Drug-target-ADR Network and Possible Implications of Structural Variants in Adverse Events.
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ABSTRACT:
SUBMITTER: Dafniet B
PROVIDER: S-EPMC8047896 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human leukocyte antigens (HLA) are an important family of genes involved in the immune system. Their primary function is to allow the host immune system to be able to distinguish between self and non-self peptides-e.g. derived from invading pathogens. However, these genes have also been implicated in immune-mediated adverse drug reactions (ADRs), presenting a problem to patients, clinicians and pharmaceutical companies. We have previously developed the Allele Frequency Net Database (AFND) that captures the allelic and haplotype frequencies for these HLA genes across many healthy populations from around the world. Here, we report the development and release of the HLA-ADR database that captures data from publications where HLA alleles and haplotypes have been associated with ADRs (e.g. Stevens-Johnson Syndrome/toxic epidermal necrolysis and drug-induced liver injury). HLA-ADR was created by using data obtained through systematic review of the literature and semi-automated literature mining. The database also draws on data already present in AFND allowing users to compare and analyze allele frequencies in both ADR patients and healthy populations. The HLA-ADR database provides clinicians and researchers with a centralized resource from which to investigate immune-mediated ADRs.Database URL: http://www.allelefrequencies.net/hla-adr/.
| S-EPMC5647400 | biostudies-literature
Project description:Adverse drug reactions (ADRs) are caused by interactions between drugs or their metabolites and specific proteins. Knowledge of these proteins is important for facilitating mechanistic research of ADRs and new drug discovery. Here, we identified 41 network modules from an ADR-protein network; analysed the function of each module; revealed the potential accompanying actions of the ADRs and the new ADR-related proteins (ADRPs) to a unique ADR and studied the characteristics of composition, subcellular location and tissue distribution of these ADRPs by comparing them with drug-related proteins (DRPs). The results indicated that ADRs are mainly caused by risk drug-related proteins (RDRPs) and that drug off-target effects are a secondary cause. Biological processes that enzymes involve are the main reason for the occurrence of ADRs. However, drug-related transporters have a higher risk of inducing ADRs than drug-related enzymes do, and ADRPs locating in the cell membrane tend to induce multiple ADRs.
| S-EPMC3638162 | biostudies-literature
Project description:The level of attrition on drug discovery, particularly at advanced stages, is very high due to unexpected adverse drug reactions (ADRs) caused by drug candidates, and thus, being able to predict undesirable responses when modulating certain protein targets would contribute to the development of safer drugs and have important economic implications. On the one hand, there are a number of databases that compile information of drug-target interactions. On the other hand, there are a number of public resources that compile information on drugs and ADR. It is therefore possible to link target and ADRs using drug entities as connecting elements. Here, we present T-ARDIS (Target-Adverse Reaction Database Integrated Search) database, a resource that provides comprehensive information on proteins and associated ADRs. By combining the information from drug-protein and drug-ADR databases, we statistically identify significant associations between proteins and ADRs. Besides describing the relationship between proteins and ADRs, T-ARDIS provides detailed description about proteins along with the drug and adverse reaction information. Currently T-ARDIS contains over 3000 ADR and 248 targets for a total of more 17 000 pairwise interactions. Each entry can be retrieved through multiple search terms including target Uniprot ID, gene name, adverse effect and drug name. Ultimately, the T-ARDIS database has been created in response to the increasing interest in identifying early in the drug development pipeline potentially problematic protein targets whose modulation could result in ADRs. Database URL: http://www.bioinsilico.org/T-ARDIS.
| S-EPMC8533369 | biostudies-literature
Project description:BACKGROUND:Drug-related adverse events (AEs) are reported to be common amongst patients receiving outpatient parenteral antimicrobial therapy (OPAT). However, comparative data regarding intravenous (iv) catheter-related AEs are lacking. OBJECTIVES:To compare drug- and iv catheter-related AEs from a large UK OPAT centre. PATIENTS AND METHODS:We reviewed 544 OPAT episodes [median (IQR) age: 57 (39-71) years, 60% male, 13% with diabetes] with a median (IQR) duration of 7 (2-18) days. Clinically significant drug- and iv catheter-related AEs were calculated as a percentage of OPAT episodes with an AE and also as AEs per 1000 iv drug/catheter days. RESULTS:Drug-related AEs complicated 13 (2.4%) OPAT episodes at 1.7 (95% CI 0.9-2.9) per 1000 drug days. Catheter-related AEs occurred more frequently, complicating 32 (5.9%) episodes at 5.7 (95% CI 4.2-7.9) per 1000 iv catheter days (χ2 test for difference in AE rate: P < 0.001). Non-radiologically guided midline catheters were associated with the most frequent AEs (n = 23) at 15.6 (95% CI 10.3-23.4) per 1000 iv catheter days compared with other types of iv catheters (HR 8.4, 95% CI 2.4-51.9, P < 0.004), and self-administration was associated with a higher rate of catheter-related AEs at 12.0 (95% CI 6.0-23.9) per 1000 iv catheter days (HR 4.15, 95% CI 1.7-9.1, P = 0.007). CONCLUSIONS:Clinically significant iv catheter-related AEs occurred more frequently than drug-related AEs, especially when using non-radiologically guided midline catheters. Regular review of the need for iv therapy and switching to oral antimicrobials when appropriate is likely to minimize OPAT-related AEs.
| S-EPMC6376853 | biostudies-other
Project description:BackgroundPharmacokinetics and pharmacodynamics of drugs in elderly individuals differ from those in younger adults; thus, adverse drug events (ADEs) are common in older patients with polypharmacy because co-existing comorbidities elevate the risk of ADEs occurring. However, ADEs have not yet been characterised based on the elderly patients of Japanese origin and polypharmacy.ObjectiveThe 100 most commonly reported ADEs were grouped into four classes (Class 1-Class 4) based on elderly patients with polypharmacy.Patients and methodsIn this study, logistic regression analysis was performed using cases recorded in the Japanese Adverse Drug Event Report (JADER) database.ResultsADEs in elderly patients treated with polypharmacy-in whom the risk of electrolyte abnormalities, renal and respiratory disorders, and coagulopathy was high-were categorised as 'Class 1 [E(+), P(+)]', while ADEs in elderly patients not treated with polypharmacy-in whom the risk of delirium and fall was high-were categorised as 'Class 2 [E(+), P(-)]'. When there was no association with being elderly, ADEs associated with polypharmacy that carried a high risk of myelosuppression and infection were categorised as 'Class 3 [E(-), P(+)]', and allergic ADEs that were not affected by being elderly or polypharmacy, were categorised as 'Class 4 [E(-), P(-)]'. Class 1 events as well as Class 3 ADEs occurred more frequently in females than in males, whereas Class 3 ADEs (deep vein thrombosis and pulmonary embolism) occurred more frequently in males.ConclusionsClass 1 and Class 2 ADEs should be investigated in analyses that focus on individual drugs.
| S-EPMC7984209 | biostudies-literature
Project description:Inappropriate prescribing (IP) in older patients is highly prevalent and is associated with an increased risk of adverse drug events (ADEs), morbidity, mortality and healthcare utilisation. Consequently, IP is a major safety concern and with changing population demographics, it is likely to become even more prevalent in the future. IP can be detected using explicit or implicit prescribing indicators. Theoretically, the routine clinical application of these IP criteria could represent an inexpensive and time efficient method to optimise prescribing practice. However, IP criteria must be sensitive, specific, have good inter-rater reliability and incorporate those medications most commonly associated with ADEs in older people. To be clinically relevant, use of prescribing appropriateness tools must translate into positive patient outcomes, such as reduced rates of ADEs. To accurately measure these outcomes, a reliable method of assessing the relationship between the administration of a drug and an adverse clinical event is required. The Naranjo criteria are the most widely used tool for assessing ADE causality, however, they are often difficult to interpret in the context of older patients. ADE causality criteria that allow for the multiple co-morbidities and prescribed medications in older people are required. Ultimately, the current high prevalence of IP and ADEs is unacceptable. IP screening criteria need to be tested as an intervention to assess their impact on the incidence of ADEs in vulnerable older patients. There is a role for IP screening tools in everyday clinical practice. These should enhance, not replace good clinical judgement, which in turn should be based on sound pharmacogeriatric training.
| S-EPMC2642820 | biostudies-other
Project description:Adverse drug events are unintended and harmful events related to medications. Adverse drug events are important for patient care, quality improvement, drug safety research, and postmarketing surveillance, but they are vastly underreported.Our objectives were to identify barriers to adverse drug event documentation and factors contributing to underreporting.This qualitative study was conducted in 1 ambulatory center, and the emergency departments and inpatient wards of 3 acute care hospitals in British Columbia between March 2014 and December 2016. We completed workplace observations and focus groups with general practitioners, hospitalists, emergency physicians, and hospital and community pharmacists. We analyzed field notes by coding and iteratively analyzing our data to identify emerging concepts, generate thematic and event summaries, and create workflow diagrams. Clinicians validated emerging concepts by applying them to cases from their clinical practice.We completed 238 hours of observations during which clinicians investigated 65 suspect adverse drug events. The observed events were often complex and diagnosed over time, requiring the input of multiple providers. Providers documented adverse drug events in charts to support continuity of care but never reported them to external agencies. Providers faced time constraints, and reporting would have required duplication of documentation.Existing reporting systems are not suited to capture the complex nature of adverse drug events or adapted to workflow and are simply not used by frontline clinicians. Systems that are integrated into electronic medical records, make use of existing data to avoid duplication of documentation, and generate alerts to improve safety may address the shortcomings of existing systems and generate robust adverse drug event data as a by-product of safer care.
| S-EPMC5849794 | biostudies-other
Project description:Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.
| S-EPMC8720925 | biostudies-literature
Project description:Objectives: Remdesivir has shown promise in the management of patients with COVID-19 although recent studies have shown concerns with its effectiveness in practice. Despite this there is a need to document potential adverse drug events (ADEs) to guide future decisions as limited ADE data available before the COVID-19 pandemic. Methods: Interrogation of WHO VigiBase® from 2015 to 2020 coupled with published studies of ADEs in COVID-19 patients. The main outcome measures are the extent of ADEs broken down by factors including age, seriousness, region and organ. Results: A total 1086 ADEs were reported from the 439 individual case reports up to July 19, 2020, in the VigiBase®, reduced to 1004 once duplicates were excluded. Almost all ADEs concerned COVID-19 patients (92.5%), with an appreciable number from the Americas (67.7%). The majority of ADEs were from males > 45 years and were serious (82.5%). An increase in hepatic enzymes (32.1%), renal injury (14.4%), rise in creatinine levels (11.2%), and respiratory failure (6.4%) were the most frequently reported ADEs. Conclusions: Deterioration of liver and kidney function are frequently observed ADEs with remdesivir; consequently, patients should be monitored for these ADEs. The findings are in line with ADEs included in regulatory authority documents.
| S-EPMC7784780 | biostudies-literature
Project description:Background and objectivesThe impact of AKI on adverse drug events and therapeutic failures and the medication errors leading to these events have not been well described.Design, setting, participants, & measurementsA single-center observational study of 396 hospitalized patients with a minimum 0.5 mg/dl change in serum creatinine who were prescribed a nephrotoxic or renally eliminated medication was conducted. The population was stratified into two groups by the direction of their initial serum creatinine change: AKI and AKI recovery. Adverse drug events, potential adverse drug events, therapeutic failures, and potential therapeutic failures for 148 drugs and 46 outcomes were retrospectively measured. Events were classified for preventability and severity by expert adjudication. Multivariable analysis identified medication classes predisposing AKI patients to adverse drug events.ResultsForty-three percent of patients experienced a potential adverse drug event, adverse drug event, therapeutic failure, or potential therapeutic failure; 66% of study events were preventable. Failure to adjust for kidney function (63%) and use of nephrotoxic medications during AKI (28%) were the most common potential adverse drug events. Worsening AKI and hypotension were the most common preventable adverse drug events. Most adverse drug events were considered serious (63%) or life-threatening (31%), with one fatal adverse drug event. Among AKI patients, administration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antibiotics, and antithrombotics was most strongly associated with the development of an adverse drug event or potential adverse drug event.ConclusionsAdverse drug events and potential therapeutic failures are common and frequently severe in patients with AKI exposed to nephrotoxic or renally eliminated medications.
| S-EPMC3700703 | biostudies-literature