bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐dose pharmacokinetics of co‐crystal of tramadol–celecoxib: Results of a four‐way randomized open‐label phase I clinical trial in healthy subjects
Authors: Videla Sebastián , Lahjou Mounia , Vaqué Anna , Sust Mariano , Encabo Mercedes , Soler Lluis , Sans Artur , Sicard Eric , Gascón Neus , Encina Gregorio , Plata‐Salamán Carlos
Published: August 2017

Aims

Co‐crystal of tramadol–celecoxib (CTC) is a novel co‐crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E‐58425) and Mundipharma Research (MR308). This Phase I study compared single‐dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate‐release (IR) tramadol and celecoxib] alone and in open combination.

Methods

Healthy adults aged 18–55 years were orally administered four treatments under fasted conditions (separated by 7‐day wash‐out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer‐generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg).

Results

Thirty‐six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments‐1, –2 and –4, respectively, were 263, 346 and 349 ng ml–1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml–1 (mean cumulative area under the plasma concentration–time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml–1; 2183, 3093 and 2856 ng h ml–1; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported.

Conclusion

PK parameters of each API in CTC were modified by co‐crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination.
Olodaterol shows anti‐fibrotic efficacy in in vitro and in vivo models of pulmonary fibrosis
Authors: Herrmann Franziska Elena , Wollin Lutz , Wirth Johannes , Gantner Florian , Lämmle Bärbel , Wex Eva
Published: August 2017

Background and Purpose

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of β2‐adrenoceptors (β2‐AR) has been shown to inhibit pro‐fibrotic events primarily in cell lines, the role of β2‐adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti‐fibrotic activity of the long‐acting β2‐adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis.

Experimental Approach

We assessed the activity of olodaterol to inhibit various pro‐fibrotic mechanisms, induced by different pro‐fibrotic mediators, in primary HLF from control donors and patients with IPF (IPF‐LF). The in vivo anti‐fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF‐β1.

Key Results

In both HLF and IPF‐LF, olodaterol attenuated TGF‐β‐induced expression of α‐smooth muscle actin, fibronectin and endothelin‐1 (ET‐1), FGF‐ and PDGF‐induced motility and proliferation and TGF‐β/ET‐1‐induced contraction. In vivo olodaterol significantly attenuated the bleomycin‐induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro‐fibrotic mediators (TGF‐ß, MMP‐9 and tissue inhibitor of metalloproteinase‐1). Forced vital capacity was increased only with the preventive treatment regimen. In the TGF‐β‐overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression.

Conclusion and Implications

Olodaterol showed anti‐fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis.
Knowledge, attitudes, and behaviours of healthcare professionals regarding child maltreatment in China
Authors: Li X. , Yue Q. , Wang S. , Wang H. , Jiang J. , Gong L. , Liu W. , Huang X. , Xu T.
Published: August 2017

Background

A new, recently issued national law and regulation in China conferred the responsibility of healthcare professionals in child maltreatment intervention. However, few studies have reported on the recognition and reporting of child maltreatment by healthcare professionals in China. The aim of this study was to assess healthcare professionals' knowledge, attitudes, and self‐perceived behaviour in terms of identifying, assessing, and reporting child maltreatment cases in China.

Methods

A cross‐sectional survey of 877 healthcare professionals from four provinces was conducted using a structured questionnaire.

Results

The respondents demonstrated insufficient knowledge on identifying potential child maltreatment cases. Over 30% of them were less than confident in the medical examination, evaluation, and treatment of child maltreatment cases, especially with regard to cases involving sexual abuse. Only 3.19% of respondents had ever received training on child maltreatment intervention, and as a result, lack of knowledge with regard to dealing with child maltreatment cases, referral procedures, and regulations was indicated to be the main cause of underreporting.

Conclusions

Healthcare professionals in China have insufficient knowledge, skills, and confidence when it comes to dealing with all aspects of child maltreatment. Although participants reported a positive attitude towards their role in detecting and reporting child maltreatment cases, there are obstacles that hinder them from doing so. Appropriate training courses should be developed to empower professionals with knowledge and skills, as well as increase their confidence in dealing with suspected child maltreatment cases.
Early experience affects learning performance and neophobia in a cooperatively breeding cichlid
Authors: Bannier Francis , Tebbich Sabine , Taborsky Barbara
Published: August 2017

The ability to respond flexibly to environmental challenges, for instance by learning or by responding appropriately to novel stimuli, may be crucial for survival and reproductive success. Experiences made during early ontogeny can shape the degree of behavioural flexibility maintained by individuals during later life. In natural habitats, animals are exposed to a multitude of social and non‐social ecological factors during early ontogeny, but their relative influences on future learning ability and behavioural flexibility are only poorly understood. In the cooperatively breeding cichlidNeolamprologus pulcher, we investigated whether early social and predator experiences shape the learning performance, flexibility, and response to novelty of adults. Fish were reared either with or without parents and helpers and with or without perceived predation risk in a full‐factorial experiment. We investigated the influence of these treatments on learning performance and flexibility in a spatial acquisition and reversal learning task. To test for response to novelty, we performed a neophobia test. We found that fish reared with predator experience, but without the presence of older group members outperformed fish with other rearing backgrounds in reversal learning and that individuals, which had been reared in a socially more complex environment together with older group members responded less neophobic toward a novel object than individuals reared among siblings only. Comparative evidence from fish and rats suggests that these developmental effects may be driven by the cues of safety perceived in the presence of guarding parents.
Territoriality mediates atypical size‐symmetric cannibalism in the Amblypygi Phrynus longipes
Authors: Chapin Kenneth J. , Reed‐Guy Sarah
Published: August 2017

Cannibalism can have important demographic and ecological effects on populations. Typically, cannibalism is size‐structured, where larger individuals eat smaller conspecifics. Initial cursory observations of the whip spider, Phrynus longipes, however, suggested that cannibalism might not be size‐structured in this species, perhaps because cannibalism is often a by‐product of territory contests. We staged paired interactions and recorded latency to escalate to physical aggression or cannibalize to understand the dynamics of cannibalism and resource contests. We employed a multimodel comparative approach to tease apart the contest characteristics that best predicted cannibalism during behavioral trials between P. longipes opponents. We found that, while armament size symmetry predicted escalation of contests, cannibalism was best predicted by body mass asymmetry. Further, cannibalism was most likely to occur among individuals similar in armament, but dissimilar in body mass. This suggests a discrepancy between phenotypes that may have evolved to communicate resource holding potential (e.g., armaments which benefit individuals if dishonest), and body mass as a cue of resource holding potential.
Associations between lobster phyllosoma and gelatinous zooplankton in relation to oceanographic properties in the northern Gulf of Mexico
Authors: Greer Adam T. , Briseño‐Avena Christian , Deary Alison L. , Cowen Robert K. , Hernandez Frank J. , Graham William M.
Published: August 2017

Lobster phyllosoma are known to associate with large cnidarian medusae; however, direct quantitative observations are difficult because gelatinous zooplankton are extremely fragile, and the phyllosoma easily detach from their host when sampled by plankton nets. We provide the first large scale quantitative information of the distribution of this association using an in situ imaging system, with synoptic measurements of water column properties. All phyllosoma were identified as slipper lobsters (Scyllarus chacei) and were associated with previously unreported “hosts” such as small hydromedusae, doliolids, and siphonophores in the northern Gulf of Mexico. Along the shelf, phyllosoma were more likely to be present at greater depths and higher salinities. Approximately 30% of the 347 lobster phyllosoma imaged were attached to at least one gelatinous organism, and salinity and depth were positively related to the probability of attachment on 30 October, but did not show a significant relationship for the other days of sampling. Many of the phyllosoma were larger than the gelatinous organisms to which they were attached, and some gelatinous zooplankton showed damage likely from feeding by the phyllosoma. In this coastal environment, gelatinous zooplankton tended to be more abundant in the same offshore region where phyllosoma occurred, so these gelatinous “hosts” may provide a steady food supply in the more oligotrophic waters on the outer shelf. Similar complex interactions among zooplankton may influence the life histories of other species, hindering our ability to forecast ecosystem level processes until the population level consequences of species interactions are fully understood.
A B‐Spline Framework for Smooth Derivative Computation in Well Test Analysis Using Diagnostic Plots
Authors: Tago Josué , Hernández‐Espriú Antonio
Published: August 2017

In the oil and gas industry, well test analysis using derivative plots, has been the core technique in examining reservoir and well behavior over the last three decades. Recently, diagnostics plots have gained recognition in the field of hydrogeology; however, this tool is still underused by groundwater professionals. The foremost drawback is that the derivative function must be computed from noisy field measurements, usually based on finite‐difference schemes, which complicates the analysis. We propose a B‐spline framework for smooth derivative computation, referred to as Constrained Quartic B‐Splines with Free Knots. The approach presents the following novelties in relation to methodological precedents: (1) the use of automatic equality derivative constraints, (2) a knot removal strategy and (3) the introduction of a Boolean shape parameter that defines the number of initial knots to choose. These can lead to evaluate both simple (manually recorded drawdown measurements) and complex (transducer measured records) datasets. Furthermore, we propose an additional shape preserving smoothing preprocess procedure, as a simple, fast and robust method to deal with extremely noisy signals. Our framework was tested in four pumping tests by comparing the spline derivative with regards to the Bourdet algorithm, and we found that the latter is rather noisy (even for large differentiation intervals) and the second derivative response is basically unreadable. In contrast, the spline first and second derivative led to smoother responses, which are more suitable for interpretation. We concluded that the proposed framework is a welcome contribution to evaluate reliable aquifer tests using derivative‐diagnostic plots.
Understanding the Geometry of Connected Fracture Flow with Multiperiod Oscillatory Hydraulic Tests
Authors: Sayler Claire , Cardiff Michael , Fort Michael D.
Published: August 2017

An understanding of the spatial and hydraulic properties of fast preferential flow pathways in the subsurface is necessary in applications ranging from contaminant fate and transport modeling to design of energy extraction systems. One method for the characterization of fracture properties over interwellbore scales is Multiperiod Oscillatory Hydraulic (MOH) testing, in which the aquifer response to oscillatory pressure stimulations is observed. MOH tests were conducted on isolated intervals of wells in siliciclastic and carbonate aquifers in southern Wisconsin. The goal was to characterize the spatial properties of discrete fractures over interwellbore scales. MOH tests were conducted on two discrete fractured intervals intersecting two boreholes at one field site, and a nest of three piezometers at another field site. Fracture diffusivity estimates were obtained using analytical solutions that relate diffusivity to observed phase lag and amplitude decay. In addition, MOH tests were used to investigate the spatial extent of flow using different conceptual models of fracture geometry. Results indicated that fracture geometry at both field sites can be approximated by permeable two‐dimensional fracture planes, oriented near‐horizontally at one site, and near‐vertically at the other. The technique used on MOH field data to characterize fracture geometry shows promise in revealing fracture network characteristics important to groundwater flow and transport.
Spatial distribution of the apatite fission‐track ages in the Toki granite, central Japan: Exhumation rate of a Cretaceous pluton emplaced in the East Asian continental margin
Authors: Yuguchi Takashi , Sueoka Shigeru , Iwano Hideki , Danhara Tohru , Ishibashi Masayuki , Sasao Eiji , Nishiyama Tadao
Published: August 2017

The Cretaceous Toki granitic pluton of the Tono district, central Japan was emplaced in the East Asian continental margin at about 70 Ma. The Toki granite has apatite fission‐track (AFT) ages ranging from 52.1 ±2.8 Ma to 37.1 ±3.6 Ma (number of measurements, n = 33); this indicates the three‐dimensional thermal evolution during the pluton's low‐temperature history (temperature in the AFT partial annealing zone: 60–120 °C). The majority of the Toki granite has a spatial distribution of older ages in the shallower parts and younger ages in the deeper parts, representing that the shallower regions arrived (were exhumed) at the AFT closure depth earlier than the deeper regions. Such a cooling pattern was predominantly constrained by the exhumation of the Toki granitic pluton and was related to the regional denudation of the Tono district. The age–elevation relationships (AERs) of the Toki granite indicate a fast exhumation rate of about 0.16 ±0.04 mm/year between 50 Ma and 40 Ma. The AFT inverse calculation using HeFTy program gives time‐temperature paths (t–T paths), suggesting that the pluton experienced continuous slow cooling without massive reheating since about 40 Ma until the present day. A combination of the AERs and AFT inverse calculations represents the following exhumation history of the Toki granite: (i) the fast exhumation at a rate of 0.16 ±0.04 mm/year between 50 Ma and 40 Ma; (ii) slow exhumation at less than 0.16 ±0.04 mm/year after 40 Ma; and (iii) exposure at the surface prior to 30–20 Ma. The Tono district, which contains the Toki granite, underwent slow denudation at a rate of less than 0.16 ±0.04 mm/year within the East Asian continental margin before the Japan Sea opening at 25–15 Ma and then within the Southwest Japan Arc after the Japan Sea opening, which is in good agreement with representative denudation rates obtained in low‐relief hill and plain fields.
Case of hydrocele testis caused by vaginalitis, a rare manifestation of immunoglobulin G4‐related disease
Authors: Tokura Yuumi , Kobayashi Minoru , Kusakabe Takashi , Kamai Takao
Published: August 2017

We report an extremely rare manifestation of immunoglobulin G4‐related disease, presented with hydrocele testis. A planned hydrocelectomy was converted to a high orchiectomy because of bloody fluid, suggestive of paratesticular malignancy. The histopathology showed vaginalitis, which was finally diagnosed as immunoglobulin G4‐related disease. To the best of our knowledge, this is the first report of immunoglobulin G4‐related disease representing hydrocele testis.
Getting the control across: Control transmission in information systems offshoring projects
Authors: Mähring Magnus , Wiener Martin , Remus Ulrich
Published: August 2017

Offshoring of information systems (IS) projects has become a widespread global practice. While prior research suggests that controlling, and communicating with, offshore vendors represent key managerial challenges, the topic of how control is communicated, or transmitted, from client to vendor has been widely neglected. Our study focuses on control transmission in the critical relationship between client and offshore vendor managers, and its impact on the performance of IS offshoring projects. Drawing on a matched‐pair survey with 172 client and vendor managers from 86 projects, our results provide several new insights to the IS literature: First, we find that both behaviour and outcome control have the capacity to be transmitted consistently in lateral IS offshore project relationships. Second, our results show that consistent transmission translates into a performance effect only for outcome control. Third, we find that high‐performing offshore projects are characterized by both greater control transmission consistency and greater use of outcome control compared to low‐performing projects. In sum, our study extends theory on IS project control by highlighting that effective control of IS offshoring projects is not only about selecting proper controls but also about ensuring that, as a controller, you get the control across to the controllee.
Physicians' communication of risks from non‐steroidal anti‐inflammatory drugs and attitude towards providing adverse drug reaction information to patients
Authors: Phueanpinit Pacharaporn , Pongwecharak Juraporn , Sumanont Sermsak , Krska Janet , Jarernsiripornkul Narumol
Published: August 2017

Rationale, aims, and objectives

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are frequently prescribed for orthopaedic conditions, therefore this study aimed to explore orthopaedic physicians' perceptions of their role in NSAID‐risk communication, their attitudes towards the necessity of informing patients about adverse drug reactions (ADR), and factors associated with these.

Methods

Self‐administered questionnaires were mailed to all 206 orthopaedic physicians working at hospitals in Northeastern Thailand. Attitudes were assessed using 17 statements and total scores classed as poor, moderate and good attitude.

Results

Sixty‐six questionnaires were returned (32.04%). The responses showed that 75% of physicians claimed to communicate NSAID ADR information, more frequently about gastrointestinal (GI) complications, than about renal and cardiovascular (CVS) complications. ADR management (36%) and monitoring (30%) were not frequently communicated. The time spent with patients was associated with provision of ADR and monitoring advice. Renal function was the risk factor of greatest concern for prescribing any NSAID, followed by history of GI complications, and allergy for non‐selective NSAIDs, and history of CVS diseases and age for selective COX‐2 NSAIDs. Most physicians (41) had moderate attitude towards providing information and 24 good attitude. Fewer physicians working in tertiary hospitals than general and community hospital physicians considered that time limitations prevented counseling and that patient information leaflets offered easily accessible information. Additionally, more physicians who did not inform patients about ADRs agreed that ADR communication can lead to anxiety and discontinuing treatment.

Conclusion

The study indicates that, although orthopaedic physicians had positive attitudes towards providing ADR information to patients, improvement is needed in communicating NSAID risk information.
Biological notes on the reef stingray, Urobatis concentricus, an endemic species of Mexico
Authors: Ehemann N. R. , Pérez‐Palafox X. A. , Pabón‐Aldana K. , Mejía‐Falla P. A. , Navia A. F. , Cruz‐Escalona V. H.
Published: August 2017

This study found that the reef stingray Urobatis concentricus presents a matrotrophic aplacental viviparous reproduction with yolk sac and trophonemata formation. Growth of ovarian follicles occurs asynchronously and continuously with fecundity of three embryos per female. A maximum size of 58·4 cm total length and 37·6 cm disc width was recorded, corresponding to a mature female of 3 or 4 years of age.
False belief attribution in children with Williams syndrome: the answer is in the emotion
Authors: Campos R. , Martínez‐Castilla P. , Sotillo M.
Published: August 2017

Background

Individuals with Williams syndrome (WS) show difficulties in attributing false beliefs, whereas they are better at attributing emotions. This study examines whether being asked about the emotion linked to a false belief, instead of explicitly about the belief, facilitates performance on theory of mind (ToM) tasks.

Method

Thirty children with WS and 90 typically developing children, who were individually matched on mental age (50–112 months), were administered six explicit (i.e. questions on belief) and six implicit (i.e. questions on emotion) trials of false belief tasks.

Results

Theory of mind competences were related to cognitive development. Children with WS performed comparably to typically developing children on the emotion questions.

Conclusion

Correct answers to questions on emotion reveal an implicit understanding of false belief. The Representational redescription process could be impaired in the domain of ToM in this population. This finding has relevant implications for the design of supports aiming to optimise the development of ToM competences in individuals with WS.
First case report of non‐human primates (Alouatta clamitans) with the hypervirulent Klebsiella pneumoniae serotype K1 strain ST 23: A possible emerging wildlife pathogen
Authors: Anzai Eleine Kuroki , de Souza Júnior Júlio César , Peruchi Amanda Rezende , Fonseca Juliana Mello , Gumpl Elke Kreuscher , Pignatari Antônio Carlos Campos , Hirano Zelinda Maria Braga , Silveira Alessandro Conrado de Oliveira
Published: August 2017

Background

Hypervirulent strain of Klebsiella pneumoniae genotype K1 isolates have recently emerged, causing severe pyogenic liver abscess complicated by devastating metastatic infections in humans.

Methods

We describe a short outbreak of the non‐human primate (NHP) research center, associated with a hypervirulent K. pneumoniae. The genetic similarity of the strains was evaluated by pulsed‐field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) techniques, and virulence encoding genes were detected by polymerase chain reaction (PCR).

Results

The isolates were phenotypically like strains causing community‐acquired invasive liver abscess syndrome in humans. All strains exhibited identical PFGE patterns and were found to belong to ST23 and presented a hypermucovisity phenotype and possessed magA and rmpA gene.

Conclusion

This is the first case report of NHPs caused by K. pneumoniae displaying a hypermucoviscosity phenotype and belonging to capsular serotypes K1 and ST23.
A mobile APP for sharing contacts on your cell
Authors: William Rebeck George , Pak Daniel T. S.
Published: August 2017

The Review highlighted in this Editorial followed a CAEN Return Home Grant
Pulmonary delivery of tea tree oil-β-cyclodextrin inclusion complexes for the treatment of fungal and bacterial pneumonia
Authors: Li Miao , Zhu Lifei , Zhang Tongtong , Liu Boming , Du Lina , Jin Yiguang
Published: August 2017

Objectives

Bacterial pneumonia is a common cause of death worldwide. Tea tree oil (TTO) is a potent antimicrobial natural product, which is formulated in dry powder inhalers (DPIs) for the treatment of fungal and bacterial pneumonia.

Methods

Tea tree oil-β-cyclodextrin inclusion complexes (TTO-β-CD) were prepared and characterized. Aerodynamic properties of TTO-β-CD powders were measured. The rat models of fungal (Candida albicans) and bacterial (Acinetobacter baumannii) pneumonia were prepared. Saline, TTO, TTO-β-CD and the positive drug (fluconazole or penicillin) were directly delivered to the rat lungs. Pathological and biological assays were conducted.

Key findings

Tea tree oil-β-CD powders had an appropriate aerodynamic diameter of 5.59 μm and the fine particle fraction of 51.22%, suitable for pulmonary delivery. TTO-β-CD showed higher and similar antipneumonic effects on the rat models than fluconazole and penicillin, respectively. The effects of TTO-β-CD were higher than TTO alone. The antipneumonic mechanisms involved blocking the recruitment of leucocytes and neutrophils, eliminating the microbes, downregulating pro-inflammatory cytokines (including tumour necrosis factor-α, interleukin-1β and interleukin-6), suppressing cyclooxygenase 2 expression, and further reducing lung injury.

Conclusions

Inhaled TTO-β-CD powders have the advantages of portability, high stability, self-administration, high lung deposition and good antipneumonic effect. It is a promising DPI for the treatment of fungal and bacterial pneumonia.
Pharmacokinetic and ocular microdialysis study of oral ginkgo biloba extract in rabbits by UPLC-MS/MS determination
Authors: Wang Shuya , Li Ding , Pi Jiaxin , Li Wen , Zhang Bing , Qi Dongli , Li Nan , Guo Pan , Liu Zhidong
Published: August 2017

Objectives

The purpose of this work was to determine and investigate the absorption of ginkgo terpenoids (GT) in plasma and aqueous humour after oral administration of ginkgo biloba extract (GBE) by UPLC-MS/MS method.

Methods

The UPLC-MS/MS determination of GT employed the multiple reaction monitoring mode using an electrospray negative ionization. The rabbits were orally administered the suspension of GBE at a dose of 500 mg/kg. Serial plasma and dialysate samples were collected at the corresponding time and then analysed by UPLC-MS/MS.

Key findings

In plasma, the mean AUC from 0 to 48 h was 14.12, 12.59, 23.75, 1.51 h μg/ml for GLJ and 5.34 h μg/ml for GLA, GLB, GLC, GLJ and BLL, respectively. In aqueous humour, the five ginkgo terpenoids have been detected. Compared with the other four GT, BLL has better absorption in the eyes.

Conclusions

A selective and reproducible UPLC-MS/MS method was developed and validated to determine and investigate the absorption of ginkgo terpenoids in plasma and aqueous humour of rabbits after oral administration of GBE. The main five ginkgo terpenoids could be absorbed into eyes.
In-silico profiling of the biological activities of Amaryllidaceae alkaloids
Authors: Shawky Eman
Published: August 2017

Objectives

The large number of publications about Amaryllidaceae alkaloids reflects the abundance and variety in biological activity of these alkaloids. An in-silico approach was implemented in this work to rationalize the individual alkaloids to molecular biological activity.

Methods

A database was generated containing 313 Amaryllidaceae alkaloids which were then subjected to in-silico-validated structure-based virtual screening using extra precision (XP) approach of Glide docking program. Further pharmacophore detection of the high scorers resulted in a hybrid model considering the structural and spatial characteristics of the molecules. The focus was laid on representative targets against viral infections, acetylcholinesterase and cancer. BEDROC studies were used for validation of the accuracy of docking methods.

Key findings

As expected, galanthamine-type alkaloids were the most active against hACHE; yet, lycorenine- and tazettine-type alkaloids contributed significantly, while lycorine-type alkaloids dominated the hit list against HIV-1 PR target protein and were significantly active against HIV-1 RT and influenza NA. Surprisingly, belladine-type alkaloids showed the highest number of hits against HDAC2, while lycorine- and narciclasine-type alkaloids dominated the hit lists against Aurora kinase A and VEGFR2.

Conclusions

This report provides useful information on Amaryllidaceae alkaloids and serves as a starting point to access their undiscovered biological activity.
Improved pharmacokinetic and pharmacodynamic attributes of artemether–lumefantrine-loaded solid SMEDDS for oral administration
Authors: Bhandari Sameer , Bhandari Vikram , Sood Jatin , Jaswal Sunil , Rana Vikas , Bedi Neena , Sehgal Rakesh , Tiwary Ashok K
Published: August 2017

Objectives

To evaluate the in-vivo efficacy of solid SMEDDS containing combination of artemether and lumefantrine.

Methods

Formulation development of solid SMEDDS containing combination of artemether and lumefantrine was carried out using spray drying technique. These S-SMEDDS were evaluated for reduction in parasitemia and mortality as well as subacute toxicity in mice. Haematology, biochemical parameters and histopathology were performed for evaluating safety of formulation. Pharmacokinetic characterization of both drugs was performed after oral administration in rats.

Key findings

Optimized solid SMEDDS containing low, medium and high dose were more effective in reducing parasitemia and mortality of mice as compared to marketed tablets containing high dose of these drugs. Single oral administration of solid SMEDDS containing high-dose combination could maintain plasma concentration of lumefantrine above the minimum effective concentration for ≈4 days.

Conclusions

Solid SMEDDS containing low-, medium- and high-dose combination of artemether and lumefantrine are more effective than marketed tablets.
Intranasal administration of brain-targeted HP-β-CD/chitosan nanoparticles for delivery of scutellarin, a compound with protective effect in cerebral ischaemia
Authors: Liu Shanshan , Ho Paul C
Published: August 2017

Objectives

Scutellarin (SCU) is a traditional Chinese medicine used for the treatment of ischaemic cerebrovascular disease, but its clinic applications have been limited due to its poor water solubility, poor bioavailability and short half-life. In comparison with the conventional oral and intravenous administration, nasal administration may help targeting the drug more directly to brain. Thus, we proposed to employ a novel SCU-loaded HP-β-CD/chitosan nanoparticles (CD/CS-SCU-NPs) to deliver SCU to brain through the nasal route.

Methods

CD/CS-SCU-NPs were prepared by an ionic cross-linking method. The NPs formulation was tested in vivo in C57BL mice. The concentrations of SCU in brain and plasma after intranasal and oral administration of the CD/CS-SCU-NPs and after intranasal administration of SCU solution (SCU-SL) were determined and brain targeting parameters were calculated.

Key findings

Compared to the intranasal administration of SCU-SL, intranasal and oral administration of the CD/CS-SCU-NPs increased accumulation of SCU in brain, indicating that CD/CS-SCU-NPs have obvious brain targeting advantage, although the advantage is more evident after intranasal administration.

Conclusions

Findings from in-vivo study indicated that much higher SCU brain exposure was observed after intranasal administration of the CD/CS-SCU-NPs. Administration of CD/CS-SCU-NPs through the nasal route would have potential to treat ischemic cerebrovascular disease.
Circannual variation of mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma
Authors: Cusato Jessica , De Francia Silvia , Allegra Sarah , Carrella Simona , Pirro Elisa , Piccione Francesca Maria , De Martino Francesca , Ferrero Anna , Daffara Fulvia Claudia , Terzolo Massimo , Berruti Alfredo , Di Carlo Francesco , Tampellini Marco , D'Avolio Antonio
Published: August 2017

Objectives

Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'-DDE (dichlorodiphenylethene) and o,p'-DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren® for at least 6 months.

Methods

We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used.

Key findings

Results showed an evidence of a seasonal trend for the three substance (o,p'-DDD, o,p'-DDE and o,p'-DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window.

Conclusions

In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required.
The conditional stimulation of rat organic cation transporter 2, but not its human ortholog, by mesoridazine: the possibility of the involvement of the high-affinity binding site of the transporter in the stimulation
Authors: Hyung Sungwoo , Pyeon Wonji , Park Ji Eun , Song Yoo-Kyung , Chung Suk-Jae
Published: August 2017

Objectives

To study the functional consequences of the human and rat forms of OCT2 in the presence of phenothiazines.

Methods

MDCK cells expressing human or rat OCT2 were established, and MPP+ transport was determined by uptake assays. Concentration dependency was studied for the stimulatory/inhibitory effects of phenothiazines on MPP+ transport.

Key findings

Among the 11 phenothiazines examined, the majority were found to have comparable effects on transporter function between the orthologous forms, while three phenothiazines, particularly mesoridazine, had complex impacts on transporter function. For rOCT2, mesoridazine stimulated transport at 0.1 and 1 μmMPP+ with the mesoridazine concentration–uptake curve becoming bell-shaped. This conditional effect became less pronounced at 30 μmMPP+, resulting in an inhibition curve with a typical profile. For hOCT2, mesoridazine behaved as a typical inhibitor of transporter function at all MPP+ concentrations, although the kinetics of inhibition were still affected by the substrate concentration.

Conclusions

The conditional stimulation by mesoridazine in rOCT2, and the lack thereof in hOCT2, may be a manifestation of the interaction of phenothiazine with substrate binding at the high-affinity site of the OCT2. As OCT2 was previously indicated in some drug–drug interactions, the conditional stimulation of OCT2 and its potential species-differences may be of practical relevance.
The contribution of food composition resources to nutrition science methodology
Authors: Finglas P. , Roe M. , Pinchen H. , Astley S.
Published: August 2017

Advances in nutrition science methods and tools have underpinned better understanding of the complex interactions between diet, nutrition and health. One example is the development of food composition tables, which provide detailed information about the energy and nutrient content of foods. They are important in many fields, including clinical practice and research, and are used in a variety of ways; for example, to assess national population‐level programmes and surveys, formulate emergency food supplies and develop therapeutic diets. In recent years, food composition tables have widened in scope and accessibility but most do not include bioactive compounds, the consumption of which is associated with reduced risk of cancer and cardiovascular disease.

Established in 2009, European Food Information Resource (EuroFIR) Association Internationale Sans But Lucratif (AISBL) is a non‐profit member‐based association in Belgium and a leading advocate for food information in Europe. It promotes the use of food composition data across the wider food, nutrition and health research and policy landscapes, raises awareness and understanding of the value of these data, especially for consumers in making healthier dietary choices, and works with other organisations [e.g. Food and Agriculture Organization (FAO) of the United Nations] to facilitate improved data quality, storage and access to encourage wider exploitation of food composition data for both research and commercial purposes.

EuroFIR has produced a range of tools to help data compilers and helped develop a European standard for food composition data to support the exchange and comparison of data. It is essential that investment to improve these tools and develop new methods continues, especially in regions without food composition databases. Such activities also need to be cost‐effective and scientifically robust, and engage effectively with stakeholders.
75 years of Family Food, 50 years of the British Nutrition Foundation
Authors: Lee D. , Worth I.
Published: August 2017

The Family Food survey recently published its 75th consecutive year of estimates. It has been monitoring household expenditure, purchases and derived nutritional intake since 1940. The story of its inception involves some significant names in the history of nutrition, some of whom were also important figures in the early years of the British Nutrition Foundation. This paper recounts the history of the survey from 1940 to the present day and comments on some selected long‐term nutritional trends the data reveal.
The contribution of epidemiology to nutrition science
Authors: Wiseman M.
Published: August 2017

Epidemiology is the study of the distribution of the occurrence and causes of disease. The non‐random distribution of the incidence of diseases, and factors associated with them, gives clues both to their causation and to possibilities of prevention. While an understanding of the biological processes that underpin associations can be useful in ascribing causality, it is not essential, nor necessary for developing preventive options. Epidemiology is essentially an observational discipline and therefore does not have the advantages of randomised experimental studies of avoiding confounding and other problems relating to measurement, in particular relating to diet and nutrition status. However, epidemiologic studies do have advantages of observing hard outcomes in typical populations over decades, which is valuable when exploring aetiology of chronic non‐communicable diseases. Nutritional epidemiology has been the main basis for understanding the causes and potential prevention of obesity, type 2 diabetes, cancer and cardiovascular diseases. When better integrated with in vitro and in vivo experimental data from humans and animals, nutritional epidemiology will remain a critical tool in the armoury for understanding the causes of disease, and offer targets for prevention.
Governmental financial resilience under austerity in Austria, England and Italy: How do local governments cope with financial shocks?
Authors: Barbera Carmela , Jones Martin , Korac Sanja , Saliterer Iris , Steccolini Ileana
Published: August 2017

The recent economic and fiscal crisis provides an opportunity for learning lessons of general and practical relevance about how governments face shocks affecting their financial conditions. This article draws on the resilience concept to investigate the organizational capacities that are deployed and/or built by local governments (LGs) to respond to such shocks, looking at their combinations and interactions with environmental conditions. The article presents the results of a multiple‐case analysis of 12 European LGs across Austria, Italy and England. The analysis allows us to highlight and operationalize different patterns of financial resilience, that is, self‐regulation, constrained or reactive adaptation, contented or powerless fatalism, that are the result of the interaction and development over time of different internal and external dimensions.
Influence of gaseous inclusions on aluminum-tungsten coatings investigated by XPS
Authors: Marin Alexandru , Lungu Cristian P. , Porosnicu Corneliu
Published: August 2017

Although international thermonuclear experimental reactor project employs the use of beryllium–tungsten system as plasma-facing material in nuclear fusion devices, the scientific fusion community still considers aluminum–tungsten configuration a promising candidate for fusion-related devices, aluminum aiming to be a beryllium replacement. This study provides in-depth x-ray photoelectron spectroscopy results on the interaction of aluminum and tungsten atoms in the surface layers prepared in various gaseous environments, important for the fusion community: vacuum, nitrogen, helium, and oxygen. A surprising outcome of the analysis is the suggested aluminum–tungsten surface alloying even at temperatures below 100 °C as well as the chemical interaction between aluminum and tungsten atoms, with the formation of aluminum tungstate, the two surface processes reinforcing the conclusion of surface mixing metals. Additionally, aluminum has a particular behavior by protecting and maintaining tungsten in an alloyed and unoxidized state for vacuum, nitrogen, and helium plasma environments, while in the presence of oxygen manages to preserve tungsten state of alloying.
A Randomized Controlled Trial Shows that both 14-Day Hybrid and Bismuth Quadruple Therapies Cure Most Patients with Helicobacter pylori Infection in Populations with Moderate Antibiotic Resistance
Authors: Tsay Feng-Woei , Wu Deng-Chyang , Yu Hsien-Chung , Kao Sung-Shuo , Lin Kung-Hung , Cheng Jin-Shiung , Wang Huay-Min , Chen Wen-Chi , Sun Wei-Chih , Tsai Kuo-Wang , Hsu Ping-I
Published: August 2017

Hybrid therapy is a novel two-step treatment achieving a high eradication rate for
Helicobacter pylori
infection. Currently, whether this new therapy achieves a higher eradication rate than bismuth quadruple therapy remains an unanswered question. The aim of this prospective, randomized comparative study was to investigate the efficacies of 14-day hybrid therapy and bismuth quadruple therapy in the treatment of
H. pylori
infection. From July 2013 to June 2015, eligible
H. pylori
-infected subjects were randomly assigned to receive either 14-day bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) or 14-day hybrid therapy (a 7-day dual therapy with pantoprazole plus amoxicillin, followed by a 7-day quadruple therapy with pantoprazole plus amoxicillin, clarithromycin, and metronidazole).
H. pylori
status was examined 6 weeks after the end of treatment. Three hundred thirty
H. pylori
-infected participants were randomized to receive 14-day bismuth quadruple therapy (
n
= 164) or 14-day hybrid therapy (
n
= 166). The eradication rates by intention-to-treat analysis were similar: 93.9% versus 92.8%, respectively (95% confidence interval [CI], −4.3% to 5.4%;
P
= 0.68). Per-protocol analysis yielded similar results (96.7% versus 94.9%, respectively;
P
= 0.44). However, bismuth quadruple therapy had a higher frequency of adverse events than hybrid therapy (55.5% versus 15.7%, respectively; 95% CI, 30.4% to 49.2%;
P
< 0.001). The two treatments exhibited comparable drug adherence (93.9% versus 97%, respectively). The resistance rates of antibiotics were: clarithromycin, 16.7% of patients; amoxicillin, 1.3%; metronidazole, 25%; and tetracycline, 0%. In the bismuth quadruple therapy group, the eradication rate of metronidazole-resistant strains was lower than that of metronidazole-susceptible strains (70.0% versus 96.4%, respectively;
P
= 0.04). In the hybrid therapy group, no significant impact of clarithromycin or metronidazole resistance on eradication rates was identified. Both 14-day hybrid and bismuth quadruple therapies cure most patients with
H. pylori
infection in populations with moderate antibiotic resistance. However, the 14-day hybrid therapy has fewer adverse effects than the bismuth quadruple therapy. (This study has been registered at ClinicalTrials.gov under identifier NCT02541864.)
No Clinically Relevant Drug-Drug Interactions between Methadone or Buprenorphine-Naloxone and Antiviral Combination Glecaprevir and Pibrentasvir
Authors: Kosloski Matthew P. , Zhao Weihan , Asatryan Armen , Kort Jens , Geoffroy Pierre , Liu Wei
Published: August 2017

The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (
R
)- and (
S
)-methadone (≤5% difference) and for buprenorphine and naloxone (≤24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone.