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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]

2‐Hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) is an experimental therapy for Niemann‐Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1−/− mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120‐mg dose of [14C]‐HP‐β‐CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24 hours postdose for subsequent processing and quantitative whole‐body autoradiographic analysis. HP‐β‐CD‐derived radioactivity absorbed from the CBMC was widely distributed to cat tissues; most tissues were observed to have reached their highest concentration at 1 hour postdose. HP‐β‐CD‐derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403 μg Eq/g or 0.28 mM) and remained high (49.7 μg Eq/g or 0.03 mM) at 24 hours. The relatively long half‐life (11‐30 hours) in cerebral ventricles and the subarachnoid space surrounding the brain and spinal cord might contribute to the efficacy of HP‐β‐CD in NPC1 cats. Other tissues with high concentrations of radioactivity were nasal turbinates, pituitary gland, and urinary bladder, while relatively low concentrations were observed in blood and bile. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess participation in sport and physical activity following open reduction and internal fixation of a Lisfranc injury in a cohort of recreational athletes. Methods: This study identified all adult patients aged 55 years or younger who presented with a Lisfranc injury and underwent open reduction and internal fixation (ORIF) using a Lisfranc screw combined with bridge plating technique. Sports and physical activity participation was assessed with a new sports-specific, patient-administered questionnaire. Clinical outcomes were assessed with the Foot and Ankle Outcome Score (FAOS). Thirty-three patients qualified for the study (21 men/12 women). Mean age and follow-up were 31.2 (range, 18-55) years and 2.9 (range, 1.5-5.4) years, respectively. Results: Postoperatively, 31 patients (94%) were able to return to some form of sport. Twenty-two patients (66%) returned to playing sport at or above their preinjury level. Of the 11 patients who played less sport, 6 had ongoing pain, and the remaining 5 were asymptomatic but were participating less frequently because of other lifestyle reasons. In addition, of the 33 patients, 11 (33%) had some degree of ongoing pain that might limit their ability to return to sports and physical activities. There was strong correlation between overall FAOS and the Sports Questionnaire. Conclusion: Most patients who sustained a Lisfranc injury could return to sport and physical activity after ORIF. Patients should be counseled preoperatively that about 1 in 3 might experience continued pain at the injury site. Level of Evidence: Level IV, retrospective case series. [ABSTRACT FROM AUTHOR]

The article focuses on a research on prevention of cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease by intracisternal cyclodextrin. Topics discussed include hepatic disease and progressive neurological disease due to increase in unesterified cholesterol and several sphingolipids; subcutaneous administration 2-hydroxypropyl-b-cyclodextrin (HPbCD) to cats; and efficacy and safety of drug administration directly into the central nervous system.

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]

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.

The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [(14)C]MEP or [(14)C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [(14)C]MEP or [(14)C]DEP (164 μg/kg). The absorption, metabolism, excretion and pharmacokinetics of [(14)C]MEP and [(14)C]DEP were nearly identical. [(14)C]DEP was rapidly and nearly completely metabolized to [(14)C]MEP following either intravenous or oral administration. [(14)C]MEP and[(14)C]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.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulfate conjugation (directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.

Expanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy for Bacillus anthracis infections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t(1/2)], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t(1/2), approximately 2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment of Bacillus anthracis infections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (> or = 4 log10 reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilized Bacillus anthracis cultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that "partially humanized" levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that "humanize" antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified.