Sample-Specific MS/MS Methods in High-Throughput Mass Spectrometry.

The drug discovery process increasingly relies on high-throughput sample analysis to accelerate the identification of viable drug candidates. Recently, chromatographic-free high-throughput mass spectrometry (HT-MS) technologies have emerged, significantly increasing sample readout speed and enabling the analysis of large sample sets. These HT-MS platforms continuously acquire data from various samples into a single data file, presenting challenges in applying distinctive data acquisition methods to specific samples.

Applying Automation and High-Throughput MALDI Mass Spectrometry for Peptide Metabolic Stability Screening.

The discovery of peptide therapeutics represents a fast-growing segment of pharmaceutical research. During the early discovery process, a large number of peptide candidates needs to be rapidly screened for metabolic stability in relevant biological matrices. In most cases, peptide stability assays are quantified using LC-MS/MS, which may take hours to analyze 384 samples and generates liters of solvent waste.

Podiatrists' views and experiences of using real time clinical gait analysis in the assessment and treatment of posterior tibial tendon dysfunction.

Background: Real time clinical gait analysis (RTCGA) is often incorporated as part of a general or lower limb musculoskeletal (MSK) adult patient assessment. However, it is not known if RTCGA is clinically effective as a useful outcome measure or aids in decision making. Whether there is a clinical worth in conducting RTCGA in adult MSK consultations remains controversial.

Quantitation of Super Basic Peptides in Biological Matrices by a Generic Perfluoropentanoic Acid-Based Liquid Chromatography-Mass Spectrometry Method.

Peptides represent a promising modality for the design of novel therapeutics that can potentially modulate traditionally non-druggable targets. Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) are two large families that are being explored extensively as drug delivery vehicles, imaging reagents, or therapeutic treatments for various diseases. Many CPPs and AMPs are cationic among which a significant portion is extremely basic and hydrophilic (e.

Real time non-instrumented clinical gait analysis as part of a clinical musculoskeletal assessment in the treatment of lower limb symptoms in adults: A systematic review.

Background: The aim of this review was to evaluate and summarise the current evidence on non-computerised or non-recorded real time adult gait assessment conducted within the clinical musculoskeletal setting. It was hoped a protocol for best practice and a framework for further research could be developed from this search.

Research Question: Can a protocol for best practice and a framework for further research be established from previous literature relating to non-computerised or non-recorded real time adult gait analysis in a musculoskeletal clinical setting.

Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model.

Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model.

If It Doesn't Work, Why Do We Still Do It? The Continuing Use of Subtalar Joint Neutral Theory in the Face of Overpowering Critical Research.

The use of subtalar joint neutral (STJN) in the assessment and treatment of foot-related musculoskeletal symptomology is common in daily practice and still widely taught. The main pioneer of this theory was Dr Merton L. Root, and it has been labeled with a variety of names: "the foot morphology theory," "the subtalar joint neutral theory," or simply "Rootian theory" or "Root model.

Industry Perspective on Contemporary Protein-Binding Methodologies: Considerations for Regulatory Drug-Drug Interaction and Related Guidelines on Highly Bound Drugs.

Regulatory agencies have recently issued drug-drug interaction guidelines, which require determination of plasma protein binding (PPB). To err on the conservative side, the agencies recommend that a 0.01 lower limit of fraction unbound (f) be used for highly bound compounds (>99%), irrespective of the actual measured values.

Understanding and reducing the experimental variability of in vitro plasma protein binding measurements.

The experimental measurement of plasma protein binding is a useful in vitro Absorption Distribution Metabolism and Excretion(ADME) assay currently conducted in both screening and definitive early development candidate modes. The fraction unbound is utilized to calculate important pharmacokinetic (PK) parameters such as unbound clearance and unbound volume of distribution in animals that can be used to make human PK and dose predictions and estimate clinically relevant drug-drug interaction potential. Although these types of assays have been executed for decades, a rigorous statistical analysis of sources of variability has not been conducted because of the tedious nature of the manual experiment.

The medial oblique shell inclination technique: a method to increase subtalar supination moments in foot orthoses.

A medially deviated axis has been cited as an etiologic factor in increasing pronatory moments across the subtalar joint axis. Orthoses are often used to reduce these pronatory moments, aiming to off-load related injured structures. By aligning the posting or incline of an orthosis shell medial to the axis and parallel to it, the amount of moments applied will be theoretically greater than if prescribed at a less-than-optimal angle.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Control and measurement of plasma pH in equilibrium dialysis: influence on drug plasma protein binding.

Past publications have highlighted the influence of postdialysis plasma pH on the measured fraction unbound in plasma (fup). There is disparity in the industry as to which of two main methods is more suitable for controlling postdialysis plasma pH: the use of either a stronger buffer or a CO(2) atmosphere for the incubation. In the current study, it has been found that 10% CO(2) could be too high for the buffering capacities of both 100 mM sodium phosphate (pH 7.

A review of the theoretical unified approach to podiatric biomechanics in relation to foot orthoses therapy.

Background: Diverse theories of orthoses application have evolved with the continual development of podiatric biomechanics and orthotic management. This theoretical disparity can lead to confusion in clinical, educational, and research situations. However, although approaches are varied, the common consensus is that foot orthoses outcomes are generally positive.