Developing and Evaluating the Greenness of a Reliable, All-in-One Thin-Film Microextraction Protocol for Determining Fentanyl, Methadone, and Zolpidem in Plasma, Urine, and Oral Fluid.

This paper proposes an all-in-one microextraction-based protocol capable of determining and quantifying fentanyl, methadone, and zolpidem in plasma, urine, and saliva at concentrations below those required by international regulatory organizations. A homemade thin-film microextraction device featuring an octyl-cyanopropyl stationary phase was coupled with LC-MS/MS. The proposed method was developed and validated according to FDA criteria, providing extraction efficiency values ranging from 26.7% to 76.2% with no significant matrix effects (2.6% to 15.5% signal suppression). The developed protocol provided low limits of quantification (mostly equal to 1 ng mL-1) and good reproducibility (intra- and inter-day RSDs of less than 9.6% and 12.0%, respectively) and accuracy (89% to 104% of the test concentration). An assessment of the protocol's environmental impact indicated that attention must be devoted to eliminating the use of toxic reagents and developing its capability for in situ sampling and in-field analysis using portable instruments. The proposed TFME-based protocol provides clinical laboratories with a versatile, one-step tool that enables the simultaneous monitoring of fentanyl, methadone, and zolpidem using the most popular biological matrices.

Prevalence and predictors of inappropriate dosing of direct oral anticoagulants.

BACKGROUND: Information on inappropriate dosing of direct oral anticoagulants (DOACs) is scarce in the Australian context. AIM: To describe the prevalence and potential predictors of inappropriate dosing of DOACs. METHODS: Patients who received DOACs during admission under a general medical unit over a 2-year period (from January 2017 to December 2018) were retrospectively studied. Appropriateness of the dosing regimen was verified against the recommendations of the Therapeutic Goods Administration of Australia. Data were obtained from medical records and analysed in univariate and multivariate logistic regression models. The variables associated with under- and overdosing were also determined. RESULTS: A total of 203 (mean age 71.6 ± 14.5 years, females 52%) patients were studied. Inappropriate dosing occurred in 44 (22%) patients: underdosing 27 (13%) and overdosing 17 (8%). Age ≥75 years (P < 0.01), lower estimated creatinine clearance (CrCl) (P < 0.01), prescription of DOAC prior to index admission (P < 0.01) and higher Charlson Comorbidity Index (P < 0.01), HAS-BLED (P < 0.01) and CHA2 DS2 -VASc (P < 0.01) scores had a significant univariate association with inappropriate dosing. However, in the multivariate logistic regression only lower CrCl (odds ratio (OR) 1.04, 95% confidence interval (CI): 1.01-1.07, P < 0.01) and prescription of DOAC prior to index admission (OR 2.62, 95% CI: 1.01-6.75, P = 0.047) remained significantly associated with inappropriate dosing. Impaired renal function also had a significant association with underdosing (OR 1.04, 95% CI: 1.01-1.07, P = 0.01) and borderline significance with overdosing (OR 1.03, 95% CI: 1.00-1.07, P = 0.06). CONCLUSION: Inappropriate dosing of DOACs, especially underdosing, is common in clinical practice. Clinicians should exercise due diligence when prescribing DOACs to patients with renal impairment and in outpatient settings.

A hybrid design for dose-finding oncology clinical trials.

Identifying the maximum tolerated dose (MTD) and recommending a Phase II dose for an investigational treatment is crucial in cancer drug development. A suboptimal dose often leads to a failed late-stage trial, while an overly toxic dose causes harm to patients. There is a very rich literature on trial designs for dose-finding oncology clinical trials. We propose a novel hybrid design that maximizes the merits and minimizes the limitations of the existing designs. Building on two existing dose-finding designs: a model-assisted design (the modified toxicity probability interval) and a dose-toxicity model-based design, a hybrid design of the modified toxicity probability interval design and a dose-toxicity model such as the logistic regression model is proposed, incorporating optimal properties from these existing approaches. The performance of the hybrid design was tested in a real trial example and through simulation scenarios. The hybrid design controlled the overdosing toxicity well and led to a recommended dose closer to the true MTD due to its ability to calibrate for an intermediate dose. The robust performance of the proposed hybrid design is illustrated through the real trial dataset and simulations. The simulation results demonstrated that the proposed hybrid design can achieve excellent and robust operating characteristics compared to other existing designs and can be an effective model for determining the MTD and recommended Phase II dose in oncology dose-finding trials. For practical feasibility, an R-shiny tool was developed and is freely available to guide clinicians in every step of the dose finding process.

Psychological therapies and non-suicidal self-injury in LGBTIQ in accident and emergency departments in the UK: a scoping review.

BACKGROUND: To identify psychological interventions that improve outcomes for those who overdose, especially amongst Lesbian, Gay, Bisexual, Transgender, Intersex and Questioning populations. OBJECTIVE: To recognize and assess the results from all studies including randomized control trials (RCTs) that have studied the efficiency of psychiatric and psychological assessment of people who have depression that undergo non-suicidal self-injury (NSSI) by self-poisoning, presenting to UK Accident and Emergency Departments. METHOD: A scoping review of all studies including RCTs of psychiatric and psychological therapy treatments. Studies were selected according to types of engagement and intervention received. All studies including RCTs available in databases since 1998 in the Wiley version of the Cochrane controlled trials register in 1998 till 2021, Psych INFO, Medline, Google Scholar and from manually searching of journals were included. Studies that included information on repetition of the NSSI behaviour were also included. Altogether this amounts to 3900 randomized study participants with outcome data. RESULTS: Seven trials reported repetition of NSSI as an outcome measure which were classified into four categories. Problem-solving therapy is indicated as a promising therapy and has shown to significantly reduce repetition in participants who NSSI by overdosing than patients in the control treatment groups consisting of standard after care. CONCLUSION: The data show that manualized cognitive therapy psychological intervention was more effective than TAU after care. However, these differences are not statistically significant with p = .15; CI 0.61, 1.0 which crosses the line of no effect. And psychodynamic interpersonal therapy is more effective than the standard treatment. Despite being only one study in this subgroup the analysis shows a statistical significance with p = .009, CI 0.08; 0.7.

Assessing dosing errors in legacy and low dose tip ENFit® syringes.

WHAT IS KNOWN AND OBJECTIVE: To avoid misconnections between different medical devices, a unique standardized design of connectors (ENFit® ) for enteral medical devices has been developed. It was expected that the syringes with these connectors will replace the pre-existing syringes, henceforth referred to as legacy syringes. However, the changes in the connector's design led to concerns regarding dosing errors for low volume syringes (≤2 ml). Therefore, novel low dose tip (LDT) syringes were designed to address these concerns. These LDT syringes can connect with the standardized ENFit® male connectors. Only a few studies have investigated dosing errors, and findings have largely been mixed. The objective of this report was to calculate the contributions of unavoidable dosing errors for LDT syringes, compare with legacy syringes and to suggest strategies to optimize dose accuracy for enteral applications. METHODS: Studies performed with a limited number of syringes to date may not reflect the actual diversity of dosing error that can occur across syringe orientations, batches, manufacturers, medications, etc. A computer-aided design software SolidWorks® was used to calculate the dosing errors in 0.5 and 1.0 ml legacy syringe connectors and were compared with dosing errors in LDT syringe connectors with the same nominal volume. Influence of orientation during delivery, spillage and flushing on dosing error was also investigated. RESULTS AND DISCUSSION: For 0.5 and 1.0 ml LDT syringes, in absence of medication in the moat area, the maximum dosing error will be ±5% when delivering 100% of nominal volume, which is also equal to the dosing error in 0.5 and 1.0 ml slip tip legacy syringes. However, with medication present in moat area, and with syringe reused during flushing, the LDT dosing error can range from 1% to 18% and 28% to 35% for 1.0 and 0.5 ml syringes, respectively. The corresponding dosing error for legacy syringes would be when the same syringe is used for flushing or when syringe disengages pointing vertically up. The corresponding dosing errors for legacy syringes could range from -7 to 12% and -9% to 19% for 1.0 and 0.5 ml syringes, respectively. Dosing errors for legacy and LDT syringes increase as the nominal capacity of syringe reduces, or when the dose delivered is lower than the nominal capacity of the syringe. WHAT IS NEW AND CONCLUSION: For LDT syringes, dosing errors can be reduced by clearing the moat area of the syringe and by using a new syringe for flushing post-delivery of medication. For legacy syringes, dosing errors can be minimized by ensuring the female connector points up during disengagement from the syringe post-medication administration, and by using a new syringe for flushing.

A frightening giant QRS complex in a 3-months-old infant.

A 3-months-old infant was urgently admitted for drowsiness and lack of appetite started 24 h before. The ECG showed sinus rhythm with a prolonged AV interval (200 ms) and very large QRS complexes (280 ms) due to Flecainide overdosing following incorrectly administration for poor communication between parents resulted in both giving a dose to the infant. Flecainide serum level was 1.2µg/ml, confirming the diagnosis of an accidental drug intoxication. The patient started continue hydration with a close monitoring. Three hours later a significant narrowing of the QRS complex (150 ms) was observed, then over the following 24 h, the QRS almost completely normalized.

Paracetamol overdosing in a tertiary care hospital: implementation and outcome analysis of a preventive alert programme.

WHAT IS KNOWN AND OBJECTIVES: Paracetamol is a frequently used antipyretic and analgesic drug, but also a dose-dependent hepatotoxin. Unintentional paracetamol overdosing is a common medication error in hospitals. The present study aimed at (i) analysis of unintentional paracetamol overdosing in hospitalized patients; (ii) development, implementation and outcome analysis of an alert algorithm for the prevention of relevant paracetamol overdosing. METHODS: All patients who received paracetamol in a Swiss tertiary care hospital during 2011 to 2014 were analysed to detect cases of paracetamol overdosing in a local pharmacoepidemiological database. In 2014, an automated algorithm screened the hospital's electronic prescribing system for patients at risk of overdosing, followed by expert validation. When imminent relevant overdosing was confirmed, alerts were issued to prescribers. Relevance was defined as prescriptions that permitted repeated daily paracetamol exposure of ≥5 g. RESULTS AND DISCUSSION: From 2011 to 2013, relevant overdosing occurred in 11 patients (5-8 g/day for 3 to 5 days), which corresponds to 0·4 % of all patients exposed to any paracetamol overdosing (mean n = 988 per year). In 2014, alerts were issued by experts in 23 cases with subsequent changes to prescriptions in 21 (91·3 %) thereof. Although the occurrence of any paracetamol overdosing declined only marginally in 2014 (n = 914), no relevant overdosing occurred anymore. WHAT IS NEW AND CONCLUSION: Unintentional paracetamol overdosing was frequent but only a small fraction thereof was deemed relevant. This proof of concept study analysed local hospital data and developed a preventive system combining sensitive automated detection with subsequent specific expert validation. The resulting alerts achieved high compliance and prevented relevant paracetamol overdosing.

Development of a Real-Time Dashboard for Overdose Touchpoints: User-Centered Design Approach.

BACKGROUND: Overdose Fatality Review (OFR) is an important public health tool for shaping overdose prevention strategies in communities. However, OFR teams review only a few cases at a time, which typically represent a small fraction of the total fatalities in their jurisdiction. Such limited review could result in a partial understanding of local overdose patterns, leading to policy recommendations that do not fully address the broader community needs. OBJECTIVE: This study explored the potential to enhance conventional OFRs with a data dashboard, incorporating visualizations of touchpoints-events that precede overdoses-to highlight prevention opportunities. METHODS: We conducted 2 focus groups and a survey of OFR experts to characterize their information needs and design a real-time dashboard that tracks and measures decedents' past interactions with services in Indiana. Experts (N=27) were engaged, yielding insights on essential data features to incorporate and providing feedback to guide the development of visualizations. RESULTS: The findings highlighted the importance of showing decedents' interactions with health services (emergency medical services) and the justice system (incarcerations). Emphasis was also placed on maintaining decedent anonymity, particularly in small communities, and the need for training OFR members in data interpretation. The developed dashboard summarizes key touchpoint metrics, including prevalence, interaction frequency, and time intervals between touchpoints and overdoses, with data viewable at the county and state levels. In an initial evaluation, the dashboard was well received for its comprehensive data coverage and its potential for enhancing OFR recommendations and case selection. CONCLUSIONS: The Indiana touchpoints dashboard is the first to display real-time visualizations that link administrative and overdose mortality data across the state. This resource equips local health officials and OFRs with timely, quantitative, and spatiotemporal insights into overdose risk factors in their communities, facilitating data-driven interventions and policy changes. However, fully integrating the dashboard into OFR practices will likely require training teams in data interpretation and decision-making.

Users' Acceptability and Perceived Efficacy of mHealth for Opioid Use Disorder: Scoping Review.

BACKGROUND: The opioid crisis continues to pose significant challenges to global public health, necessitating the development of novel interventions to support individuals in managing their substance use and preventing overdose-related deaths. Mobile health (mHealth), as a promising platform for addressing opioid use disorder, requires a comprehensive understanding of user perspectives to minimize barriers to care and optimize the benefits of mHealth interventions. OBJECTIVE: This study aims to synthesize qualitative insights into opioid users' acceptability and perceived efficacy of mHealth and wearable technologies for opioid use disorder. METHODS: A scoping review of PubMed (MEDLINE) and Google Scholar databases was conducted to identify research on opioid user perspectives concerning mHealth-assisted interventions, including wearable sensors, SMS text messaging, and app-based technology. RESULTS: Overall, users demonstrate a high willingness to engage with mHealth interventions to prevent overdose-related deaths and manage opioid use. Users perceive mHealth as an opportunity to access care and desire the involvement of trusted health care professionals in these technologies. User comfort with wearing opioid sensors emerged as a significant factor. Personally tailored content, social support, and encouragement are preferred by users. Privacy concerns and limited access to technology pose barriers to care. CONCLUSIONS: To maximize benefits and minimize risks for users, it is crucial to implement robust privacy measures, provide comprehensive user training, integrate behavior change techniques, offer professional and peer support, deliver tailored messages, incorporate behavior change theories, assess readiness for change, design stigma-reducing apps, use visual elements, and conduct user-focused research for effective opioid management in mHealth interventions. mHealth demonstrates considerable potential as a tool for addressing opioid use disorder and preventing overdose-related deaths, given the high acceptability and perceived benefits reported by users.

The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations. MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]. RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90). CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Closed System Transfer Devices (CSTDs): Understanding Potential Over- and Under- Dosing of Liquid Vial Drug Products and How to Generally Mitigate.

Closed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs' performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP<1151> conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred.

Prevalence and risk of inappropriate dosing of direct oral anticoagulants in two Swiss atrial fibrillation registries.

BACKGROUND: Direct oral anticoagulants (DOACs) have a favourable risk-benefit profile compared to vitamin K-antagonists (VKAs) in atrial fibrillation (AF). Dosing is based on age, weight and renal function, without need of routine monitoring. METHODS AND RESULTS: In two prospective, multicentre AF cohorts (Swiss-AF, BEAT-AF) patients were stratified as receiving VKAs or adequately-, under- or overdosed DOACs, according to label. Primary outcome was a composite of major adverse clinical events (MACE), defined as cardiovascular death, myocardial infarction (MI), ischaemic stroke and systemic embolism. Secondary outcomes included major bleeding. Adjustment for confounding was performed. Median follow-up was 4 years. Of 3236 patients, 1875 (58%) were on VKAs and 1361 (42%) were on DOACs, of which 1137 (83%) were adequately-, 134 (10%) over- and 90 (7%) under-dosed. Compared to adequately dosed individuals, overdosed patients were more likely to be older and female. Underdosing correlated with concomitant aspirin therapy and coronary artery disease. Both groups had higher CHA2DS2-VASc scores. Patients on overdosed DOACs had higher incidence of MACE (HR 1.75; CI 1.10-2.79; adjusted-HR: 1.22) and major bleeding (HR 1.99; CI 1.14-3.48; adjusted-HR: 1.51). Underdosing was not associated with a higher incidence of MACE (HR 0.94; CI 0.46-1.92; adjusted-HR 0.61) or major bleeding (HR 1.07; CI 0.46-2.46; adjusted-HR 0.82). After adjustment, all CIs crossed 1.0. CONCLUSION: Inappropriate DOAC-dosing was more prevalent in multimorbid patients, but did not correlate with higher risks of adverse events after adjusting for confounders. DOAC prescription should follow label.

High Risk, High Dose?-Pharmacotherapeutic Prescription Patterns of Offender and Non-Offender Patients with Schizophrenia Spectrum Disorder.

Compared to acute or community settings, forensic psychiatric settings, in general, have been reported to make greater use of antipsychotic polypharmacy and/or high dose pharmacotherapy, including overdosing. However, there is a scarcity of research specifically on offender patients with schizophrenia spectrum disorders (SSD), although they make up a large proportion of forensic psychiatric patients. Our study, therefore, aimed at evaluating prescription patterns in offender patients compared to non-offender patients with SSD. After initial statistical analysis with null-hypothesis significance testing, we evaluated the interplay of the significant variables and ranked them in accordance with their predictive power through application of supervised machine learning algorithms. While offender patients received higher doses of antipsychotics, non-offender patients were more likely to receive polypharmacologic treatment as well as additional antidepressants and benzodiazepines. To the authors' knowledge, this is the first study to evaluate a homogenous group of offender patients with SSD in comparison to non-offender controls regarding patterns of antipsychotic and other psychopharmacologic prescription patterns.

Impact of a Forced Dose-Equivalent Levothyroxine Brand Switch on Plasma Thyrotropin: A Cohort Study.

Background: Patients with primary hypothyroidism are treated with levothyroxine (LT4) to normalize their serum thyrotropin (TSH). Finding the optimal dosage is a long-lasting process, and a small change can have major impact. Currently, limited data are available on the impact of dose-equivalent substitution between brands. This study aimed to determine the effect of the shortage of the LT4 brand Thyrax® in the Netherlands and the resulting dose-equivalent switch to another brand on plasma TSH concentrations in a large cohort of patients. Methods: Observational cohort study. Two registries representative for the Dutch population containing prescription and laboratory test data: the Nivel Primary Care Database and the PHARMO Database Network. Patients using at least 25 µg Thyrax daily for one year or longer were included. Two cohorts were formed: a switch cohort consisting of patients who switched from Thyrax to an alternative brand, and a Thyrax cohort including patients who continued to use Thyrax. Patients in the switch cohort did switch from Thyrax to a different brand of LT4 in 2016 and had two consecutive TSH measurements on the same dose of LT4, one before and one 6 weeks after the switch. Patients in the Thyrax cohort had two consecutive TSH measurements on the same dose of Thyrax that were 6 weeks apart. Results: In the Thyrax cohort, 19% of euthyroid patients using ≤100 µg had a TSH level outside the reference range at the subsequent measurement compared with 24% in the switch cohort (p < 0.0001). For patients using >100 µg Thyrax, these figures were 24% and 63%, respectively (p < 0.0001). Furthermore, patients using >50 µg Thyrax were four to five times more likely to become hyperthyroid after a dose-equivalent switch to a different brand compared with patients who stayed on Thyrax. Conclusions: In euthyroid patients continuing the LT4 product Thyrax at the same dose, TSH was out of range in 19-24% at least 6 weeks later. A dose-equivalent switch from Thyrax to other LT4 brands induced biochemical signs of overdosing in an even larger proportion (24-63%) of patients. The results indicate that a dose-equivalent LT4 brand switch may necessitate a dose adjustment in a large number of patients.

An HIV-infected Patient with No Serious Adverse Events after Overdosing on Raltegravir.

Patients with HIV infection represent a high-risk group for medication overdose because of the high frequency of complicating psychiatric disorders. Raltegravir is well-known for its low frequency of adverse effects. We herein report a 42-year-old Japanese man with HIV infection who was hospitalized 6 hours after overdosing with 24,000 mg of raltegravir in a suicide attempt. No serious adverse events occurred, although the plasma concentration of raltegravir at 18 hours after the overdose was 79,871.1 ng/mL. Raltegravir may be well-indicated for HIV patients at risk of overdosing.

Activated Clotting Time Monitoring during Atrial Fibrillation Catheter Ablation: Does the Anticoagulant Matter?

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs) with intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 s, as for vitamin K antagonist (VKA). We determined whether ACT monitoring might be transposed from VKA to DOAC-treated patients. Blood was taken from 124 patients receiving uninterrupted dabigatran, rivaroxaban, apixaban, or VKA or being untreated. DOAC concentration or INR (VKA) were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU in vivo. At baseline, anticoagulants prolonged ACT differently, ACT was longer with dabigatran and shorter with apixaban despite similar concentrations. ACT strongly correlated with INR and dabigatran concentration, but not with apixaban or rivaroxaban concentrations. Moreover, UFH effects on ACT prolongation depended on the anticoagulant: dose-response curves in samples with VKA and dabigatran were parallel whereas ACT prolongation in response to UFH was significantly smaller with rivaroxaban and especially apixaban. Therefore, UFH to achieve ACT at 300 s might be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa-inhibitors, especially apixaban. Targeting 300 s might expose to UFH overdosing and bleeding, questioning the current anticoagulation strategy.

Label Adherence of Direct Oral Anticoagulants Dosing and Clinical Outcomes in Patients With Atrial Fibrillation.

Background Dose adjustment of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in some patients with atrial fibrillation (AF), based on selected patient factors or concomitant medications. We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off-label NOAC dosing and clinical outcomes. Methods and Results We evaluated 53 649 AF patients treated with an NOAC using Korean National Health Insurance Service database during the period from 2013 to 2016. NOAC doses were classified as either underdosed or overdosed, consistent with Korea Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all-cause mortality. Overall, 16 757 NOAC-treated patients (31.2%) were underdosed, 4492 were overdosed (8.4%), and 32 400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (aged 71±8 and 75±7 years versus 70±9 years, respectively; P<0.001) and had higher CHA2DS2-VASc scores (4.6±1.7 and 5.3±1.7 versus 4.5±1.8, respectively; P<0.001). NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 versus 4.03 events/100 patient-years, P<0.001), major bleeding (4.77 versus 2.94 events/100 patient-years, P<0.001), and all-cause mortality (5.43 versus 3.05 events/100 patient-years, P<0.001) compared with label-adherent use. Conclusions In real-world practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with worse clinical outcomes in Asian AF patients.

Acute Methotrexate Toxicity Due to Overdosing in Psoriasis: A Series of Seven Cases.

Overdosing is the major cause of acute methotrexate toxicity in psoriasis patients. There are no published data regarding the acute cumulative dose causing acute toxicity, duration to achieve acute cumulative toxic dose and various reasons for wrong dosing of methotrexate in Indian patients. We are presenting a series of seven cases of toxicity due to overdosing of methotrexate in psoriasis. The acute cumulative dose of methotrexate ranging from 35 mg to 150 mg, taken over 3-7 days was responsible for acute toxicity in the psoriasis cases. Lack of counselling regarding the disease course, drug dosing, schedule and awareness about possible outcome of high and daily dose were found to be the causes of overdosing and toxicity in our patients. All cases presented with ulceration, bleeding and pain in skin lesions and five cases had oral mucosal ulceration and genital mucosa was involved in two cases. All cases were given injectable folinic acid. Five cases recovered and two cases expired. Authors postulate counselling about the course of disease, regarding dosing schedule of methotrexate and consequences of methotrexate overdosing is mandatory for all patients of psoriasis in country like India where drug regulation is not strict to prevent methotrexate toxicity and its dreaded consequences.

Facilitate Treatment Adjustment After Overdosing: Another Step Toward 21st-Century Medicine.

Overdosing occurs frequently because of prescription errors in neonates, infants, children, adolescents, and adults. Currently there is no quantitative approach that can be used by clinicians to adjust dosing so that toxic drug concentrations can be brought back to levels observed with safe and efficacious therapeutic doses. We present a mathematical solution that offers the time between last overdosing and next therapeutic dose to achieve therapeutic drug concentrations as soon as possible. To facilitate applications of this solution in clinical practice, a minimal amount of information has to be provided, and no simulations are necessary to compute the optimal waiting time. For educational purposes, we provide access to an online decision support tool for overdosing situations (Time to next Dose Calculator) that (1) computes the waiting time after accidental overdosing in patients with normal elimination and (2) computes the waiting time and adjusted reference dosing for patients with abnormal elimination. This user-friendly online tool will help clinicians to quickly adjust a dosing schedule in overdosing situations to mitigate risk for negative clinical consequences.