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This study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. A Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. Single-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC50 and MIC90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). Contezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.

Background Parents often do not consider fever as an important physiological response and mechanism of defense against infections that leads to inappropriate use of antipyretics and potentially dangerous side effects. This study is designed to evaluate the appropriateness of antipyretics dosages generally administered to children with fever, and to identify factors that may influence dosage accuracy. Results In this cross-sectional study we analyzed the clinical records of 1397 children aged >1 month and < 16 years, requiring a primary care (ambulatory) outpatient visit due to fever. We evaluated the number of children who had received >90 mg/kg/day of acetaminophen, the prescriber, the medication formula and the educational level of the caregiver who administered acetaminophen. Among those children included in our study, 74 % were administered acetaminophen for body temperature ≤ 38.4 °C. 24.12 % of children received >90 mg/kg/day of acetaminophen. Parents with university qualifications most commonly self-administered acetaminophen to their children, in a higher than standard dose. Self medication was also described in 60 % of children, whose acetaminophen was administered for temperatures < 38 °C. Acetaminophen over-dosage was also favored by the use of drug formulations as drops or syrup. Conclusions Our study shows that preventive action should be taken regarding the use of acetaminophen as antipyretic drug in children in order to reduce the fever phobia and self-prescription, especially of caregivers with higher educational levels. It is also necessary to promote a more appropriate use of acetaminophen in those parents using drops or syrup formulations.

An important endpoint in treating chronic kidney disease, a prevalent disease that can lead to kidney failure and cardiovascular disease, is reducing proteinuria. Proteinuria is an independent risk factor for disease progression and the development of cardiovascular disease and is a key factor that can be used to guide therapy designed to maximize kidney protection. Proteinuria is targeted by using pharmacologic agents that suppress the renin-angiotensin-aldosterone system (RAAS), a regulator of intravascular volume and blood pressure; this has been shown to decrease proteinuria, slow disease progression, and improve coronary disease outcome, independent of effects on blood pressure. The efficacy of RAAS blockers, including angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, may be limited by currently recommended doses, which are based on treatment of hypertension. Data are now emerging from clinical trials demonstrating that use of ‘supratherapeutic doses’ (doses greater than those approved for lowering blood pressure), compared with standard doses, has favorable safety, tolerability, and efficacy in reducing proteinuria in both diabetic and nondiabetic patients with chronic kidney disease. Supratherapeutic dosing may be a valuable approach for optimizing RAAS blockade and providing renoprotection.

Carbamazepine is a medication used to treat a variety of neurological and psychiatric conditions including seizure disorders, neuropathic pain syndromes, and bipolar disorder. Unfortunately, its pharmacokinetics and side effect profile may lead to significant toxicities due to its sodium channel blockade. In 2019, there were over 1500 cases of isolated carbamazepine toxicity reported to poison centers across the United States. Carbamazepine toxicity may result in vague neurological symptoms in milder cases, but in severe toxicity, it can cause cardiovascular instability, intractable seizures, and coma. In this article, we describe a case of a 40-year-old female who presented to a local emergency department with focal neurological deficits after repeated supratherapeutic dosing of carbamazepine.. This case highlights a key cerebrovascular accident mimic that emergency physicians should consider from acute toxicity that can be seen with carbamazepine in a patient who was taking the medication as prescribed.

Objective: Supratherapeutic INRs exceeding 4.5 are associated with increased risk of haemorrhage. The aim of this study was to evaluate the efficacy of an educational program focused at improving emergency clinician compliance with the Thrombosis and Haemostasis Society of Australia and New Zealand (THANZ) guidelines. Design: A pre and post-intervention study was undertaken. Retrospective data from 1 July 2014 to 30 June 2015 and prospective data 1 January 2016 to 31 December 2016 were collected. Setting: This study was conducted in a large tertiary care hospital in Melbourne, Victoria, Australia. Subjects: Included were all consecutive patients in the study periods that presented to the emergency department with an initial INR result of > 4.5 on warfarin only. Interventions: Development and delivery of an educational program in accordance with the current THANZ guidelines was implemented. Main outcome measures: To improve education regarding the correct management of emergency patients on warfarin with a supratherapeutic INR. Results: Data on 158 patients with an INR > 4.5 were collected. Data on 46 patients were excluded. Management in 31 patients did not follow recommended guidelines. There was no difference detected between groups with 17 compliant with guidelines pre-intervention and 14 post intervention; p=0.87. Conclusion: Emergency department management of patients on warfarin with supratherapeutic INR's requires continual quality improvement. Frequency of emergency clinician compliance with the current evidence-based guidelines was moderate and did not improve significantly with targeted education. This highlights the complexities of warfarin management and the need for multi-disciplinary engagement of patients presenting with supratherapeutic INRs.

Generation of protein-derived acetaminophen-cysteine (APAP-CYS) is reported after ingestion of large and therapeutic dosages of acetaminophen in healthy and in liver-damaged patients. The incidence of protein-derived APAP-CYS adducts in repeated supratherapeutic dosages of APAP is not known. Methods: for 12 months, a standardized and comprehensive questionnaire was used to interview every consecutive patient at a pain management clinic. Patients found to ingest more than 4 g of APAP per day for a minimum of 14 consecutive days at the time of the encounter were invited to have blood drawn for hepatic transaminases and APAP-CYS adduct levels. Twelve subjects out of 990 interviewees met inclusion criteria. Ten of the 12 had measurable protein-derived APAP-CYS, none had evidence of liver injury. Patients that ingest repeated supratherapeutic amounts of APAP over several weeks may generate APAP-CYS protein adducts in the absence of hepatic injury.