The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons

Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11–2.16], p =.01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased β1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.</p

Survival outcomes of patients with advanced mucosal melanoma diagnosed from 2013 to 2017 in the Netherlands - A nationwide population-based study

Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM). Methods: Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry – the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS. Results: In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015–2017, compared with 2013–2014. ECOG performance score ≥1 (HR = 1.99 [1.26–3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96–2.76]; p = 0.069) in MM were associated with worse survival. Conclusions: Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations

Depression, antidepressants and fall risk: therapeutic dilemmas—a clinical review

Purpose: The aim of this clinical review was to summarize the existing knowledge on fall risk associated with antidepressant use in older adults, describe underlying mechanisms, and assist clinicians in decision-making with regard to (de-) prescribing antidepressants in older persons. Methodology: We comprehensively examined the literature based on a literature search in Pubmed and Google Scholar, and identified additional relevant articles from reference lists, with an emphasis on the most commonly prescribed drugs in depression in geriatric patients. We discuss use of antidepressants, potential fall-related side effects, and deprescribing of antidepressants in older persons. Results: Untreated depression and antidepressant use both contribute to fall risk. Antidepressants are equally effective, but differ in fall-related side effect profile. They contribute to (or cause) falling through orthostatic hypotension, sedation/impaired attention, hyponatremia, movement disorder and cardiac toxicity. Falling is an important driver of morbidity and mortality and, therefore, requires prevention. If clinical condition allows, withdrawal of antidepressants is recommended in fall-prone elderly persons. An important barrier is reluctance of prescribers to deprescribe antidepressants resulting from fear of withdrawal symptoms or disease relapse/recurrence, and the level of complexity of deprescribing antidepressants in older persons with multiple comorbidities and medications. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antidepressants. Conclusions: (De-) prescribing antidepressants in fall-prone older adults is often challenging, but detailed insight in fall-related side effect profile of the different antidepressants and a recently developed expert-based decision aid STOPPFalls assists prescribers in clinical decision-making

Depression, antidepressants and fall risk: therapeutic dilemmas—a clinical review

Purpose: The aim of this clinical review was to summarize the existing knowledge on fall risk associated with antidepressant use in older adults, describe underlying mechanisms, and assist clinicians in decision-making with regard to (de-) prescribing antidepressants in older persons. Methodology: We comprehensively examined the literature based on a literature search in Pubmed and Google Scholar, and identified additional relevant articles from reference lists, with an emphasis on the most commonly prescribed drugs in depression in geriatric patients. We discuss use of antidepressants, potential fall-related side effects, and deprescribing of antidepressants in older persons. Results: Untreated depression and antidepressant use both contribute to fall risk. Antidepressants are equally effective, but differ in fall-related side effect profile. They contribute to (or cause) falling through orthostatic hypotension, sedation/impaired attention, hyponatremia, movement disorder and cardiac toxicity. Falling is an important driver of morbidity and mortality and, therefore, requires prevention. If clinical condition allows, withdrawal of antidepressants is recommended in fall-prone elderly persons. An important barrier is reluctance of prescribers to deprescribe antidepressants resulting from fear of withdrawal symptoms or disease relapse/recurrence, and the level of complexity of deprescribing antidepressants in older persons with multiple comorbidities and medications. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antidepressants. Conclusions: (De-) prescribing antidepressants in fall-prone older adults is often challenging, but detailed insight in fall-related side effect profile of the different antidepressants and a recently developed expert-based decision aid STOPPFalls assists prescribers in clinical decision-making

Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination

BackgroundVulvar high-grade squamous intraepithelial lesion (vHSIL) is predominantly induced by high-risk human papilloma virus type 16 (HPV16). In two independent trials, therapeutic vaccination against the HPV16 E6 and E7 oncoproteins resulted in objective partial and complete responses (PRs/CRs) in half of the patients with HPV16+ vHSIL at 12-month follow-up. Here, the prevaccination and postvaccination vHSIL immune microenvironment in relation to the vaccine-induced clinical response was investigated.MethodsTwo novel seven-color multiplex immunofluorescence panels to identify T cells (CD3, CD8, Foxp3, Tim3, Tbet, PD-1, DAPI) and myeloid cells (CD14, CD33, CD68, CD163, CD11c, PD-L1, DAPI) were designed and fully optimized for formalin-fixed paraffin-embedded tissue. 29 prevaccination and 24 postvaccination biopsies of patients with vHSIL, and 27 healthy vulva excisions, were stained, scanned with the Vectra multispectral imaging system, and automatically phenotyped and counted using inForm advanced image analysis software.ResultsHealthy vulvar tissue is strongly infiltrated by CD4 and CD8 T cells expressing Tbet and/or PD-1 and CD14+HLA-DR+ inflammatory myeloid cells. The presence of such a coordinated pre-existing proinflammatory microenvironment in HPV16+ vHSIL is associated with CR after vaccination. In partial responders, a disconnection between T cell and CD14+ myeloid cell infiltration was observed, whereas clinical non-responders displayed overall lower immune cell infiltration. Vaccination improved the coordination of local immunity, reflected by increased numbers of CD4+Tbet+ T cells and HLA-DR+CD14+ expressing myeloid cells in patients with a PR or CR, but not in patients with no response. CD8+ T cell infiltration was not increased after vaccination.ConclusionA prevaccination inflamed type 1 immune contexture is required for stronger vaccine-induced immune infiltration and is associated with better clinical response. Therapeutic vaccination did not overtly increase immune infiltration of cold lesions

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges. This was a randomized, double-blind, placebo-controlled study with single ascending low doses of LPS (0.5, 1 and 2 ng/kg body weight) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS: placebo 6:2). The in vivo inflammatory response was assessed by measurement of cytokines and CRP. Ex vivo LPS challenges were performed (at -2, 6, 12, 24, 48 and 72 hours relative to in vivo LPS administration) to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release (TNF-alpha, IL-1 beta, IL-6, IL-8). LPS administration dose-dependently increased body temperature (+1.5 degrees C for 2 ng/kg LPS), heart rate (+28 bpm for 2 ng/kg LPS), CRP and circulating cytokines which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (0.5 ng/kg, contrast for timeframe 0-6 hours: TNF-alpha+413%, IL-6+288%, IL-8+254%; all p <= 0.0001). In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release (IL-1 beta, IL-6 and TNF-alpha), with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. We demonstrated that an in vivo LPS challenge, with LPS doses as low as 0.5 ng/kg, elicits a cytokine response that is clearly distinctive from baseline cytokine levels. This study expanded the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring pharmacological or nutritional immune-modulating effect

Characterization of immune cell, endothelial, and renal responses upon experimental human endotoxemia

Introduction: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low-to moderate dose (0.5, 1 or 2 ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. Methods: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2 ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS: placebo 6: 2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. Results: Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P-Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2 ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. Discussion: We demonstrated that administration of a single LPS dose of 2 ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the human endotoxemia model in future clinical pharmacology studie

Are higher antidepressant plasma concentrations associated with fall risk in older antidepressant users?

Purpose: Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods: For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC?MS) at baseline and at 2?years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results: In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07?5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion: There might be an association between plasma concentrations?of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed