This article, the seventh in the series, presents kinetic
and photochemical data sheets evaluated by the IUPAC Task Group on
Atmospheric Chemical Kinetic Data Evaluation. It covers an extension of ...the
gas-phase and photochemical reactions related to Criegee intermediates
previously published in Atmospheric Chemistry and Physics (ACP) in 2006 and implemented on the IUPAC website up
to 2020. The article consists of an introduction, description of laboratory
measurements, a discussion of rate coefficients for reactions of O3 with
alkenes producing Criegee intermediates, rate coefficients of unimolecular
and bimolecular reactions and photochemical data for reactions of Criegee
intermediates, and an overview of the atmospheric chemistry of Criegee
intermediates. Summary tables of the recommended kinetic and mechanistic
parameters for the evaluated reactions are provided. Data sheets summarizing
information upon which the recommendations are based are given in two files,
provided as a Supplement to this article.
Aims
The aim of this study was to determine the differences and potential mechanistic rationale for observed adverse drug reactions (ADRs) between four approved PARP inhibitors (PARPi).
Methods
The ...Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profiles and NHS secondary care medicines database enabled the identification of suspected ADRs associated with the PARPi in the UK from launch to 2020. The polypharmacology of the PARPi were data‐mined from several public data sources.
Results
The overall ADRs per 100 000 Rx identified across the four PARPi are statistically significant (χ2 test, P < .001). Rucaparib has the greatest relative suspected ADRs, which can be explained by its least clean kinome and physicochemical properties. The suspected gastrointestinal ADRs of rucaparib and niraparib can be ascribed to their kinase polypharmacology. Suspected blood and lymphatic system ADRs of PARPi can be linked to their high volume of distribution (Vd). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the Vd trend.
Hypertension is only associated with niraparib and could be explained by the therapeutically achievable inhibition of DYRK1A and/or transporters. Arrhythmia cases are potentially linked to the structural features of hERG ion‐channel inhibition found in rucaparib and niraparib. Enhanced psychiatric/nervous disorders associated with niraparib can be interpreted from the diverse neurotransporter off‐targets reported.
Conclusions
Despite their similar mode of action, the differential polypharmacology of PARP inhibitors influences their ADR profile.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To report two patients with herpetic zoster panuveitis and chorioretinopathy with choroidal hypopigmentation.
Retrospective chart review of two patients.
We report a series of two patients with a ...history of HZO with orbital inflammation and panuveitis, who developed patchy choroidal depigmentation consistent with a choroidopathy. The lesions were extensive and involved the posterior pole and mid-periphery in both cases. Both cases demonstrated scattered areas of ellipsoid zone loss, and fluorescein angiography showed corresponding late hyperfluorescence. OCTA in one case demonstrated flow voids at the level of choriocapillaris.
Our series suggests that herpetic chorioretinopathy may be a relatively benign process that presents late and may involve large areas of the posterior choroid.
Background. Human metapneumovirus (HMPV) is a leading cause of acute respiratory tract infection, with significant morbidity and mortality. No licensed vaccines or therapeutic agents exist. ...Monoclonal antibodies (mAbs) are effective at preventing other infectious diseases and could be used against HMPV in high-risk hosts. Methods. In vitro assays were performed to assess the neutralizing activity and affinity kinetics of human mAb 54G10. A new mouse model was developed to assess prophylactic and therapeutic efficacy in vivo. The epitope of 54G10 was identified by generating mAb-resistant mutants (MARMs). Results. At low concentrations, 54G10 neutralized all 4 subgroups of HMPV in vitro and had subnanomolar affinity for the fusion protein. DBA/2 mice were permissive for all 4 HMPV subgroups, and 54G10 was effective both prophylactically and therapeutically against HMPV in vivo. Sequencing of HMPV MARMs identified the 54G10 epitope, which was similar to an antigenic site on respiratory syncytial virus (RSV). 54G10 also exhibited in vitro neutralizing activity and in vivo protective and therapeutic efficacy against RSV. Conclusions. Human mAb 54G10 has broad neutralizing activity against HMPV and could have prophylactic and therapeutic utility clinically. The conserved epitope could represent a structural vaccine target for HMPV and RSV.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Globally, chronic kidney disease (CKD) is one of the leading causes of mortality. Impaired renal function makes CKD patients vulnerable to drug-related problems (DRPs).
The aim of this systematic ...review was to investigate the prevalence and nature of DRPs among hospital in-patients with CKD.
A systematic review of the literature was conducted using Medline, EMBASE, PsycINFO, Web of Science (Core Collection), CINAHL plus (EBSCO), Cochrane Library (Wiley), Scopus (ELSEVIER) and PubMed (U.S.NLM) from index inception to January 2020. Studies investigating DRPs in hospitalised CKD patients published in the English language were included. Two independent reviewers extracted the data and undertook quality assessment using the Joanna Briggs Institute (JBI) tool.
A total of 2895 unique titles were identified; with 20 meeting the inclusion criteria. DRPs prevalence in CKD was reported between 12 and 87%. The most common DRPs included ineffective treatment, inappropriate drug choice and dosing problems. Antibiotics, H2-antihistamines and oral antidiabetics (metformin) were common drug classes involved in DRPs. Factors associated with DRPs included severity of CKD, the number of medications taken, age, length of hospital stay, and gender.
This systematic review provides evidence that DRPs are a frequent occurrence and burden for hospitalised patients with stage 1-4 CKD. Heterogeneity in study design, case detection and definitions are common, and future studies should use clearer definitions and study designs. Protocol Registration: PROSPERO: CRD42018096364.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Adverse drug reactions (ADRs) can have significant negative impact on peoples' daily lives, with physical, economic, social and/or psychological effects. Patient reporting of ADRs has ...been facilitated by pharmacovigilance systems across Europe. However, capturing data on patients' experiences of ADRs has proved challenging. Existing patient reports to the UK Yellow Card Scheme contain free‐text comments which could be useful sources of information.
Objectives
To investigate patients' experiences of ADRs and their impact on patients as described in free‐text data within patient Yellow Card (YC) reports submitted to the Medicines and Healthcare products Regulatory Agency.
Methods
A qualitative review of narrative texts was conducted on free‐text data from 2255 patient YC reports from July to December 2015.
Results
Three key narrative themes emerged from analysis of the free‐text data in 2255 reports: (1) identification of ADRs, (2) severity and impact of ADRs, and (3) management of ADRs. Temporal associations were the most common method of identification followed by differential diagnoses and confirmation with information sources such as healthcare professionals (HCPs). A combination of explicit and implicit impacts were described: physical, psychological, economic and social effects often persisted and caused serious disruption to many patients' lives. A range of strategies were used to manage ADRs, including consultation with HCPs, stopping/reducing the medicine or taking medicines to alleviate symptoms.
Conclusion
Free‐text data from YC reports has been an underutilised resource to date, but this research has confirmed its potential value to pharmacovigilance and medication safety research.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which ...downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here, we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacological neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacological suppression.
Coroners inquire into sudden, unexpected, or unnatural deaths. We have previously established 99 cases (100 deaths) in England and Wales in which medicines or part of the medication process or both ...were mentioned in coroners' 'Regulation 28 Reports to Prevent Future Deaths' (coroners' reports).
We wished to see what responses were made by National Health Service (NHS) organizations and others to these 99 coroners' reports.
Where possible, we identified the party or parties to whom these reports were addressed (names were occasionally redacted). We then sought responses, either from the UK judiciary website or by making requests to the addressee directly or, for NHS and government entities, under the Freedom of Information Act 2000. Responses were analysed by theme to indicate the steps taken to prevent future deaths.
We were able to analyse one or more responses to 69/99 cases from 106 organizations. We analysed 201 separate actions proposed or taken to address the 160 concerns expressed by coroners. Staff education or training was the most common form of action taken (44/201). Some organisations made changes in process (24/201) or policy (17/201), and some felt existing policies were sufficient to address some concerns (22/201).
Coroners' concerns are often of national importance but are not currently shared nationally. Only a minority of responses to coroners' reports concerning medicines are in the public domain. Processes for auditing responses and assessing their effectiveness are opaque. Few of the responses appear to provide robust and generally applicable ways to prevent future deaths.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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