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The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [14C]MEP or [14C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [14C]MEP or [14C]DEP (164 μg/kg). The absorption, metabolism, excretion and pharmacokinetics of [14C]MEP and [14C]DEP were nearly identical. [14C]DEP was rapidly and nearly completely metabolized to [14C]MEP following either intravenous or oral administration. [14C]MEP and[14C]DEP were rapidly absorbed, the elimination half-life was estimated to be 1 hour. Approximately 90%–96% of the dose was excreted in urine with 2%–3% of the dose in faeces. MEP accounted for the majority of the dose in plasma and urine; in addition, three minor metabolites (M1, M2 and M3) were detected. The minor metabolites were neither phthalic acid nor glucuronide/sulfate conjugates. The nearly identical metabolism and pharmacokinetics of MEP and DEP in juvenile dogs justifies the use of DEP toxicity data in the risk assessment of MEP exposure. [ABSTRACT FROM AUTHOR]

Objective: Optimal utilisation of theatre time increases efficiency and reduces the cost of health care. The accuracy of surgical time estimation between different members of the theatre team has not been well documented, and may aid in more efficient utilisation of available theatre time. This study aims to identify the cohort of theatre staff with greatest accuracy in estimating orthopaedic surgical time. Methods: This study was conducted in a prospective fashion using consecutive orthopaedic trauma and elective operative lists over a period of 3 months. Prior to each operating list, a senior member of each of the anaesthetic, orthopaedic and scrub/scout nursing teams predicted the surgical duration for orthopaedic procedures after being provided with information regarding the individual cases. The absolute difference between estimated and actual surgical times was calculated. Results: When expressed as a percentage difference from true surgical time, the orthopaedic team provided the most accurate estimates, with a mean difference of 33.0%. This was followed by nursing staff (40.5%) and anaesthetics (50.9%). Similarly, a higher proportion of estimates by the orthopaedic team were within the limits of 20% underestimation and 10% overestimation (deemed clinically significant). Conclusions: Surgical times for orthopaedic trauma and elective cases are most accurately estimated by the operating team. These estimates should be implemented when planning theatre utilisation, and may benefit computer algorithms for theatre scheduling. What is known about the topic? The ability of surgeons, nurses and anaesthetists to accurately predict surgical times is often debated, with heated discussions if additional cases can fit onto a scheduled list. What does the paper add? Our paper demonstrated that despite all groups being inaccurate with timing predictions, orthopaedic surgeons were the most accurate. What are the implications for practitioners? With ever-growing pressure on health systems, it is paramount that available theatre resources are utilised with maximal efficiency. [ABSTRACT FROM AUTHOR]

Background: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.Methods: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.Findings: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423).Interpretation: Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD.Funding: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. [ABSTRACT FROM AUTHOR]