Inappropriate use of medication is widespread, especially in older people, and is associated with risks, including adverse drug reactions, hospitalization and increased mortality. Optimization of ...appropriate medication use to minimize these harms is an ongoing challenge in healthcare. The term ‘deprescribing’ has been used to describe the complex process that is required for safe and effective cessation of medication. Patients play an important role in their own health and, while they may complain about the number of medications they have to take, they may also be reluctant to cease a medication when given the opportunity to do so. A review of previously proposed deprescribing processes and relevant literature was used to develop the patient‐centred deprescribing process, which is a five‐step cycle that encompasses gaining a comprehensive medication history, identifying potentially inappropriate medications, determining whether the potentially inappropriate medication can be ceased, planning the withdrawal regimen (e.g. tapering where necessary) and provision of monitoring, support and documentation. This is the first deprescribing process developed using knowledge of the patients' views of medication cessation; it focuses on engaging patients throughout the process, with the aim of improving long‐term health outcomes. Despite a comprehensive review of the literature, there is still a lack in the evidence base on which to conduct deprescribing. The next step in broadening the evidence to support deprescribing will be to test the developed process to determine feasibility in the clinical setting.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Inappropriate medication use is common in the elderly and the risks associated with their use are well known. The term deprescribing has been utilised to describe the complex process that ...is required for the safe and effective cessation of inappropriate medications. Given the primacy of the consumer in health care, their views must be central in the development of any deprescribing process.
Objectives
The aim of this study was to identify barriers and enablers that may influence a patient’s decision to cease a medication.
Data sources
A systematic search of MEDLINE, International Pharmaceutical Abstracts, EMBASE, CINAHL, Informit and Scopus was conducted and augmented with a manual search. Numerous search terms relating to withdrawal of medications and consumers’ beliefs were utilised.
Study eligibility criteria
Articles were included if the barriers or enablers were directly patient/carer reported and related to long-term medication(s) that they were currently taking or had recently ceased.
Study appraisal and synthesis methods
Determination of relevance and data extraction was performed independently by two reviewers. Content analysis with coding was utilised for synthesis of results.
Results
Twenty-one articles met the criteria and were included in the review. Three themes, disagreement/agreement with ‘appropriateness’ of cessation, absence/presence of a ‘process’ for cessation, and negative/positive ‘influences’ to cease medication, were identified as both potential barriers and enablers, with ‘fear’ of cessation and ‘dislike’ of medications as a fourth barrier and enabler, respectively. The most common barrier/enabler identified was ‘appropriateness’ of cessation, with 15 studies identifying this as a barrier and 18 as an enabler.
Conclusions and implications of key findings
The decision to stop a medication by an individual is influenced by multiple competing barriers and enablers. Knowledge of these will aid in the development of a deprescribing process, particularly in approaching the topic of cessation with the patient and what process should be utilised. However, further research is required to determine if the proposed patient-centred deprescribing process will result in improved patient outcomes.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Immune checkpoint inhibitors (ICI) are an important development in the treatment of advanced cancer. A substantial proportion of patients treated with ICI do not respond, and additionally patients ...discontinue treatment due to adverse effects. While many novel biological markers related to the specific mechanisms of ICI actions have been investigated, there has also been considerable research to identify routinely available blood and clinical markers that may predict response to ICI therapy. If validated, these markers have the advantage of being easily integrated into clinical use for nominal expense. Several markers have shown promise, including baseline and post-treatment changes in leucocyte counts, lactate dehydrogenase and C-reactive protein. While promising, the results between studies have been inconsistent due to small sample sizes, follow-up time and variability in the assessed markers. To date, research on routinely available blood and clinical markers has focussed primarily on ICI use in melanoma, the use of ipilimumab and on univariate associations, but preliminary evidence is emerging for other cancer types, other ICIs and for combining markers in multivariable clinical prediction models.
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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
Objectives
To capture people's attitudes, beliefs, and experiences regarding the number of medications they are taking and their feelings about stopping medications.
Design
Administration of a ...validated questionnaire.
Setting
Multidisciplinary ambulatory consulting service at the Royal Adelaide Hospital.
Participants
Participants were individuals aged 18 and older (median 71.5) taking at least one regular prescription medication; 100 participants completed all items of the questionnaire, 65 of whom were aged 65 and older.
Measurements
Participants were administered the 15‐item Patients' Attitudes Towards Deprescribing (PATD) questionnaire.
Results
Participants were taking an average of 10 different prescription and nonprescription (including complementary), regular and as‐needed medications. More than 60% felt that they were taking a “large number” of medications, and 92% stated that they would be willing to stop one or more of their current medications if possible. Number of regular medications, age, and number of medical conditions were not found to be correlated with willingness to stop a medication. The findings were similar in older and younger participants.
Conclusion
This study has shown that a cohort of mostly older adults were largely accepting of a trial of cessation of medication(s) that their prescriber deemed to be no longer required. Because few factors were associated with willingness to cease medications, all patients should be individually evaluated for deprescribing.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chemotherapeutic treatment of cancer often fails due to overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCG2, triggering active efflux of various structurally unrelated ...drugs. This so-called multidrug resistance (MDR) may be reversed by selective, potent, and nontoxic inhibitors of ABCG2. As only a few potent inhibitors are known, new compounds based on a 4-substituted-2-phenylquinazoline scaffold were investigated. Substitution with hydroxy, cyano, nitro, acetamido, and fluoro led to high inhibitory activities toward ABCG2. The ability to reverse MDR of the most active compounds was confirmed in a MTT efficacy assay. Moreover, a negligibly low intrinsic cytotoxicity was found resulting in a high therapeutic ratio. Investigations of the inhibitory activity toward ABCB1 and ABCC1 yielded a high selectivity toward ABCG2 for the quinazoline compounds. Quinoline-based analogues showed lower inhibitory activity and selectivity. The study yielded a variety of promising compounds, some with superior properties compared to those of the standard inhibitor Ko143.
Objectives
To systematically review clinical outcomes associated with medication regimen complexity in older people.
Design
Systematic review of EMBASE, MEDLINE, International Pharmaceutical s, ...Cumulative Index to Nursing and Allied Health Literature, and the Cochrane library.
Setting
Hospitals, home, and long‐term care.
Participants
English‐language peer‐reviewed original research published before June 2016 was eligible if regimen complexity was quantified using a metric that considered number of medications and at least one other parameter, regimen complexity was calculated for participants’ overall regimen, at least 80% of participants were aged 60 and older, and the study investigated a clinical outcome associated with regimen complexity.
Measurements
Quality assessment was conducted using an adapted version of the Joanna Briggs Institute critical appraisal tool.
Results
Sixteen observational studies met the inclusion criteria. Regimen complexity was associated with medication nonadherence (2/6 studies) and higher rates of hospitalization (2/4 studies). One study found that participants with less‐complex medication administration were more likely to stop medications when feeling worse. One study each identified an association between regimen complexity and higher ability to administer medications as directed, medication self‐administration errors, caregiver medication administration hassles, hospital discharge to non‐home settings, postdischarge potential adverse drug events, all‐cause mortality, and lower patient knowledge of their medication. Regimen complexity had no association with postdischarge medication modification, change in medication‐ and health‐related problems, emergency department visits, or quality of life as rated by nursing staff.
Conclusion
Research into whether medication regimen complexity is associated with nonadherence and hospitalization has produced inconsistent results. Moderate‐quality evidence from four studies (two each for nonadherence and hospitalization) suggests that medication regimen complexity is associated with nonadherence and higher rates of hospitalization.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease affecting 0.5–1% of adults worldwide. Achieving long term remission or low disease activity is possible through early diagnosis, ...rapid initiation of disease modifying anti-rheumatic drugs (DMARDs) and implementation of a treat to target approach. Initial DMARD therapy usually involves methotrexate (MTX), either alone or in combination with other agents, however 40% of RA patients do not respond adequately, putting them at risk of disease progression and unnecessary exposure to MTX related adverse effects. Early predictors of MTX response would therefore enable a more personalized treatment strategy, ensuring timely access to MTX for those likely to respond and importantly, early initiation of alternative treatment for those in which MTX is unlikely to be efficacious. Predicting response to treatment will most likely require consideration of the clinical characteristics of the patient and interrogation of a number of factors including genetic, epigenetic, cell free DNA (cfDNA) and microRNA (miRNA), all of which can be investigated through blood derived liquid biopsies. This review will summarize the existing literature examining the use of epigenetic factors, cfDNA and miRNA as response predictors among RA patients treated with MTX.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that can lead to permanent disability and deformity. Despite current treatment modalities, many patients are still unable to ...reach remission. Interleukin-1 receptor-associated kinase 4 (IRAK-4) inhibitors are novel agents designed to suppress immune signaling pathways involved in inflammation and joint destruction in RA. Four IRAK-4 inhibitors have entered clinical trials.
This review summarizes the current stage of development of IRAK-4 inhibitors in clinical trials, detailing their chemistry, pharmacokinetics, and therapeutic potential in the treatment of RA. PubMed, Embase and restricted Google searches were conducted using the term 'IRAK-4ʹ, and publicly accessible clinical trial databases were reviewed.
IRAK-4 inhibitors are an exciting therapeutic option in RA management because unlike other targeted disease-modifying agents, they target the innate immune system. The role of IRAK-4 as a key component of Toll/Interleukin-1 receptor signaling and its potential for a low rate of infectious complications is particularly exciting and this may facilitate their use in combination treatment. A key aspect of upcoming clinical trials will be the identification of biomarkers predictive of treatment efficacy, which will help to define if and how they will be used in the clinic.
Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by ...cross‐resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects—the metabolism and distribution of drugs as well as their own regulation—is adenosine triphosphate‐binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance‐associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer‐related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)‐adducts of certain cytostatics. Contrary to other transport proteins involved in cancer‐related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1‐associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β‐amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The global distribution of tropical fire ants (Solenopsis geminata) raises concerns about anaphylaxis and serious medical issues in numerous countries. This investigation focused on the ...cross-reactivity of allergen-specific IgE antibodies between S. geminata and Myrmecia pilosula (Jack Jumper ant) venom proteins due to the potential emergence of cross-reactive allergies in the future. Antibody epitope analysis unveiled one predominant conformational epitope on Sol g 1.1 (PI score of 0.989), followed by Sol g 2.2, Sol g 4.1, and Sol g 3.1. Additionally, Pilosulin 1 showed high allergenic potential (PI score of 0.94), with Pilosulin 5a (PI score of 0.797) leading in B-cell epitopes. The sequence analysis indicated that Sol g 2.2 and Sol g 4.1 pose a high risk of cross-reactivity with Pilosulins 4.1a and 5a. Furthermore, the cross-reactivity of recombinant Sol g proteins with M. pilosula-specific IgE antibodies from 41 patients revealed high cross-reactivity for r-Sol g 3.1 (58.53%) and r-Sol g 4.1 (43.90%), followed by r-Sol g 2.2 (26.82%), and r-Sol g 1.1 (9.75%). Therefore, this study demonstrates cross-reactivity (85.36%) between S. geminata and M. pilosula, highlighting the allergenic risk. Understanding these reactions is vital for the prevention of severe allergic reactions, especially in individuals with pre-existing Jumper Jack ant allergy, informing future management strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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