DZK model for each explosive component. Furthermore, for the multicomponent insensitive explosive PBXC10 (70% TATB, 25% HMX, and 5% Kel-F800 by weight) with different explosive particle sizes, both shock initiation experiments and corresponding numerical simulations are performed, and there is satisfactory agreement between the numerical results and the available experimental data.

Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials.

Background:  Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults.

Objective:  This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults.

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design.

Background: Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.

Objectives: To address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period.

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism.

Background: The current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting.

Numerical simulation analyses of β ↔ δ phase transition for a finite-sized HMX single crystal subjected to thermal loading.

Phase transition of HMX single crystals is the very first process prior to chemical reaction and ignition of polymer-bonded explosives (PBX). A mesoscale β ↔ δ phase transition model is developed to investigate the role of solid phase transformation on the thermo-mechanical behavior of HMX single crystals. The model captures nonlinear elasticity, dislocation-based crystalline plasticity and temperature-dependent phase transition.