Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer.

BACKGROUND: Minimally invasive intratumoural administration of thermoresponsive hydrogels, that transition from liquid to gel in response to temperature, has been proposed as a potential treatment modality for solid tumours. The aim of this study was to assess the inherent cytotoxicity of a poloxamer-based thermoresponsive hydrogel in a murine xenograft model of lung cancer. METHODS: In vitro viability assessment was carried out in a lung cancer (A549) and non-cancerous (Balb/c 3T3 clone A31) cell line. Following intratumoural administration of saline or the thermoresponsive hydrogel to an A549 xenograft model in female Athymic Nude-Foxn1nu mice (n = 6/group), localisation was confirmed using IVIS imaging. Tumour volume was assessed using callipers measurements over 14 days. Blood serum was analysed for liver and kidney damage and ex vivo tissue samples were histologically assessed. RESULTS: The thermoresponsive hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. Tumour volume increase was statistically significantly lower than saline treated control at day 14 (n = 6, p = 0.0001), with no associated damage of hepatic or renal tissue observed. CONCLUSIONS: Presented is a poloxamer-based thermoresponsive hydrogel, suitable for intratumoural administration and retention, which has demonstrated preliminary evidence of local tumour control, with minimal off-site toxicity.

Medication safety incidents associated with the remote delivery of primary care: a rapid review.

OBJECTIVES: The COVID-19 pandemic triggered rapid, fundamental changes, notably increased remote delivery of primary care. While the impact of these changes on medication safety is not yet fully understood, research conducted before the pandemic may provide evidence for possible consequences. To examine the published literature on medication safety incidents associated with the remote delivery of primary care, with a focus on telemedicine and electronic prescribing. METHODS: A rapid review was conducted according to the Cochrane Rapid Reviews Methods Group guidance. An electronic search was carried out on Embase and Medline (via PubMed) using key search terms 'medication error', 'electronic prescribing', 'telemedicine' and 'primary care'. Identified studies were synthesised narratively; reported medication safety incidents were categorised according to the WHO Conceptual Framework for the International Classification for Patient Safety. KEY FINDINGS: Fifteen studies were deemed eligible for inclusion. All 15 studies reported medication incidents associated with electronic prescribing; no studies were identified that reported medication safety incidents associated with telemedicine. The most commonly reported medication safety incidents were 'wrong label/instruction' and 'wrong dose/strength/frequency'. The frequency of medication safety incidents ranged from 0.89 to 81.98 incidents per 100 electronic prescriptions analysed. SUMMARY: This review of medication safety incidents associated with the remote delivery of primary care identified common incident types associated with electronic prescriptions. There was a wide variation in reported frequencies of medication safety incidents associated with electronic prescriptions. Further research is required to determine the impact of the COVID-19 pandemic on medication safety in primary care, particularly the increased use of telemedicine.

Changes to primary care delivery during the COVID-19 pandemic and perceived impact on medication safety: A survey study.

Introduction: The COVID-19 pandemic has had a profound impact on the delivery of primary care around the world. In Ireland, the use of technologies such as virtual consultations and the electronic transfer of prescriptions became widespread in order to deliver care to patients while minimising infection risk. The impact of these changes on medication safety is not yet known. Objectives: The aims of this survey study were to investigate 1) the changes that have occurred in Irish primary care since the start of the COVID-19 pandemic and 2) the impact of these changes on medication safety. Methods: Anonymous, online surveys were distributed to general practitioners (GPs) and pharmacists from August-September 2021. Surveys contained quantitative (multiple-choice, Likert scale) and qualitative (free-text) questions concerning workflow changes, medication safety incidents and near misses, and GP/pharmacist perspectives on medication safety and COVID-19. Reported medication safety incidents and near misses were categorised according to the WHO Conceptual Framework for the International Classification for Patient Safety. Results: In total, there were 251 responses to the survey, comprising of 211 pharmacists and 40 GPs. The most significant workflow changes during the pandemic were the widespread use of a secure clinical email service (Healthmail) that facilitates electronic prescription transfer and communication (75.3% of respondents) and the increased use of telephone consultations (49%). Overall, Healthmail was widely perceived to have had a positive impact on medication safety. Most GPs did not perceive a change in the frequency of medication safety incidents during the pandemic, while most pharmacists reported a slight increase in incidents. Survey participants highlighted pressure, patient expectations, and patient monitoring as significant challenges encountered during the pandemic. Conclusions: During the pandemic, a number of significant changes occurred in primary care in Ireland, particularly involving communication of healthcare information, with varying impacts on workflow and medication safety. Future research should focus on the optimisation of electronic prescribing and telemedicine services in Ireland, patient perspectives on the changes in primary care, and interventions to improve medication safety in primary care.

Targeting Internalized Staphylococcus aureus Using Vancomycin-Loaded Nanoparticles to Treat Recurrent Bloodstream Infections.

The bacterial pathogen Staphylococcus aureus is a leading cause of bloodstream infections, where patients often suffer from relapse despite antibiotic therapy. Traditional anti-staphylococcal drugs display reduced effectivity against internalised bacteria, but nanoparticles conjugated with antibiotics can overcome these challenges. In the present study, we aimed to characterise the internalisation and re-emergence of S. aureus from human endothelial cells and construct a new formulation of nanoparticles that target intracellular bacteria. Using an in vitro infection model, we demonstrated that S. aureus invades and persists within endothelial cells, mediated through bacterial extracellular surface adhesion, Fibronectin-binding protein A/B. After internalising, S. aureus localises to vacuoles as determined by transmission electron microscopy. Viable S. aureus emerges from endothelial cells after 48 h, supporting the notion that intracellular persistence contributes to infection relapses during bloodstream infections. Poly lactic-co-glycolic acid nanoparticles were formulated using a water-in-oil double emulsion method, which loaded 10% vancomycin HCl with 82.85% ± 12 encapsulation efficiency. These non-toxic nanoparticles were successfully taken up by cells and demonstrated a biphasic controlled release of 91 ± 4% vancomycin. They significantly reduced S. aureus intracellular growth within infected endothelial cells, which suggests future potential applications for targeting internalised bacteria and reducing mortality associated with bacteraemia.

Persistent inhibition of hippocampal long-term potentiation in vivo by learned helplessness stress.

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.

Prevalence of potentially serious alcohol-medication interactions in older adults in a community pharmacy setting: a cross-sectional study.

OBJECTIVE: Previous prevalence estimates of POtentially Serious Alcohol-Medication INteractions in Older adults (POSAMINO) are based on in-home inventories of medications; however, this method is associated with under-reporting of medications when compared with dispensing records. This study aims to estimate the prevalence of POSAMINO among community-dwelling older adults using drug dispensing data from the community pharmacy setting. DESIGN: Cross-sectional study. SETTING: Irish Community Pharmacy. PARTICIPANTS: 1599 consecutive older adults presenting with a prescription to 1 of 120 community pharmacies nationwide; community-dwelling, aged ≥65 years, able to speak and understand English, with no evidence of cognitive impairment. The mean age of sample was 75.5 years (SD 6.5); 55% (n=884) female. MEASURES: 38 POSAMINO criteria were identified using participants' pharmacy dispensing records linked to self-reported alcohol consumption (beverage-specific quantity and frequency measures) over the last 12 months. RESULTS: The overall prevalence of POSAMINO in the study population was 28%, with 10% at risk of at least one POSAMINO criteria and 18% at risk of two or more. Exposure to POSAMINO most commonly involved cardiovascular agents (19%) and central nervous system agents (15%). Exposure to a higher number of POSAMINO criteria was associated with younger age (adjusted incident rate ratio (AIRR): 0.97; 95% CI: 0.95 to 0.98), male sex (AIRR: 0.55; 95% CI: 0.45 to 0.67) and a higher number of comorbidities (AIRR: 1.05; 95% CI: 1.01 to 1.13). CONCLUSION: This study adds to the growing body of evidence, which suggests that older adults are vulnerable to potentially serious alcohol-medication interactions, particularly those involving cardiovascular and central nervous system agents, increasing their risk of orthostatic hypotension, gastrointestinal bleeds and increased sedation. Application of the POSAMINO criteria at the point of prescribing may facilitate the risk stratification of older adults and prioritise alcohol screening and brief alcohol interventions in those at greatest risk of harm.

Evaluation of the effect of insulin sensitivity-enhancing lifestyle- and dietary-related adjuncts on antidepressant treatment response: A systematic review and meta-analysis.

BACKGROUND: Depression is associated with insulin resistance (IR). However, the potential beneficial effect, on antidepressant treatment response, of adjunctive therapy with insulin sensitivity-enhancing lifestyle and dietary interventions (exercise; supplementation with: vitamin D, magnesium, zinc, probiotics or omega-3 fatty acids) has not been systematically explored. AIMS: To determine the effect of the above stated adjuncts on antidepressant treatment response in clinically depressed patients via a systematic review and meta-analysis. METHODS: RCTs which assessed the effect, on antidepressant treatment response of adjunctive therapy with any of the interventions in comparison with treatment as usual were included. RESULTS: The interventions had a significant antidepressant effect, with SMD for follow-up (end of study) scores and change (from baseline) scores being -0.88, [95% CI: -1.19 to -0.57; P < 0.001] and -1.98 [95% CI -2.86 to -1.10; P < 0.001], respectively. The odds ratio (OR) for remission was 2.28 (95% CI 1.42 to 3.66; P < 0.001). The number-needed-to-treat (NNT) for remission was 6. Subgroup analysis of the follow-up scores revealed age effect: SMD significant in those with mean age ≤50 (-1.02 SMD; 95% CI: -1.40 to -0.64; p < 0.001) and insignificant in those with mean age >50 (-0.38 SMD (95% CI: -0.82 to 0.05; P = 0.08)). Also, the interventions were more beneficial among outpatients- SMD: -0.97 (95% CI: -1.32 to -0.62; P < 0.001) compared to inpatients- SMD: -0.34 (95% CI: -0.88 to 0.20; P = 0.22). Sensitivity analysis did not change the results. CONCLUSION: The finding that antidepressant treatment response may be improved using insulin sensitivity-enhancing lifestyle and dietary adjuncts is worthy of further exploration.

Do interruptions to the continuity of methadone maintenance treatment in specialist addiction settings increase the risk of drug-related poisoning deaths? A retrospective cohort study.

AIMS: To examine the risk of mortality associated with interruptions to the continuity of methadone maintenance treatment (MMT), including transfers between services, in opioid-dependent individuals attending specialist addiction services. DESIGN: Retrospective cohort study using addiction services and primary care dispensing records, the National Methadone Register and National Drug-Related Death Index (NDRDI). SETTING: Geographically defined population in Dublin, Ireland. PARTICIPANTS: A total of 2899 people prescribed and dispensed methadone in specialist addiction services between January 2010 and December 2015. There were five exposure groups: weeks 1-4 following transfer between treatment providers; weeks 1-4 out of treatment; weeks 5-52 out of treatment; weeks 1-4 of treatment initiation; and weeks 5+ of continuous treatment (reference category). MEASUREMENTS: Primary outcome: drug-related poisoning (DRP) deaths. Secondary outcome: all-cause mortality (ACM). Mortality rates calculated by dividing number of deaths (DRP; ACM) in exposure groups by person-years exposure. Unadjusted and adjusted Poisson regression (covariates age, sex, incarceration, methadone dose and comorbidities) estimated differences in mortality rates. FINDINGS: There were 154 ACM deaths, 55 (35.7%) identified as DRP deaths. No deaths were observed in the first month following transfer between treatment providers. The risk of DRP mortality was highest in weeks 1-4 out of treatment [adjusted relative risk (aRR = 4.04, 95% confidence interval (CI) = 1.43-11.43, P = 0.009] and weeks 1-4 of treatment initiation (ARR = 3.4, 95% CI = 1.2-9.64, P = 0.02). Similarly, risk of ACM was highest in weeks 1-4 out of treatment (ARR = 11.78, 95% CI = 7.73-17.94, P < 0.001), weeks 1-4 of treatment initiation (aRR = 5.11, 95% CI = 2.95-8.83, P < 0.001) and weeks 5-52 off treatment (aRR = 2.04, 95% CI = 1.2-3.47, P = 0.009). CONCLUSIONS: Interruptions to the continuity of methadone maintenance treatment by treatment provider do not appear to be periods of risk for drug-related poisoning or all-cause mortality deaths. Risk of drug related poisoning and all-cause mortality deaths appears to be greatest during the first 4 weeks of treatment initiation/re-initiation and after treatment cessation.

Evaluation of the effect of insulin sensitivity-enhancing lifestyle- and dietary-related adjuncts on antidepressant treatment response: protocol for a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of disability worldwide and is known to be associated with insulin resistance (IR). Insulin resistance worsens the symptoms of depression and reduces the effectiveness of antidepressant medications in some depressed patients. Many studies have assessed the effect of adjunctive exercise, vitamin D supplementation, zinc supplementation, magnesium, probiotics, unsaturated fatty acids, and hygienic-dietary recommendations (sleep hygiene, healthy diet, physical activity, and sunlight exposure, combined or singly used), individually, on antidepressant treatment response. However, despite the reported insulin sensitivity-enhancing potential of these adjuncts, no systematic review has collectively analysed their antidepressant effect with regards to insulin sensitivity. METHODS/DESIGN: In this systematic review, we will analyse the effect of the above-stated adjuncts on antidepressant treatment response (primary outcome) in comparison with treatment as usual with or without adjunctive placebo after identifying the relevant trials from a systematic literature search. Randomised controlled trials involving clinically depressed patients with diagnosis of major depressive, dysthymic or bipolar disorder will be considered. Changes in insulin sensitivity parameters, following treatment, will also be analysed as the secondary outcome. Effect estimates of the included trials will be combined using random-effects meta-analysis, while addressing risk of bias issues. Any significant heterogeneity between studies will be explored using sensitivity and subgroup analyses. DISCUSSION: The findings of this review will contribute to the evidence base regarding the utility of non-pharmacological insulin-sensitising treatments in enhancing conventional antidepressant treatment response.

5-HT2 receptor-mediated reversal of the inhibition of hippocampal long-term potentiation by acute inescapable stress.

The serotonergic system is known to modulate and mediate many of the central nervous system effects of stress. Here we investigated the ability of serotonergic agents to reverse the inhibition of the induction of hippocampal long-term potentiation (LTP) caused by prior exposure to inescapable stress. Elevated platform stress prevented the induction of LTP in the CA1 area of anaesthetized rats. An agent that increases extracellular 5-HT concentration, fenfluramine (5 mg/kg, i.p.) enabled the induction of LTP in previously stressed animals. Consistent with a role for enhanced activation of 5-HT(2) receptors, the facilitatory effect of fenfluramine was prevented by the 5-HT(2) receptor antagonist cinanserin (30 mg/kg). Agents that directly activate 5-HT(2) receptors, including the 5-HT(2B) receptor agonist BW 723C86 (30 mg/kg) and the 5-HT(2C) receptor agonist MK-212 (3 mg/kg), mimicked the restorative effect of fenfluramine. Fenfluramine also opposed inhibition of LTP caused by the NMDA-receptor antagonist D-AP5 (100 nmol, i.c.v.) which suggests that the facilitatory action of serotonergic agents is not restricted to stress-mediated inhibition of LTP. These findings support an important role for activation of 5-HT(2) receptors by systemically applied agents to enable recovery from the inhibition of LTP by stress.

Physical and structural stability of the monoclonal antibody, trastuzumab (Herceptin®), intravenous solutions.

A major limitation of biological therapeutics is their propensity for degradation particularly in aqueous solutions hence resulting in their short shelf-life. In this study, the stability of trastuzumab (Herceptin®) intravenous (i.v.) solutions, an IgG1 monoclonal antibody (mAb), indicated for the treatment of HER2 positive breast cancer, stored under refrigerated conditions, was evaluated over 28 days. No change in visual appearance or average particle size was observed. The pH values of the trastuzumab i.v. solutions remained stable over time. Interestingly, no change in trastuzumab monomer concentration was observed throughout the 28-day study, as determined by SEC-HPLC. SDSPAGE showed only a monomer band corresponding to the molecular weight of trastuzumab. Circular dichroism spectra obtained following 28-day storage demonstrated integrity of the secondary structural conformation of trastuzumab. Results from this study show that trastuzumab i.v. solutions remain physically and structurally stable on storage at 2-8°C for 28 days. These findings suggest that trastuzumab in solution may not be as sensitive to degradation as expected for a mAb and therefore may have important implications in extending trastuzumab shelf life for clinical use and reducing associated healthcare cost.

Effect of microencapsulation shear stress on the structural integrity and biological activity of a model monoclonal antibody, trastuzumab.

The aim of the present study was to investigate the influence of process shear stressors on the stability of a model monoclonal antibody, trastuzumab. Trastuzumab, at concentrations of 0.4-4.0 mg/mL, was subjected to sonication, freeze-thaw, lyophilisation, spray drying and was encapsulated into micro- and nanoparticles. The stressed samples were analysed for structural integrity by gel electrophoresis, SDS-PAGE, and size exclusion chromatography (SEC), while the conformational integrity was analysed by circular dichroism (CD). Biological activity of the stressed trastuzumab was investigated by measuring the inhibition of cell proliferation of HER-2 expressing cell lines. Results show that trastuzumab was resistant to the process shear stresses applied and to microencapsulation processes. At the lowest concentration of 0.4 mg/mL, a low percent ( 0.05). The results of this study conclude that trastuzumab may be resistant to various processing stresses. These findings have important implications with respect to pharmaceutical processing of monoclonal antibodies.