Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release.

Cotadutide (Cota) is a lipidated dual GLP-1 and Glucagon receptor agonist that was investigated for the treatment of various metabolic diseases, it is designed for once daily subcutaneous (SC) administration. Invasive daily injections can result in poor patient compliance with chronic disease, and here, we demonstrate an innovative strategy of encapsulating reversible cota self-assembled fibers within an in-situ forming depot of low molecular weight poly(lactic-co-glycolic) acid (LWPLGA) for sustained delivery GLP-1 and Glucagon receptor agonist with controlled burst release. This could be a suitable alternative to other sustained delivery strategies for fibrillating peptides.

Release from Polymeric Core/Shell Nanoparticles through the Lens of Multiscale Modeling.

The large number of studies involving nanoparticles for cancer therapy is due to their peculiar features: they protect loaded active molecules while extending circulation time and can extravasate from the blood flow to the tumor to deliver drugs directly in the target area. Mathematical modeling can provide a preliminary exploration of design space to optimize an experimental activity that often relies on a trial-and-error approach. However, because of the characteristic size of these vectors (10-1000 nm), numerous phenomena of interest occur at different time and length scales, making a single modeling technique insufficient to fully characterize the system of interest.

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters.

Purpose: To construct a detailed mechanistic and physiologically based biopharmaceutics model capable of predicting 1) device-formulation-tissue interaction during the injection process and 2) binding, degradation, local distribution, diffusion, and drug absorption, following subcutaneous injection. This paper is part of a series and focusses on the first aspect.

Methods: A mathematical model, SubQ-Sim, was developed incorporating the details of the various substructures within the subcutaneous environment together with the calculation of dynamic drug disposition towards the lymph ducts and venous capillaries.

Design and optimisation of dendrimer-conjugated Bcl-2/x inhibitor, AZD0466, with improved therapeutic index for cancer therapy.

Dual Bcl-2/Bcl-x inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-x inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer.

Evaluation of a multi-agent chemotherapy protocol combining dexamethasone, melphalan, actinomycin D, and cytarabine for the treatment of resistant canine non-Hodgkin high-grade lymphomas: a single centre's experience.

The DMAC protocol (dexamethasone, melphalan, actinomycin-D, cytarabine) has been evaluated in American studies for the treatment of relapsed canine lymphoma, comparing similarly to other rescue protocols. The aim of this study was to evaluate efficacy and toxicity of DMAC, in a larger UK cohort of resistant canine lymphomas. Medical records of dogs with resistant non-Hodgkin high-grade lymphomas that received DMAC as a rescue protocol were reviewed from 2007 to 2017.

Nanocrystal formulations of a poorly soluble drug. 1. In vitro characterization of stability, stabilizer adsorption and uptake in liver cells.

In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v.

Why is it hard to terminate failing projects in pharmaceutical R&D?

'Quick-kill' strategies in pharmaceutical research and development aim to reduce late-stage attrition by bringing project termination decisions forward, to an earlier point in the process. How can the barriers to implementing such strategies be overcome?

In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim.

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation.

Diurnal rhythm in British Antarctic personnel.

Introduction: The diurnal rhythm of saliva cortisol and its association to adaptation, performance and health were examined in personnel over-wintering at two British Antarctic stations.

Methods: In total, 55 healthy individuals (49 males, 6 females) participated in the study. Cortisol in saliva was sampled on 3 consecutive days (at awakening, 15 and 45 min after waking, at 15.

Exploiting induced variation to dissect quantitative traits in barley.

The identification of genes underlying complex quantitative traits such as grain yield by means of conventional genetic analysis (positional cloning) requires the development of several large mapping populations. However, it is possible that phenotypically related, but more extreme, allelic variants generated by mutational studies could provide a means for more efficient cloning of QTLs (quantitative trait loci). In barley (Hordeum vulgare), with the development of high-throughput genome analysis tools, efficient genome-wide identification of genetic loci harbouring mutant alleles has recently become possible.

Wideband energy reflectance measurements of ossicular chain discontinuity and repair in human temporal bone.

Objective: Recent studies have suggested the potential of wideband energy reflectance (ER) for the assessment of middle ear disorders. The purpose of this study was to examine the use of wideband ER in the evaluation of an ossicular discontinuity and its repair in human cadaver temporal bones.

Design: ER measurements at ambient pressure were made on five human cadaver ears in three conditions: (1) baseline with intact ossicular chain, (2) with the ossicular chain cut using an argon laser, and (3) with the ossicular chain repaired.

Psychological selection of Antarctic personnel: the "SOAP" instrument.

Introduction: The potential advantage of including a psychological test battery in the selection process for service in the Antarctic was examined in 348 applicants for employment in Antarctica with the British Antarctic Survey (BAS).

Methods: Applicants were screened with the Selection of Antarctic Personnel battery (SOAP) consisting of nine well-known psychological instruments. The SOAP scores were not revealed to the BAS selection panel members, who based the selection on operational criteria, interview, and a general medical examination.

Telemedicine in the British Antarctic survey.

Medicine in the Antarctic is probably the most isolated situation in which a doctor can practise, differing in degree of severity even from that of the Arctic region. The increasing use of Telemedicine has helped to reduce this isolation and to improve access to secondary healthcare for those who live in the most remote bases in the world. The article describes the way in which Antarctic Telemedicine has evolved in the British Antarctic survey, outlining the use of low cost and low technology systems to improve the availability of emergency advice, both to the doctor and to isolated field parties, specialist consultation, medical education, and healthcare records.

In vivo characterization of piezoelectric transducers for implantable hearing AIDS.

Background: Piezoelectric bimorph transducers may be used at the input stage of implantable hearing aids to convert ossicle vibrations into electrical waveforms, and at the output stage to convert electrical signals into mechanical motion that drives the ossicles. This study assessed transducer performance in anesthetized, acutely implanted cats using computer-averaged, laser-Doppler vibrometer measures and cochlear potentials.

Methods: Measures of output linearity and distortion for a transducer placed on the umbo were obtained from averaged laser-Doppler vibrometer outputs.

Wideband energy reflectance measurements in adults with middle-ear disorders.

The purpose of this study was to examine wideband energy reflectance (ER) at ambient pressure in adults with a variety of middle-ear disorders. The ER results from 9 participants with middle-ear disorders and 1 participant with bilateral sensorineural hearing loss were compared with data provided by a group of 40 young adults with normal hearing sensitivity. Wideband ER results for the participant with sensorineural hearing loss followed the typical pattern of the data for young adults with normal hearing.

The envoy® totally implantable hearing system, st. Croix medical.

The Totally Implantable Envoy® System is currently undergoing clinical trials in both the United States and Europe. The fully implantable hearing device is intended for use in patients with sensorineural hearing loss. The device employs piezoelectric transducers to sense ossicle motion and drive the stapes.