Risk assessment tool for compatibility of concurrent administration of intravenous medications with parenteral nutrition admixture.

Compatibility of parenteral nutrition admixture (PNA) and intravenous medications (IVMs) is a major consideration for clinicians and clinical pharmacists, especially when concurrent administration of PNA with IVMs is unavoidable. This is relatively common in children and neonates, where limited vascular access can be challenging. The purpose of this paper is to create a risk assessment tool that will assist clinical judgment in evaluating the potential incompatibility risk between PNA media and the IVMs when they are administered together through the same intravenous line.

The effect of the infusion connection point on intravenous multi-infusion drug delivery to premature neonates - Use of standard concentration infusions of critical medications.

Background: Sick neonates with haemodynamic instability often require complex medication regimens, which may result in the connection of a catecholamine infusion distally. This increases the dead volume of the infusion system, extending the time to medication delivery. This study evaluated the effects of body weight, and infusion connection point on the delivery rate of two medications infused through a multi-infusion system at infusion rates suitable for extremely and very low birth weight (ELBW and VLBW) neonates.

Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer.

Objectives: Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established.

The effect of patient's body weight, infusion connection point, and infusion pump position on intravenous multi-infusion drug delivery at low infusion rates suitable for premature neonates.

Introduction: Parenteral drug administration in the neonatal intensive care involves complex pharmacotherapy adjusted for the patient's weight, fluid allowance, and complex multi-infusion systems.

Objectives: We investigated the delivery rate of a model drug through a multi-infusion system consisting of six intravenous infusions.

Methods: Delivery rate of the model drug was determined after infusion initiation and termination.

Temperature modulates PVN pre-sympathetic neurones via transient receptor potential ion channels.

The paraventricular nucleus (PVN) of the hypothalamus plays a vital role in maintaining homeostasis and modulates cardiovascular function via autonomic pre-sympathetic neurones. We have previously shown that coupling between transient receptor potential cation channel subfamily V Member 4 (Trpv4) and small-conductance calcium-activated potassium channels (SK) in the PVN facilitate osmosensing, but since TRP channels are also thermosensitive, in this report we investigated the temperature sensitivity of these neurones. TRP channel mRNA was quantified from mouse PVN with RT-PCR and thermosensitivity of Trpv4-like PVN neuronal ion channels characterised with cell-attached patch-clamp electrophysiology.

A review of paediatric injectable drug delivery to inform the study of product acceptability - An introduction.

The EMA defines acceptability as "the overall ability and willingness of the patient to use, and their caregiver to administer, the medicine as intended" [1]. This paper seeks to outline issues of acceptability in relation to injectable therapy, namely intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration routes, and to lay a foundation to identify a minimum set of data that would satisfy Regulatory Authorities when discussing the acceptability of an injectable product. In addition, it will alert drug product developers to other factors that might contribute to good practice, alternative administration strategies and overall adherence to achieve successful treatment.

Stability and compatibility of parenteral nutrition solutions; a review of influencing factors.

Both stability and compatibility of parenteral nutrition solutions (PNS) with drug products are major concerns for clinicians and clinical pharmacists, especially when concurrent administration of PNS with intravenous medications (IVM) is unavoidable. Since the same physicochemical principles apply to both adult's and paediatrics' PNS, concerns about stability and compatibility may still apply to both. However, these concerns are relatively more common in paediatrics and neonatal clinical settings, where limited vascular access can be problematic and the coadministration of PNS and drugs is more common.

Oral drug delivery strategies for development of poorly water soluble drugs in paediatric patient population.

Selecting the appropriate formulation and solubility-enabling technology for poorly water soluble drugs is an essential element in the development of formulations for paediatric patients. Different methodologies and structured strategies are available to select a suitable approach and guide formulation scientists for development of adult formulations. However, there is paucity of available literature for selection of technology and overcoming the challenges in paediatric formulation development.

Systemic application of the transient receptor potential vanilloid-type 4 antagonist GSK2193874 induces tail vasodilation in a mouse model of thermoregulation.

In humans, skin is a primary thermoregulatory organ, with vasodilation leading to rapid body cooling, whereas in Rodentia the tail performs an analogous function. Many thermodetection mechanisms are likely to be involved including transient receptor potential vanilloid-type 4 (TRPV4), an ion channel with thermosensitive properties. Previous studies have shown that TRPV4 is a vasodilator by local action in blood vessels, so here, we investigated whether constitutive TRPV4 activity affects tail vascular tone and thermoregulation.

DeepGANnel: Synthesis of fully annotated single molecule patch-clamp data using generative adversarial networks.

Development of automated analysis tools for "single ion channel" recording is hampered by the lack of available training data. For machine learning based tools, very large training sets are necessary with sample-by-sample point labelled data (e.g.

Educating pharmacy students through a pandemic: Reflecting on our COVID-19 experience.

The impact of the COVID-19 pandemic on pharmacy education worldwide has been immense, affecting students, educators and regulatory agencies. Pharmacy programmes have had to rapidly adapt in their delivery of education, maintaining standards while also ensuring the safety of all stakeholders. In this commentary, we describe the challenges, compromises and solutions adopted by our institution throughout the pandemic, the lessons learnt, adaptive measures taken, and strategies to develop and future-proof our curricula.

Addressing the challenges of E-cigarette safety profiling by assessment of pulmonary toxicological response in bronchial and alveolar mucosa models.

Limited toxicity data on electronic cigarette (ECIG) impede evidence-based policy recommendations. We compared two popular mixed fruit flavored ECIG-liquids with and without nicotine aerosolized at 40 W (E-smoke) with respect to particle number concentrations, chemical composition, and response on physiologically relevant human bronchial and alveolar lung mucosa models cultured at air-liquid interface. E-smoke was characterized by significantly increased particle number concentrations with increased wattage (25, 40, and 55 W) and nicotine presence.

Supporting the use of sildenafil infusions in paediatric and neonatal intensive care - A compatibility study.

Objective: Intravenous (IV) sildenafil, a phosphodiesterase type 5 inhibitor, is increasingly being used for the treatment of pulmonary hypertension (PH) in the paediatric population. Sildenafil (Revatio®) is approved for the treatment of pH in adults where it is administered as a bolus injection. However, in paediatrics it is used off-label and administered by continuous IV infusion.

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts.

Unlabelled: The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes' (FLS) calcium-activated potassium channels ( ) change in activity in arthritis models and this correlates with FLS .

Objective: To investigate this activation in an model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1β.

Deep-Channel uses deep neural networks to detect single-molecule events from patch-clamp data.

Single-molecule research techniques such as patch-clamp electrophysiology deliver unique biological insight by capturing the movement of individual proteins in real time, unobscured by whole-cell ensemble averaging. The critical first step in analysis is event detection, so called "idealisation", where noisy raw data are turned into discrete records of protein movement. To date there have been practical limitations in patch-clamp data idealisation; high quality idealisation is typically laborious and becomes infeasible and subjective with complex biological data containing many distinct native single-ion channel proteins gating simultaneously.

Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine.

The development of age-appropriate formulations should focus on dosage forms that can deliver variable yet accurate doses that are safe and acceptable to the child, are matched to his/her development and ability, and avoid medication errors. However, in the past decade, the medication needs of neonates have largely been neglected. The aim of this review is to expand on what differentiates the needs of preterm and term neonates from those of the older paediatric subsets, in terms of environment of care, ability to measure and administer the dose (from the perspective of the patient and carer, the routes of administration, the device and the product), neonatal biopharmaceutics and regulatory challenges.

Enhanced activity of multiple TRIC-B channels: an endoplasmic reticulum/sarcoplasmic reticulum mechanism to boost counterion currents.

Key Points: There are two subtypes of trimeric intracellular cation (TRIC) channels but their distinct single-channel properties and physiological regulation have not been characterized. We examined the differences in function between native skeletal muscle sarcoplasmic reticulum (SR) K -channels from wild-type (WT) mice (where TRIC-A is the principal subtype) and from Tric-a knockout (KO) mice that only express TRIC-B. We find that lone SR K -channels from Tric-a KO mice have a lower open probability and gate more frequently in subconducting states than channels from WT mice but, unlike channels from WT mice, multiple channels gate with high open probability with a more than six-fold increase in activity when four channels are present in the bilayer.

Ion Channels in the Paraventricular Hypothalamic Nucleus (PVN); Emerging Diversity and Functional Roles.

The paraventricular nucleus of the hypothalamus (PVN) is critical for the regulation of homeostatic function. Although also important for endocrine regulation, it has been referred to as the "autonomic master controller." The emerging consensus is that the PVN is a multifunctional nucleus, with autonomic roles including (but not limited to) coordination of cardiovascular, thermoregulatory, metabolic, circadian and stress responses.

Methodologies for assessing the acceptability of oral formulations among children and older adults: a systematic review.

Acceptability of medicinal products in children and older populations is pivotal in ensuring adherence and therapeutic outcomes. This review systematically identifies studies reporting on formulation aspects of oral medications that affect their acceptability in these patient groups. Particular emphasis is placed on the evaluation of the methodologies employed in the studies.

Synthesis of the Ca-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: Role in β-adrenoceptor signaling.

Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca-mobilizing messengers important for modulating cardiac excitation-contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase family, catalyzes synthesis of both NAADP and cADPR However, it remains unclear whether this is the main enzyme for their production under physiological conditions. Here we show that membrane fractions from WT but not mouse hearts supported NAADP and cADPR synthesis.

Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A.

Key Points: The role of trimeric intracellular cation (TRIC) channels is not known, although evidence suggests they may regulate ryanodine receptors (RyR) via multiple mechanisms. We therefore investigated whether Tric-a gene knockout (KO) alters the single-channel function of skeletal RyR (RyR1). We find that RyR1 from Tric-a KO mice are more sensitive to inhibition by divalent cations, although they respond normally to cytosolic Ca , ATP, caffeine and luminal Ca .

Subconductance gating and voltage sensitivity of sarcoplasmic reticulum K(+) channels: a modeling approach.

Sarcoplasmic reticulum (SR) K(+) channels are voltage-regulated channels that are thought to be actively gating when the membrane potential across the SR is close to zero as is expected physiologically. A characteristic of SR K(+) channels is that they gate to subconductance open states but the relevance of the subconductance events and their contribution to the overall current flowing through the channels at physiological membrane potentials is not known. We have investigated the relationship between subconductance and full conductance openings and developed kinetic models to describe the voltage sensitivity of channel gating.

The ryanodine receptor provides high throughput Ca2+-release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation.

Once opened, ryanodine receptors (RyR) are efficient pathways for the release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR). The precise nature of the Ca2+-release event, however, requires fine-tuning for the specific process and type of cell involved. For example, the spatial organization of RyRs, the luminal [Ca2+] and the influence of soluble regulators that fluctuate under physiological and pathophysiological control mechanisms, all affect the amplitude and duration of RyR Ca2+ fluxes.

FKBP12.6 activates RyR1: investigating the amino acid residues critical for channel modulation.

We have previously shown that FKBP12 associates with RyR2 in cardiac muscle and that it modulates RyR2 function differently to FKBP12.6. We now investigate how these proteins affect the single-channel behavior of RyR1 derived from rabbit skeletal muscle.

Enhanced delivery of microRNA mimics to cardiomyocytes using ultrasound responsive microbubbles reverses hypertrophy in an in-vitro model.

Background: Cardiovascular diseases (CVD) account for 36% of deaths in Europe and the United States. Gene therapy can act as a therapeutic modality for the treatment of CVD. The use of microRNA mimetics may be advantageous as they regulate important processes in health and pathology.