Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer.

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and death. The primary analysis of KATHERINE, a phase 3, open-label trial, showed that the risk of invasive breast cancer or death was 50% lower with adjuvant trastuzumab emtansine (T-DM1) than with trastuzumab alone.

Methods: We randomly assigned patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive T-DM1 or trastuzumab for 14 cycles.

Molecular Investigation of SNAC as an Oral Peptide Permeation Enhancer in Lipid Membranes via Solid-State NMR.

Oral peptide therapeutics are increasingly favored in the pharmaceutical industry for their ease of use and better patient adherence. However, they face challenges with poor oral bioavailability due to their high molecular weight and surface polarity. Permeation enhancers (PEs) like salcaprozate sodium (SNAC) have shown promise in clinical trials, achieving about 1% bioavailability.

Molecular mechanisms for stabilizing biologics in the solid state.

Protein drugs exhibit challenges of biophysical and biochemical instability due to their structural complexity and rich dynamics. Solid-state biologics aim to enhance stability by increasing molecular rigidity within the formulation matrix, representing a primary category of drug products alongside sterile liquid formulations. Understanding the molecular mechanisms behind the stabilization and destabilization of protein drugs, influenced by formulation composition and drying processes, provides scientific rationale for drug product design.

Comparison of Efficacy and Safety of Different Types of One-Way Valves in Endoscopic Lung Volume Reduction in Patients with Severe Lung Emphysema.

Introduction: Endoscopic lung volume reduction (ELVR) with valves is an effective intervention in patients with severe lung emphysema. Two types of valves are established in clinical practice: Zephyr endobronchial valves (EBVs) and Spiration Valve System (SVS). We aimed to compare outcomes and the safety associated with these two types of one-way valves.

Molecular Mechanism of P53 Peptide Permeation through Lipid Membranes from Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

Macrocyclic peptides show promise in targeting high-value therapeutically relevant binding sites due to their high affinity and specificity. However, their clinical application is often hindered by low membrane permeability, which limits their effectiveness against intracellular targets. Previous studies focused on peptide conformations in various solvents, leaving a gap in understanding their interactions with and translocation through lipid bilayers.

App-based support for breast cancer patients to reduce psychological distress during therapy and survivorship - a multicentric randomized controlled trial.

Introduction: The negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020.

App-Based Lifestyle Intervention (PINK! Coach) in Breast Cancer Patients-A Real-World-Data Analysis.

Introduction: Overweight and a lack of physical activity not only increase the risk of recurrence in breast cancer patients but also negatively impact overall and long-term survival, as well as quality of life. The results presented here are the first real-world data from the DiGA PINK! Coach examining the physical activity and BMI of app users. Based on the literature, an approximate weight gain of 10% over 6 months and a decrease in physical activity can be expected.

Anaplasma phagocytophilum infection associated with strong inflammatory response in 3 cats.

Anaplasmosis is a vector-borne disease caused by spp. which currently is still rarely diagnosed in cats. This article describes 3 independent cases of anaplasmosis in cats from different regions of Germany presented to veterinarians in 2021.

App-Based Lifestyle Coaching (PINK!) Accompanying Breast Cancer Patients and Survivors to Reduce Psychological Distress and Fatigue and Improve Physical Activity: A Feasibility Pilot Study.

Introduction: This pilot study aimed to investigate the effects of using an app-based certified medical product named PINK! on breast cancer patients and survivors. The objectives were to measure psychological distress, physical activity, and therapy-related fatigue of patients using PINK! to identify trends and develop a study design for a subsequent multicentric proof of efficacy RCT.

Materials And Methods: PINK! offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine.

Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery.

Small molecule developability challenges have been well documented over the last two decades. One of these critical developability parameters is aqueous solubility. In general, more soluble compounds have improved oral absorption.

Correlative Image-Based Release Prediction and 3D Microstructure Characterization for a Long Acting Parenteral Implant.

Imaging-based characterization of polymeric drug-eluting implants can be challenging due to the microstructural complexity and scale of dispersed drug domains and polymer matrix. The typical evaluation via real-time (and accelerated in vitro experiments not only can be very labor intensive since implants are designed to last for 3 months or longer, but also fails to elucidate the impact of the internal microstructure on the implant release rate. A novel characterization technique, combining multi-scale high resolution three-dimensional imaging, was developed for a mechanistic understanding of the impact of formulation and manufacturing process on the implant microstructure.

N-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection.

The COVID-19 pandemic continues to have an unprecedented impact on societies and economies worldwide. There remains an ongoing need for high-performance SARS-CoV-2 tests which may be broadly deployed for infection monitoring. Here we report a highly sensitive single molecule array (Simoa) immunoassay in development for detection of SARS-CoV-2 nucleocapsid protein (N-protein) in venous and capillary blood and saliva.

Probing Protein Conformation Destabilization in Sterile Liquid Formulations through the Formation of 3,4-Dihydroxyphenylalanine.

This work demonstrates the use of a fluorescent probe to screen protein conformational changes in mixtures of monoclonal antibodies and determine the region of where such changes may originate through a footprinting mass spectrometry approach. The oxidative stress of mixtures of two different immunoglobulins (IgG1, IgG2, or IgG4) performed in the presence of 2,2'-azobis(2-amidinopropane dihydrochloride) results in sequence-specific tyrosine oxidation reactions depending on the time of incubation of the IgG molecules and the nature of the excipients present in the formulation. The combination of a fluorescence assay, based on the detection of 3,4-dihydroxyphenylalanine (DOPA) and mass spectrometry analyses, permits the identification of protein conformation changes.

Development of an ultra-high-performance liquid chromatography-charged aerosol detection/UV method for the quantitation of linear polyethylenimines in oligonucleotide polyplexes.

Linear polyethylenimines are polycationic excipients that have found many pharmaceutical applications, including as a delivery vehicle for gene therapy through formation of polyplexes with oligonucleotides. Accurate quantitation of linear polyethylenimines in both starting solution and formulation containing oligonucleotide/polyethylenimine polyplexes is critical. Existing methods using spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry time-of-flight, or nuclear magnetic resonance are either complex or suffer from low selectivity.

Base-Mediated Oxidative Degradation of Secondary Amides Derived from p-Amino Phenol to Primary Amides in Drug Molecules.

One of the most common functional groups encountered in drug molecules is the amide, and the most common degradation pathway for amides is base-mediated hydrolysis to its constituent amine and carboxylic acid. Herein, we report for the first time, a base-mediated oxidative degradation pathway of secondary amides to primary amides. This transformation also represents a novel synthetic methodology, reported for the first time in this work, in transforming secondary amides to primary amides without using any oxidative reagents.

Assessing the Impact of Different Light Sources on Product Quality During Pharmaceutical Drug Product Manufacture - Fluorescent Versus Light-Emitting Diode Light.

Pharmaceutical scientists are often asked to assess the impact of modifications to the illumination in the manufacturing and product packaging environment on product quality. To assess the impact of switching light sources, four model compounds were exposed to standard fluorescent light, LED, and "yellow light" and the extent of drug photodegradation was determined. Photodegradation under LED light is generally reduced compared to fluorescent light and is often predictable if the UV-Vis absorption spectrum of the active pharmaceutical ingredient (API) and the spectral power distribution emitted by the various light sources overlap.

Development of an automated and High throughput UHPLC/MS based workflow for cleaning verification of potent compounds in the pharmaceutical manufacturing environment.

Cleaning verification (CV) is a critical step in the pharmaceutical manufacturing process to eliminate or reduce unacceptable contamination of a product as a result of insufficiently cleaned equipment surfaces. The main concern is cross contamination with active pharmaceutical ingredients (APIs) from previous runs that may impact patient safety. Current conventional approaches involve rather tedious sample preparation and analytical methods with relative lengthy analysis time.

Probing in Vitro Release Kinetics of Long-Acting Injectable Nanosuspensions via Flow-NMR Spectroscopy.

Novel treatment routes are emerging for an array of diseases and afflictions. Complex dosage forms, based on active pharmaceutical ingredients (APIs) with previously undesirable physicochemical characteristics, are becoming mainstream and actively pursued in various pipeline initiatives. To fundamentally understand how constituents in these dosage forms interact on a molecular level, analytical methods need to be developed that encompass selectivity and sensitivity requirements previously reserved for a myriad of in vitro techniques.

Mechanistic understanding of abnormal reverse phase chromatographic behavior of basic analytes in the presence of sodium dodecyl sulfate.

In the process of dissolution method development for Merck proprietary compound A, a basic analyte, abnormal chromatographic behavior involving peak splitting and retention time shifting in the presence of sodium dodecyl sulfate (SDS) in the sample solution was observed. A mechanistic study was conducted and the level and type of surfactant, along with the pK of the analyte, were determined to be the critical variables in the degree of effect seen. Chromatographically, the effect was further impacted by the injection volume used, the pH and identity of the mobile phase buffer and the amount of system volume between the autosampler and the column.

Enrichment of Relevant Oxidative Degradation Products in Pharmaceuticals With Targeted Chemoselective Oxidation.

The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (International Conference on Harmonization Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late-stage regulatory filing, use pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time-intensive activity, either relying on the isolation of slowly formed degradation products from stressed drug product or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, because typical oxidative stressing (HO and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product.

In-Use Photostability Practice and Regulatory Evaluation for Pharmaceutical Products in an Age of Light-Emitting Diode Light Sources.

This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals.

Accelerated Forced Degradation of Pharmaceuticals in Levitated Microdroplet Reactors.

Forced degradation is a method of studying the stability of pharmaceuticals in order to design stable formulations and predict drug product shelf life. Traditional methods of reaction and analysis usually take multiple days, and include LC-UV and LC-MS product analysis. In this study, the reaction/analysis sequence was accelerated to be completed within minutes using Leidenfrost droplets as reactors (acceleration factor: 23-188) and nanoelectrospray ionization MS analysis.

Mixed Reality Meets Pharmaceutical Development.

As science evolves, the need for more efficient and innovative knowledge transfer capabilities becomes evident. Advances in drug discovery and delivery sciences have directly impacted the pharmaceutical industry, though the added complexities have not shortened the development process. These added complexities also make it difficult for scientists to rapidly and effectively transfer knowledge to offset the lengthened drug development timelines.

Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OXR subtype and culminating in the discovery of 23, a highly potent, OXR-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OXR antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

Iron(III)-Mediated Oxidative Degradation on the Benzylic Carbon of Drug Molecules in the Absence of Initiating Peroxides.

Metal ions play an important role in oxidative drug degradation. One of the most ubiquitous metal ion impurities in excipients and buffers is Fe(III). In the field of oxidative drug degradation chemistry, the role of Fe(III) has been primarily discussed in terms of its effect in reaction with trace hydroperoxide impurities.