Severe adverse reactions prompt call for trial design changes.
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ABSTRACT:
SUBMITTER: Mayor S
PROVIDER: S-EPMC1410899 | biostudies-literature | 2006 Mar
REPOSITORIES: biostudies-literature
Publications
Severe adverse reactions prompt call for trial design changes.
BMJ (Clinical research ed.) 20060301 7543
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Project description:ObjectivesA new method of HLA-B*5801 genotyping was compared with sequence-based typing (SBT) to find an accurate and prompt method in genotyping HLA-B*5801.MethodsTwo groups of patients from allopurinol-induced cutaneous adverse reactions (SCARs) and allopurinol-tolerant were both genotyped with PG5801 kit and SBT method. The genotyping results of HLA-B*5801 were compared between the two groups.ResultsThe PG5801 detection kit results were 100% (79/79) in agreement with the SBT genotyping results for identifying the HLA-B*5801 (+) patients. No false-positive or false-negative errors were found. The sensitivity, specificity, rate of adherence, positive predictive value (PPV) and negative predictive value (NPV) were 100%.ConclusionThe potential fast screening method is an ideal tool to rule out the high-risk allopurinol-induced SCARs patients.
| S-EPMC5351112 | biostudies-literature
Project description:BACKGROUND:Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. METHODS:We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. RESULTS:Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS:The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION:ClinicalTrials.gov NCT01276314. FUNDING:Ministry of Science and Technology of Taiwan.
| S-EPMC5824923 | biostudies-literature
Project description:Severe cutaneous adverse reactions (SCAR) are rare but life-threatening drug reactions mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T-cells. To obtain an unbiased assessment of SCAR cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing (5' scRNA-TCR-CITE-seq, 10x Genomics) on unaffected skin, affected skin, and blister fluid from diverse SCAR patients.
2024-09-18 | GSE275871 | GEO
Project description:BackgroundCurrently, there is limited information on the intervention efficacy for children with speech motor delay (SMD). This randomized control trial (RCT) study examined the effectiveness of Prompts for Restructuring Oral Muscular Phonetic Targets (PROMPT) intervention to improve the outcomes in children with SMD. We hypothesized that children with SMD receiving PROMPT intervention would improve more in the measured outcomes than those waitlisted and receiving home training.MethodsUsing a two-arm, parallel group, RCT, 49 children with SMD were allocated to either an intervention group (N = 24) that received 45 min of PROMPT intervention two times a week for 10 weeks or were waitlisted for the same duration and received only home training instructions (N = 25). Outcome measures for speech motor control, articulation, speech intelligibility (word and sentence levels), and functional communication were assessed at baseline and at a 10-week follow-up.ResultsPROMPT intervention was associated with notable improvements in speech motor control, speech articulation, and word-level speech intelligibility. Intervention allocation yielded weak improvements in sentence-level speech intelligibility and functional communication.ConclusionsPROMPT intervention is a clinically effective intervention approach for children with SMD.ImpactCurrently, there is limited information on the intervention efficacy for children with SMD. We report on the findings of a phase III intervention efficacy study on children with SMD using an RCT design. PROMPT intervention is a clinically effective intervention approach for children with SMD. Results of the study will be fundamental to the delivery of effective services for this population. These findings may facilitate the development of an evidence-based care pathway for children with severe speech sound disorders.
| S-EPMC7979536 | biostudies-literature
Project description:PurposeAnti-tuberculosis drugs (ATDs) can cause severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Underlying tuberculous infection and co-administration of multiple drugs may contribute to the complexity of ATD-related SCARs. This study aimed to investigate the clinical characteristics and outcomes of ATD-related SCARs.MethodsWe analyzed ATD-related SCAR cases in 2010-2015, selected from a web-based Database of the Korean Registry of SCAR.ResultsAmong 783, 53 patients with ATD-induced SCARs were enrolled, including 12 with SJS/TEN (22.6%) and 41 with DRESS (77.4%). When comparing the ATD and non-ATD groups, the prevalence of DRESS patients was higher in the ATD group than in the non-ATD group (77.4% vs. 45.8%, P < 0.001). Among patients with ATD-related SCARs, those with SJS/TEN were significantly older, had higher intensive care unit admissions, and had higher mortality than those with DRESS (70.5 vs. 50.0 years, P < 0.001; 41.7% vs. 6.1%, P = 0.010; and 33.3% vs. 2.5%, P = 0.003, respectively). ATDs were challenged in 14 cases. The ATD associated most often with SCAR cases was rifampin (81.8%), followed by isoniazid (66.7%), ethambutol (50.0%), pyrazinamide (33.3%). Six patients (42.9%) had hypersensitivity reactions to 2 or more drugs.ConclusionsDRESS was more common among the ATD-related SCAR cases. Although treatment with most ATDs carries the risk of SCAR development, the use of rifampin was most frequently involved in the occurrence of SCARs. Multiple hypersensitivity was frequently observed in ATD-related SCARs.
| S-EPMC7840880 | biostudies-literature
Project description:Molecular-targeted drugs specifically interfere with molecules that are frequently overexpressed or mutated in cancer cells. As such, these drugs are generally considered to precisely attack cancer cells, thereby inducing fewer adverse drug reactions (ADRs). However, molecular-targeted drugs can still cause characteristic ADRs that, although rarely severe, can be life-threatening. Therefore, it is becoming increasingly important to be able to predict which patients are at risk of developing ADRs after treatment with molecular-targeted therapy. The emerging field of pharmacogenetics aims to better distinguish the genetic variants associated with drug toxicity and efficacy to improve the selection of therapeutic strategies for each genetic profile. Here, we provide an overview of the current reports on the relationship between genetic variants and molecular-targeted drug-induced severe ADRs in oncology.
| S-EPMC7540972 | biostudies-literature
Project description:IntroductionSevere cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand.Methods and analysisAdult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data.Ethics and disseminationThis study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619000241134).
| S-EPMC9389100 | biostudies-literature
Project description:Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.
| S-EPMC6687717 | biostudies-literature
Project description:Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS) cause significant morbidity and mortality and impede new drug development. HLA class I associations with SJS/TEN and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome have aided preventive efforts and provided insights into immunopathogenesis. In SJS/TEN, HLA class I-restricted oligoclonal CD8+ T-cell responses occur at the tissue level. However, specific HLA risk allele(s) and antigens driving this response have not been identified for most drugs. HLA risk alleles also have incomplete positive and negative predictive values, making truly comprehensive screening currently challenging. Although, there have been key paradigm shifts in knowledge regarding drug hypersensitivity, there are still many open and unanswered questions about SCAR immunopathogenesis, as well as genetic and environmental risk. In addition to understanding the cellular and molecular basis of SCAR at the single-cell level, identification of the MHC-restricted drug-reactive self- or viral peptides driving the hypersensitivity reaction will also be critical to advancing premarketing strategies to predict risk at an individual and drug level. This will also enable identification of biologic markers for earlier diagnosis and accurate prognosis, as well as drug causality and targeted therapeutics.
| S-EPMC9976545 | biostudies-literature
Project description:PurposeNonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry.MethodsA retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids.ResultsA total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals.ConclusionsThe present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.
| S-EPMC6340804 | biostudies-literature