The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery.

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.

Artificial intelligence-powered chatbots in search engines: a cross-sectional study on the quality and risks of drug information for patients.

BACKGROUND: Search engines often serve as a primary resource for patients to obtain drug information. However, the search engine market is rapidly changing due to the introduction of artificial intelligence (AI)-powered chatbots. The consequences for medication safety when patients interact with chatbots remain largely unexplored. OBJECTIVE: To explore the quality and potential safety concerns of answers provided by an AI-powered chatbot integrated within a search engine. METHODOLOGY: Bing copilot was queried on 10 frequently asked patient questions regarding the 50 most prescribed drugs in the US outpatient market. Patient questions covered drug indications, mechanisms of action, instructions for use, adverse drug reactions and contraindications. Readability of chatbot answers was assessed using the Flesch Reading Ease Score. Completeness and accuracy were evaluated based on corresponding patient drug information in the pharmaceutical encyclopaedia drugs.com. On a preselected subset of inaccurate chatbot answers, healthcare professionals evaluated likelihood and extent of possible harm if patients follow the chatbot's given recommendations. RESULTS: Of 500 generated chatbot answers, overall readability implied that responses were difficult to read according to the Flesch Reading Ease Score. Overall median completeness and accuracy of chatbot answers were 100.0% (IQR 50.0-100.0%) and 100.0% (IQR 88.1-100.0%), respectively. Of the subset of 20 chatbot answers, experts found 66% (95% CI 50% to 85%) to be potentially harmful. 42% (95% CI 25% to 60%) of these 20 chatbot answers were found to potentially cause moderate to mild harm, and 22% (95% CI 10% to 40%) to cause severe harm or even death if patients follow the chatbot's advice. CONCLUSIONS: AI-powered chatbots are capable of providing overall complete and accurate patient drug information. Yet, experts deemed a considerable number of answers incorrect or potentially harmful. Furthermore, complexity of chatbot answers may limit patient understanding. Hence, healthcare professionals should be cautious in recommending AI-powered search engines until more precise and reliable alternatives are available.

Real-world safety profile of zanubrutinib: a disproportionality analysis based on the FAERS database.

OBJECTIVE: Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor that has been approved for the treatment of several B cell malignancies. The aim of this study was to evaluate adverse events (AEs) associated with zanubrutinib based on the real-world data. DESIGN: A disproportionality analysis was performed to identify the potential zanubrutinib-related AEs. SETTING: The Food and Drug Administration AE Reporting System database from the fourth quarter of 2019 to the third quarter of 2023. MAIN OUTCOME MEASURES: The results of the disproportionality analyses were presented as reported ORs (RORs). When the lower limit of the 95% CI for the ROR is greater than 1 and the number of AE reports is≥3, it indicates that the preferred term (PT) may be a positive AE signal. RESULTS: A total of 846 AE reports with zanubrutinib as the primary suspect drug were obtained, with 2826 AEs. A total of 74 positive PT signals were detected across 18 system organ classes (SOCs). The most significant signal for SOC was 'blood and lymphatic system disorders' (ROR=2.8, 95% CI 2.3 to 3.3), while the most significant signal for PT was 'haemorrhage subcutaneous' (ROR=190.8, 95% CI 128.0 to 284.5). 13 unexpected off-label AEs were also observed, such as abnormal hair texture, skin discolouration, hypernatraemia, pericardial effusion and hypersomnia. The median time to onset of AEs associated with zanubrutinib was 51 days (IQR 13-192 days) and was consistent with the early failure model. In comparison with zanubrutinib monotherapy, the combination of zanubrutinib and rituximab therapy was linked to a higher risk of specific AEs, including myelosuppression, pneumonia, leucopenia, thrombocytopenia, abdominal pain, anaemia, pancytopenia and respiratory failure. Furthermore, the combination of zanubrutinib and chemotherapy increased the risk of several severe AEs, such as cardiac arrest, elevated blood lactate dehydrogenase levels and pancytopenia. CONCLUSIONS: The results of the analysis provided valuable insights into the safety profile of zanubrutinib-treated patients, which was helpful for clinical monitoring and identifying potential AEs related to zanubrutinib.

Experiences from the initial 3 years of introducing the British Pharmacological Society and UK Medical Schools Council Prescribing Safety Assessment for Danish junior doctors.

AIMS: The British Pharmacological Society and UK Medical Schools Council Prescription Safety Assessment (BPS/MSC PSA) is an electronic platform developed for assessing the prescription skills of medical students. Our aim was to investigate the feasibility of the BPS/MSC PSA in addressing prescribing competencies among junior doctors in a hospital setting. METHODS: The Department of Clinical Pharmacology at Odense University Hospital established a Danish translated programme using the BPS/MSC PSA platform. We launched a formal 3-year programme in 2021, potentially assessing all first-year doctors at Odense University Hospital and Esbjerg Regional Hospital. Participation was followed by a survey. RESULTS: During the period of 2021 to 2023 n = 364 doctors were invited, from which n = 246 participated. The compliance rate increased from 38% in 2021 to 88% in 2023. The mean assessment score (points normalized to percentage) across n = 246 participants was 71%, and 94% achieved a score of at least 50%. A subset of participants responded to the survey, with the majority of those completing the questionnaire indicating that the purpose of the assessment was clear. The items related to difficulty and number of questions received comparable evaluations, and most respondents found the questions clinically relevant. CONCLUSION: It is feasible to translate and implement the BPS/MSC PSA in a Danish hospital setting. The programme provides insight into the prescribing competencies of junior doctors and the participants are generally positive.

Toward a Clinical Decision Support System for Monitoring Therapeutic Antituberculosis Medical Drugs in Tanzania (Project TuberXpert): Protocol for an Algorithm' Development and Implementation.

BACKGROUND: The end tuberculosis (TB) strategy requires a novel patient treatment approach contrary to the one-size-fits-all model. It is well known that each patient's physiology is different and leads to various rates of drug elimination. Therapeutic drug monitoring (TDM) offers a way to manage drug dosage adaptation but requires trained pharmacologists, which is scarce in resource-limited settings. OBJECTIVE: We will develop an automated clinical decision support system (CDSS) to help practitioners with the dosage adaptation of rifampicin, one of the essential medical drugs targeting TB, that is known for large pharmacokinetic variability and frequent suboptimal blood exposure. Such an advanced system will encourage the spread of a dosage-individualization culture, including among practitioners not specialized in pharmacology. Thus, the objectives of this project are to (1) develop the appropriate population pharmacokinetic (popPK) model for rifampicin for Tanzanian patients, (2) optimize the reporting of relevant information to practitioners for drug dosage adjustment, (3) automate the delivery of the report in line with the measurement of drug concentration, and (4) validate and implement the final system in the field. METHODS: A total of 3 teams will combine their efforts to deliver the first automated TDM CDSS for TB. A cross-sectional study will be conducted to define the best way to display information to clinicians. In parallel, a rifampicin popPK model will be developed taking advantage of the published literature, complemented with data provided by existing literature data from the Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (panACEA), and samples collected within this project. A decision tree will be designed and implemented as a CDSS, and an automated report generation will be developed and validated through selected case studies. Expert pharmacologists will validate the CDSS, and finally, field implementation in Tanzania will occur, coupled with a prospective study to assess clinicians' adherence to the CDSS recommendations. RESULTS: The TuberXpert project started in November 2022. In July 2024, the clinical study in Tanzania was completed with the enrollment of 50 patients to gather the required data to build a popPK model for rifampicin, together with a qualitative study defining the report design, as well as the CDSS general architecture definition. CONCLUSIONS: At the end of the TuberXpert project, Tanzania will possess a new tool to help the practitioners with the adaptation of drug dosage targeting complicated TB cases (TB or HIV, TB or diabetes mellitus, and TB or malnutrition). This automated system will be validated and used in the field and will be proposed to other countries affected by endemic TB. In addition, this approach will serve as proof of concept regarding the feasibility and suitability of CDSS-assisted TDM for further anti-TB drugs in TB-burdened areas deprived of TDM experts, including second-line treatments considered important to monitor. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/58720.

Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes.

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

Promising tools for future drug discovery and development in antiarrhythmic therapy.

Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Significance Statement Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.

Longitudinal changes in self-reported medication adherence and beliefs about post-stroke medicines in Sweden: a repeated cross-sectional study.

OBJECTIVES: To explore changes in beliefs about medicines and self-reported medication non-adherence between 3 and 24 months after stroke and to investigate associations between beliefs about medicines and non-adherence at 24 months after stroke. DESIGN: Longitudinal questionnaire survey. SETTING: Patients treated for acute stroke in 25 Swedish hospitals. PARTICIPANTS: Only patients living at home were included. Of the 594 individuals who answered the 3 month questionnaire, 401 were included at 24 months; among the remainder, 34 (5.7%) had died, 149 (25,1%) did not respond or had incomplete information on adherence and 10 (1.7%) were not living at home. MEASURES: The primary outcome was self-reported medication adherence as measured with the Medication Adherence Report Scale (MARS). The Beliefs about Medicines Questionnaires (BMQ) was used to assess personal beliefs about medicines. Background and clinical data were included from the Swedish national stroke register. RESULTS: According to dichotomised MARS sum scores, more individuals were classified as non-adherent at 24 months after stroke (n=63, 15.7%) than at 3 months after stroke (n=45, 11.2%) (p=0.030). For BMQ, the only difference over time was an increase in the Necessity subscale (p=0.007). At 24 months, in comparison to adherent patients, non-adherent patients scored statistically significant higher on negative beliefs about medicines, such as Concern (OR 1.17, 95% CI: 1.09 to 1.25), Overuse (OR: 1.37, 95% CI: 1.21 to 1.54) and Harm (OR: 1.24, 95% CI: 1.11 to 1.39), and lower on positive beliefs about medicines, namely, Necessity (OR: 0.88, 95% CI: 0.80 to 0.96) and Benefit (OR: 0.85, 95% CI: 0.74 to 0.98). CONCLUSIONS: Stroke patients' beliefs about medicines were associated with adherence, and over time beliefs remained stable across all domains, except for an increased perception of medications as being necessary. Despite this, more patients became non-adherent over time. To counteract non-adherence, interventions targeted to improve intentional adherence as well as non-intentional adherence should be investigated and implemented.

Assessment of the influence of body fat indices on antihypertensive drug responses.

AIMS: Less than 50% of patients treated for hypertension reach a target office systolic blood pressure (SBP). We aimed to evaluate the role of adiposity on antihypertensive drug responses in newly diagnosed hypertensive patients. METHODS: Estimated glomerular filtration rates, body mass index (BMI), skinfold thickness (SFT), body surface areas and waist circumferences of 150 hypertensive patients naïve to treatment were measured. Treatment protocols were started as combination of angiotensin converting enzyme inhibitor (ACE-I) plus calcium channel blocker (CCB), angiotensin receptor blocker plus CCB or ACE-I plus diuretic. Pre-treatment and change in blood pressure (ΔBP) after 4 weeks treatment were determined. Multiple linear regression analysis was used to find independent predictors of Δblood pressure changes, and multivariable binary logistic regression analysis to find independent predictors of target SBP < 140 mmHg at 4 weeks. RESULTS: A total of 104 patients reached the target systolic pressure of <140 mmHg at 4 weeks. Triceps, mid-abdomen and subscapular SFT were significantly thicker in the uncontrolled blood pressure group (P = .011, P = .006 and P = .016, respectively). Pretreatment SBP (r = 0.644), pretreatment diastolic blood pressure (DBP) (r = 0.188), subscapular SFT (r = -0.318), suprailiac SFT (r = -0.211) and ΔDBP (r = 0.433) were correlated with ΔSBP in correlation analysis. Pretreatment SBP (ß = 0.644, 95% CI = 0.697-0.993, P < .001), subscapular SFT (ß = -0.253, 95% CI = -0.886--0.329, P < .001), pretreatment DBP (ß = -0.380, 95% CI = -0.1001- -0.453, P = .001) and ΔDBP (ß = 0.401, 95% CI = 0.377-0.796, P < .001) were independent predictors of ΔSBP in multivariable linear regression analysis. Subscapular SFT was an independent predictor of target SBP < 140 mmHg in multivariable logistic regression analysis (OR = 0.895, 95% CI = 0.832-0.963, P = .003). CONCLUSIONS: Subscapular SFT may be a valuable marker for prediction of response to antihypertensive drugs.

Safety and efficacy of personalised versus standard dosing of linezolid in patients with sepsis (SePkLin): a pragmatic, multicentre, randomised, controlled and superiority clinical trial protocol.

INTRODUCTION: Linezolid is a broadly used antibiotic to treat complicated infections caused by gram-positive bacteria. Therapeutic drug monitoring of linezolid concentrations is recommended to maximise its efficacy and safety, mainly haematological toxicity. Different pharmacokinetic/pharmacodynamic targets have been proposed to improve linezolid exposure: the ratio of the area under the concentration-time curve during a 24-hour period to minimum inhibitory concentration (MIC) between 80 and 120; percentage of time that the drug concentration remains above the MIC during a dosing interval greater than 85% and the trough concentration between 2 and 7 mg/L. This clinical trial aims to evaluate the safety, efficacy and the clinical and economic utility of personalised dosing of linezolid using Bayesian forecasting methods to attain pharmacokinetic/pharmacodynamic targets, known as model-informed precision dosing. METHODS AND ANALYSIS: This is a pragmatic, multicentre, randomised, parallel, controlled, phase IV and low intervention trial. Participants will be randomly assigned 1:1 to each group (n=346 per group). Control group will receive the standard dose of linezolid. Intervention group will receive personalised dosage of linezolid based on pharmacokinetic-pharmacodynamic adjustments. The primary outcome will be the incidence of thrombocytopenia in both groups. ETHICS AND DISSEMINATION: This protocol was approved by the Ethical Committee of the Investigation with Medicines of Galicia (code 2022/140) and authorised by the Spanish Agency for Medicines and Medical Devices. The trial is implemented in accordance with the Declaration of Helsinki and the international ethical and scientific quality standard, the Good Clinical Practice. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT registration code: 2022-000144-30.

Association between exposure to proton pump inhibitors and delirium: a descriptive and disproportionality analysis of VigiBase.

OBJECTIVES: Proton pump inhibitor (PPI) exposure can lead to hyponatraemia, which is a common cause of delirium. An association between PPI exposure and delirium without hyponatraemia has been suggested in the literature. We aimed to describe the association between reports of delirium and PPI exposure and to assess the association between PPI and delirium with and without hyponatraemia. DESIGN: A descriptive and disproportionality analysis of claims data. SETTING: World pharmacovigilance database VigiBase between 1 January 1991 and 9 February 2022. PRIMARY AND SECONDARY OUTCOME MEASURES: In the first part, we described reports of delirium for which involvement of a PPI or interactions of PPIs with other drugs were suspected. In the second part, delirium cases and non-cases were used to assess the disproportionality signal using the reporting OR (ROR) for the associations of PPI exposure with delirium or delirium/hyponatraemia co-events. RESULTS: We identified 2395 reports of delirium in which involvement of PPI exposure was suspected. Omeprazole, esomeprazole and pantoprazole were the most frequently reported PPIs. Hyponatraemia was present in 11% of the reports. The disproportionality analysis included 1 264 798 reports of adverse drug reactions in patients using PPIs, including 19 081 reports of delirium. We did not find a disproportionality signal for the association between PPI use and delirium (ROR 0.89, 95% CI 0.87 to 0.91). We detected an association of PPI use with delirium/hyponatraemia co-events (ROR 1.53, 95% CI 1.41 to 1.65). CONCLUSIONS: Most reports of delirium in which the involvement of PPIs was suspected did not include concomitant hyponatraemia. However, no significant signal of disproportionate reporting of delirium was observed for PPIs compared with other drugs, except in cases of delirium associated with hyponatraemia. Hyponatraemia may be the main mechanism linking PPI exposure with delirium, and this possibility should be further explored in prospective studies. TRIAL REGISTRATION NUMBER: NCT05815550.

Relative Bioavailability Studies With Mitapivat: Formulation and Food Effect Assessments in Healthy Subjects.

Pyruvate kinase (PK) deficiency is a rare, hereditary, hemolytic anemia caused by mutations in the PKLR gene encoding the PK enzyme. Mitapivat (previously designated AG-348) is a first-in-class, oral, allosteric activator of PK. We report results from 5 Phase 1 trials in healthy adults to characterize and compare mitapivat pharmacokinetics across different formulations and analyze food effects on mitapivat bioavailability (Studies 1-5). Pharmacokinetic assessments were peak exposure, total exposure, time to maximum plasma concentration of mitapivat, and relative bioavailability (where appropriate). Plasma total exposure of mitapivat was similar in the fasted and fed (high-fat meal or different soft foods) states after capsule, tablet, and pediatric granule formulations. Although mitapivat administration with food reduced the rate of mitapivat absorption (delay in time to maximum plasma concentration; reduction in maximum concentration) versus dosing under fasted conditions, this was not considered clinically relevant, given the lack of effect on total mitapivat exposure. Consequently, the administration instructions for mitapivat relating to food state that "patients may take mitapivat tablets with or without food." These findings will continue to inform clinical studies and development of mitapivat in adult and pediatric patients with hemolytic anemias and may help inform healthcare professionals on mitapivat dosing/administration recommendations in clinical practice.

Disposal practices, knowledge and attitude of adult patients visiting outpatient pharmacy services towards unused medicines in Debre Tabor, Northwest Ethiopia: a descriptive cross-sectional study.

OBJECTIVE: Accumulation at home and improper disposal of unused medicines pose a major public health problem. Knowledge and attitude of patients may contribute to accumulation and disposal practice of unused medicines. As there are no such data at the study setting, this study aimed to assess disposal practices, knowledge and attitude of adult patients visiting outpatient pharmacy (OPD) towards unused medicines. DESIGN: Descriptive cross-sectional design. SETTING: Debre Tabor Comprehensive Specialized Hospital, Debre Tabor, Ethiopia. PARTICIPANTS: Adults who visited OPD services agreed to participate and were selected using systematic random sampling technique from 31 May to 30 June 2022. Data were collected through face-to-face interview using a questionnaire. DATA ANALYSIS: Data were entered and analysed using SPSS V.26.0. Variables of interest were described in frequency and presented in tables. RESULTS: In total, 257 participants were included in the analysis. Of these, 55.6% were male. The prevalence of unused medicines at home was 47.5%. The majority of respondents (183, 71.2%) knew that improper disposal of unused medicines could cause harm. However, more than half of respondents did not know about medicine waste and had no prior information about medicine disposal instructions. Regarding their attitude, 203 (79%) of respondents 'agreed' that there are potential risks associated with having unused medicines at home, and 163 (63.4%) 'strongly agreed' that children are more vulnerable to the risks associated with unused medicines. The most preferred disposal practice for unused medicines was throwing them in household garbage (108, 42%) followed by flushing down the toilets/sinks (77, 30%). CONCLUSION: The majority of participants disposed of unused and expired medicine in household garbage and toilets/sinks. This is in contrast to the recommendations of national and international policies and guidelines for safe and appropriate pharmaceutical waste disposal.

Cushing's Storm: A Case of Paraneoplastic Cushing's Syndrome-Induced Seizures Treated With Continuous Etomidate Infusion.

A 67-year-old female presented with abdominal pain, nausea, vomiting, and unintentional weight loss. Further work-up revealed elevated serum cortisol, hypokalemia, and metabolic alkalosis in the setting of paraneoplastic Cushing's syndrome secondary to small lung cancer. The patient then developed refractory convulsive epileptic seizure despite being on multiple anti-epileptic medications. Here, we present a unique case where continuous etomidate infusion was used to lower serum cortisol, as adrenal insufficiency is associated with etomidate use. This case emphasizes how drug side effects can be used to achieve a desired treatment outcome.

Assessment of bleeding events in patients receiving DOACs with or without statins to treat venous thromboembolism: insights from the RIETE registry.

OBJECTIVE: To evaluate the impact of coadministering statins with direct oral anticoagulants (DOACs) on the risk of major bleeding events in patients with venous thromboembolism (VTE). DESIGN: Observational cohort analysis based on a multicentre international registry. SETTING: Data were extracted from the Registro Informatizado de Enfermedad TromboEmbolica Registry, which involves 205 centres across 27 countries. PARTICIPANTS: A total of 73 659 patients diagnosed with VTE were classified based on their anticoagulant therapy (DOACs) versus low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) and concurrent use of statins. METHODS: Multivariable Cox proportional hazards models adjusted for confounding variables to assess the risk of major bleeding events stratified by the type of anticoagulant use and statin use. RESULTS: From October 2013 to February 2023, 73 659 patients were recruited: 2573 were statin users on DOACs, 14 090 were statin users on LMWH or VKA therapy, 10 088 were non-statin users on DOACs and 46 908 were non-statin users on LMWH or VKA therapy. Statin users were 10 years older and more likely to have hypertension, diabetes, renal failure or prior artery disease. During anticoagulation (median, 187 days), 1917 patients (2.6%) suffered major bleeding. Rates of major bleeding per 100 patient-years were 2.33 (95% CI 1.72 to 3.09), 3.75 (95% CI 3.43 to 4.10), 1.39 (95% CI 1.13 to 1.69) and 3.10 (95% CI 2.93 to 3.27), respectively. On multivariable analysis, patients treated with DOACs had a significantly lower risk of major bleeding compared with those on LMWH or VKA therapy (adjusted HR 0.59; 95% CI 0.48 to 0.74). The adjusted HR in statin users versus non-users was 1.03 (95% CI 0.92 to 1.14), while in statin users on DOACs versus the rest of patients, it was 1.18 (95% CI 0.79 to 1.76). CONCLUSIONS: In patients with VTE receiving statins, long-term anticoagulation with DOACs was associated with a reduced risk of major bleeding, regardless of the statin use. These findings support the safety profile of DOACs over VKAs or LMWH in the management of VTE in patients requiring statins.

Clinical Pharmacokinetics of Atropine Administered Ocularly Using an Ultrasensitive Bioanalytical Assay.

Purpose: Previous pharmacokinetic studies conducted on atropine sulfate ophthalmical solution have utilized bioanalytical assays that lacked sufficient sensitivity to fully characterize the complete pharmacokinetic profile. To address these limitations, Pharma Medica Research Inc. has developed and validated an ultrasensitive bioanalytical method capable of accurately quantifying the active enantiomer, L-hyoscyamine, with a very low limit of quantitation of 0.500 pg/mL. The objective of this study was to evaluate the pharmacokinetics of L-hyoscyamine in healthy subjects using a highly sensitive bioanalytical assay. Methods: Ten subjects were administered 0.3 mg of Isopto Atropine solution into the conjunctival sac of the eye. Blood samples were taken as early as 2 min and up to 24 h following administration. The plasma samples were assayed for L-hyoscyamine using a chiral method with an analytical range of 0.500-500 pg/mL. The pharmacokinetic parameters were estimated using both a noncompartmental and compartmental approach. Results: The pharmacokinetics of L-hyoscyamine were fully characterized as there were no samples that were below the limit of quantitation following dosing. Using noncompartmental analysis, the mean Cmax was 467.9 ± 159.4 pg/mL with a median (range) Tmax of 0.5 (0.08-1) h. The mean area under the concentration-time curve was 1668.96 ± 436.02 h·pg/mL and the mean half-life was 3.91 ± 1.16 h. Overall, the study drug was well tolerated and no serious adverse events were reported. Conclusion: Through the utilization of a proprietary ultrasensitive bioanalytical method, a comprehensive investigation into the pharmacokinetics of L-hyoscyamine has been successfully conducted. This advanced method offers significant potential for optimizing study designs and facilitating in-depth examinations of the pharmacokinetics of ocularly administered atropine formulations.

Clinical Pharmacology of Pemafibrate Extended-release Formulation in Patients with Hypertriglyceridemia-A Phase 2, Multicenter, Active-controlled, Randomized, Single-blind, Crossover study.

AIMS: Efficacy, safety, and pharmacokinetics of the selective PPARα modulator pemafibrate as once-daily extended-release (XR) tablets were compared with those of twice-daily immediate-release (IR) tablets in patients with hypertriglyceridemia. METHODS: A multicenter, randomized, single-blind, active-controlled crossover, phase 2 clinical pharmacology study was performed in patients with hypertriglyceridemia. Patients were randomly assigned to IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day before/after meals (fasted/fed) and treated for a total of eight weeks. The primary endpoint was percentage change in fasting serum triglycerides (TG). RESULTS: Of 63 randomized patients, 60 received the study drug. Patients were 78.3% male, mean age (±SD) 57.5±9.8 years, BMI 25.5±3.7 kg/m2, and fasting TG 221.3±68.1 mg/dL. Fasting serum TG decreased significantly from baseline in all groups (LS mean [95% CI];-43.6 [-47.7, -39.5] % for IR 0.2 mg/day, -41.1 [-45.1, -37.0] % for XR 0.4mg/day, -39.7 [-43.8, -35.6] % for XR 0.8 mg/day), indicating that XR 0.4 and XR 0.8 mg/day were not inferior to IR 0.2 mg/day. TG-lowering effects tended to be stronger for fed than fasted administration. MRTss, tmax, and t1/2 were longer for XR than for IR. Adverse events showed no major inter-group differences: 12.5% (5/40 patients) for IR 0.2, 17.5% (7/40) for XR 0.4, and 20.0% (8/40) for XR 0.8 mg/day. CONCLUSIONS: In patients with hypertriglyceridemia, XR substantially lowered TG at all doses, with maximum effectiveness at 0.4 mg/day, the dose approved in Japan, to a level comparable to IR 0.2 mg/day. There were no safety concerns up to 0.8 mg/day.