-
The Cochrane Database of Systematic... Jul 2023Eosinophilic esophagitis (EoE) is a chronic antigen-mediated eosinophilic inflammatory disease isolated to the esophagus. As a clinicopathologic disorder, a diagnosis of... (Review)
Review
BACKGROUND
Eosinophilic esophagitis (EoE) is a chronic antigen-mediated eosinophilic inflammatory disease isolated to the esophagus. As a clinicopathologic disorder, a diagnosis of EoE requires a constellation of clinical symptoms of esophageal dysfunction and histologic findings (at least 15 eosinophils/high-powered microscope field (eos/hpf)). Current guidelines no longer require the failure of response to proton pump inhibitor medications to establish a diagnosis of EoE, but continue to suggest the exclusion of other etiologies of esophageal eosinophilia. The treatment goals for EoE are improvement in clinical symptoms, resolution of esophageal eosinophilia and other histologic abnormalities, endoscopic improvement, improved quality of life, improved esophageal function, minimized adverse effects of treatment, and prevention of disease progression and subsequent complications. Currently, there is no cure for EoE, making long-term treatment necessary. Standard treatment modalities include dietary modifications, esophageal dilation, and pharmacologic therapy. Effective pharmacologic therapies include corticosteroids, rapidly emerging biological therapies, and proton pump inhibitor medications.
OBJECTIVES
To evaluate the efficacy and safety of medical interventions for people with eosinophilic esophagitis.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP to 3 March 2023.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing any medical intervention or food elimination diet for the treatment of eosinophilic esophagitis, either alone or in combination, to any other intervention (including placebo).
DATA COLLECTION AND ANALYSIS
Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as a risk ratio (RR) and as the mean or standardized mean difference (MD/SMD) with 95% confidence interval (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were: clinical, histological, and endoscopic improvement, and withdrawals due to adverse events. Secondary outcomes were: serious and total adverse events, and quality of life.
MAIN RESULTS
We included 41 RCTs with 3253 participants. Eleven studies included pediatric patients while the rest recruited both children and adults. Four studies were in patients with inactive disease while the rest were in patients with active disease. We identified 19 intervention comparisons. In this abstract we present the results of the primary outcomes for the two main comparisons: corticosteroids versus placebo and biologics versus placebo, based on the prespecified outcomes defined of the primary studies. Fourteen studies compared corticosteroids to placebo for induction of remission and the risk of bias for these studies was mostly low. Corticosteroids may lead to slightly better clinical improvement (20% higher), measured dichotomously (risk ratio (RR) 1.74, 95% CI 1.08 to 2.80; 6 studies, 583 participants; number needed to treat for an additional beneficial outcome (NNTB) = 4; low certainty), and may lead to slightly better clinical improvement, measured continuously (standard mean difference (SMD) 0.51, 95% CI 0.17 to 0.85; 5 studies, 475 participants; low certainty). Corticosteroids lead to a large histological improvement (63% higher), measured dichotomously (RR 11.94, 95% CI 6.56 to 21.75; 12 studies, 978 participants; NNTB = 3; high certainty), and may lead to histological improvement, measured continuously (SMD 1.42, 95% CI 1.02 to 1.82; 5 studies, 449 participants; low certainty). Corticosteroids may lead to little to no endoscopic improvement, measured dichotomously (RR 2.60, 95% CI 0.82 to 8.19; 5 studies, 596 participants; low certainty), and may lead to endoscopic improvement, measured continuously (SMD 1.33, 95% CI 0.59 to 2.08; 5 studies, 596 participants; low certainty). Corticosteroids may lead to slightly fewer withdrawals due to adverse events (RR 0.64, 95% CI 0.43 to 0.96; 14 studies, 1032 participants; low certainty). Nine studies compared biologics to placebo for induction of remission. Biologics may result in little to no difference in clinical improvement, measured dichotomously (RR 1.14, 95% CI 0.85 to 1.52; 5 studies, 410 participants; low certainty), and may result in better clinical improvement, measured continuously (SMD 0.50, 95% CI 0.22 to 0.78; 7 studies, 387 participants; moderate certainty). Biologics result in better histological improvement (55% higher), measured dichotomously (RR 6.73, 95% CI 2.58 to 17.52; 8 studies, 925 participants; NNTB = 2; moderate certainty). We could not draw conclusions for this outcome when measured continuously (SMD 1.01, 95% CI 0.36 to 1.66; 6 studies, 370 participants; very low certainty). Biologics may result in little to no difference in endoscopic improvement, measured dichotomously (effect not estimable, low certainty). We cannot draw conclusions for this outcome when measured continuously (SMD 2.79, 95% CI 0.36 to 5.22; 1 study, 11 participants; very low certainty). There may be no difference in withdrawals due to adverse events (RR 1.55, 95% CI 0.88 to 2.74; 8 studies, 792 participants; low certainty).
AUTHORS' CONCLUSIONS
Corticosteroids (as compared to placebo) may lead to clinical symptom improvement when reported both as dichotomous and continuous outcomes, from the primary study definitions. Corticosteroids lead to a large increase in histological improvement (dichotomous outcome) and may increase histological improvement (continuous outcome) when compared to placebo. Corticosteroids may or may not increase endoscopic improvement (depending on whether the outcome is measured dichotomously or continuously). Withdrawals due to adverse events (dichotomous outcome) may occur less frequently when corticosteroids are compared to placebo. Biologics (as compared to placebo) may not lead to clinical symptom improvement when reported as a dichotomous outcome and may lead to an increase in clinical symptom improvement (as a continuous outcome), from the primary study definitions. Biologics lead to a large increase in histological improvement when reported as a dichotomous outcome, but this is uncertain when reported as a continuous outcome, as compared to placebo. Biologics may not increase endoscopic improvement (dichotomous outcome), but this is uncertain when measured as a continuous outcome. Withdrawals due to adverse events as a dichotomous outcome may occur as frequently when biologics are compared to placebo.
Topics: Adult; Child; Humans; Adrenal Cortex Hormones; Biological Products; Chronic Disease; Eosinophilic Esophagitis; Proton Pump Inhibitors; Remission Induction; Randomized Controlled Trials as Topic
PubMed: 37470293
DOI: 10.1002/14651858.CD004065.pub4 -
European Journal of Human Genetics :... Mar 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.
Topics: Humans; Antipsychotic Agents; Aripiprazole; Clopenthixol; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Drug Interactions; Haloperidol; Olanzapine; Pharmacogenetics; Pimozide; Quetiapine Fumarate; Quinolones; Risperidone; Thiophenes
PubMed: 37002327
DOI: 10.1038/s41431-023-01347-3 -
Pharmacology Research & Perspectives Dec 2023Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims... (Review)
Review
Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.
Topics: Humans; Child; Pharmacogenetics; Health Knowledge, Attitudes, Practice; Health Personnel; Medical Oncology; Neoplasms
PubMed: 38013228
DOI: 10.1002/prp2.1150 -
Neuroscience and Biobehavioral Reviews Dec 2023Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing... (Meta-Analysis)
Meta-Analysis Review
Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing NAD remains challenging due to the lack of established biomarkers. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with NAD and healthy controls. Our meta-analyses indicated that TMS neurophysiological examinations revealed decreased glutamatergic function in patients with frontotemporal dementia (FTD) and decreased GABAergic function in patients with FTD, progressive supranuclear palsy, Huntington's disease, cortico-basal syndrome, and multiple system atrophy-parkinsonian type. In addition, decreased cholinergic function was found in dementia with Lewy body and vascular dementia. These results suggest the potential of TMS as an additional diagnostic tool to differentiate NAD.
Topics: Humans; Transcranial Magnetic Stimulation; Frontotemporal Dementia; Neurodegenerative Diseases; NAD; Alzheimer Disease; Cholinergic Agents; Neural Inhibition; Evoked Potentials, Motor
PubMed: 37926239
DOI: 10.1016/j.neubiorev.2023.105451 -
European Neuropsychopharmacology : the... Jul 2023Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal... (Meta-Analysis)
Meta-Analysis
Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.
Topics: Humans; Selegiline; Depressive Disorder, Major; Monoamine Oxidase Inhibitors; Attention Deficit Disorder with Hyperactivity; Methylphenidate
PubMed: 37087864
DOI: 10.1016/j.euroneuro.2023.03.012 -
Journal of Personalized Medicine Jun 2023This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota... (Review)
Review
This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction.
PubMed: 37511699
DOI: 10.3390/jpm13071086 -
Research in Social & Administrative... Nov 2023The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare... (Review)
Review
BACKGROUND
The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare professionals is the most frequently cited barrier to adopting and implementing pharmacogenomics in clinical settings.
OBJECTIVES
This study aimed to critically evaluate and determine the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice.
METHODS
Four electronic databases were searched: MEDLINE, EMBASE, CENTRAL, and PsycINFO. Studies on pharmacogenomics educational interventions for health care professionals and students with pre- and post-intervention assessments and results were included. No restrictions were placed on time, language, or educational contexts. The educational outcomes measured include both objective and subjective outcomes. The pharmacogenomics competency domains used to judge educational interventions are based on the competency domains listed by the American Association of Colleges of Pharmacies (AACP). The National Heart, Lung, and Blood Institute of the National Institutes of Health was used for the quality assessment of pre-post studies with no control group and the controlled intervention studies. No meta-analysis was conducted; the data were synthesized qualitatively. The systematic review was reported in accordance with the PRISMA statement.
RESULTS
Fifty studies were included in this review. All included studies integrated the AACP pharmacogenomics competency domains into their educational interventions. Most of the studies had educational interventions that integrated clinical cases (n = 44; 88%). Knowledge was the most frequently evaluated outcome (n = 34; 68%) and demonstrated significant improvement after the educational intervention that integrated AACP pharmacogenomics competency domains and employed active learning with clinical case inclusion.
CONCLUSION
This review provided evidence of the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice. Incorporating pharmacogenomics competency domains into education and training, with patient cases for healthcare professionals and students, dramatically improved their pharmacogenomics knowledge, attitudes, and confidence in practice.
Topics: Humans; Pharmacogenetics; Students; Health Personnel; Educational Status; Delivery of Health Care
PubMed: 37586945
DOI: 10.1016/j.sapharm.2023.07.012 -
Clinical Gastroenterology and... Nov 2023Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists.
METHODS
Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence.
RESULTS
On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I = 0%) (moderate certainty evidence).
CONCLUSION
Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.
Topics: Humans; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor Inhibitors; Immunomodulating Agents; Genotype
PubMed: 37061107
DOI: 10.1016/j.cgh.2023.03.044 -
Pharmacogenomics Jul 2023Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations.... (Review)
Review
Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations. Studies have demonstrated the efficacy of sirolimus for this disease. Studies in kidney transplant patients suggest that genetic variants can influence these pharmacokinetic parameters. Therefore, a systematic literature search was performed to gain insight into pharmacogenetic studies with sirolimus. Most studies investigated and , with inconsistent results. No pharmacogenetic studies focusing on sirolimus have been performed for low-flow vascular malformations. We analyzed two common variants of and ( and , respectively) in patients (n = 59) with congenital low-flow vascular malformations treated with sirolimus. No association with treatment outcome was identified in this small cohort of patients.
Topics: Humans; Sirolimus; Cytochrome P-450 CYP3A; Polymorphism, Single Nucleotide; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus; Genotype
PubMed: 37551646
DOI: 10.2217/pgs-2022-0147 -
Clinical and Translational Science Dec 2023Clinical implementation of pharmacogenomic (PGx)-guided prescribing in oncology lags behind research evidence generation. We aimed to identify healthcare professionals'... (Review)
Review
Clinical implementation of pharmacogenomic (PGx)-guided prescribing in oncology lags behind research evidence generation. We aimed to identify healthcare professionals' (HCPs) and consumers' knowledge, attitudes, perspectives, and education needs to inform strategies for implementation of scalable and sustainable oncology PGx programs. Systematic review of original articles indexed in EMBASE, EMCARE, MEDLINE, and PsycInfo from January 2012 until June 2022, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and using the Mixed Methods Appraisal Tool. PROSPERO registration number CRD42022352348. Of 1442 identified studies; 23 met inclusion criteria with 87% assessed high quality. Of these, 52% reported on HCPs, 35% on consumers, and 13% on both HCPs and consumers. Most were conducted in the United States (70%) and included multiple cancer types (74%). Across studies, HCPs and consumers mostly perceived value in PGx, however, both groups reported barriers to utilization, including cost, lack of consistent recommendations across guidelines, and limited knowledge among HCPs; test accuracy, clear testing benefits, and genomic information confidentiality among consumers. HCPs and consumers value and want to engage in PGx strategies in oncology care, however, are inhibited by unmet needs and practice and knowledge gaps. Implementation strategies aimed at addressing these issues may best support increased PGx uptake in oncology practice.
Topics: Humans; Pharmacogenetics; Health Knowledge, Attitudes, Practice; Health Personnel; Medical Oncology; Neoplasms
PubMed: 37991131
DOI: 10.1111/cts.13672