Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h  pg/ml, CV% = 32.86), followed by intravenous (672 h  pg/ml, CV% = 32.18) and intranasal administration (515 h  pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option

Percolation of strings and the first RHIC data on multiplicity and tranverse momentum distributions

The dependence of the multiplicity on the number of collisions and the transverse momentum distribution for central and peripheral Au-Au collisions are studied in the model of percolation of strings relative to the experimental conditions at RHIC. The comparison with the first RHIC data shows a good agreement.Comment: RevTeX, 11 pages, 4 eps figures included using epsfi

Dark matter and sub-GeV hidden U(1) in GMSB models

Motivated by the recent PAMELA and ATIC data, one is led to a scenario with heavy vector-like dark matter in association with a hidden $U(1)_X$ sector below GeV scale. Realizing this idea in the context of gauge mediated supersymmetry breaking (GMSB), a heavy scalar component charged under $U(1)_X$ is found to be a good dark matter candidate which can be searched for direct scattering mediated by the Higgs boson and/or by the hidden gauge boson. The latter turns out to put a stringent bound on the kinetic mixing parameter between $U(1)_X$ and $U(1)_Y$: $\theta \lesssim 10^{-6}$. For the typical range of model parameters, we find that the decay rates of the ordinary lightest neutralino into hidden gauge boson/gaugino and photon/gravitino are comparable, and the former decay mode leaves displaced vertices of lepton pairs and missing energy with distinctive length scale larger than 20 cm for invariant lepton pair mass below 0.5 GeV. An unsatisfactory aspect of our model is that the Sommerfeld effect cannot raise the galactic dark matter annihilation by more than 60 times for the dark matter mass below TeV.Comment: 1+15 pages, 4 figures, version published in JCAP, references added, minor change

Zinc-dysprosium functionalized amyloid fibrils

The heterometallic Zn2Dy2 entity bearing partially saturated metal centres covalently decorates a highly ordered amyloid fibril core and the functionalised assembly exhibits catalytic Lewis acid behaviour

Robust modeling of human contact networks across different scales and proximity-sensing techniques

The problem of mapping human close-range proximity networks has been tackled using a variety of technical approaches. Wearable electronic devices, in particular, have proven to be particularly successful in a variety of settings relevant for research in social science, complex networks and infectious diseases dynamics. Each device and technology used for proximity sensing (e.g., RFIDs, Bluetooth, low-power radio or infrared communication, etc.) comes with specific biases on the close-range relations it records. Hence it is important to assess which statistical features of the empirical proximity networks are robust across different measurement techniques, and which modeling frameworks generalize well across empirical data. Here we compare time-resolved proximity networks recorded in different experimental settings and show that some important statistical features are robust across all settings considered. The observed universality calls for a simplified modeling approach. We show that one such simple model is indeed able to reproduce the main statistical distributions characterizing the empirical temporal networks

Lepton mass generation and family number violation mechanism in the SU(6)⊗U(1)SU(6)\otimes U(1) model

Lepton family number violation processes arise in the $SU(6)_L \otimes U(1)_Y$ model due to the presence of an extra neutral gauge boson, Z$'$, with family changing couplings, and due to the fact that this model demands the existence of heavy exotic leptons. The mixing of the standard Z with Z$'$ and the mixing of ordinary leptons with exotic ones induce together family changing couplings on the Z and therefore nonvanishing rates for lepton family number violation processes, such as $Z \to e \bar{\mu}$, $\mu \to ee\bar{e}$ and $\mu \to e\gamma$. Additional contributions to the processes $\mu \to e \gamma$ and $\mu \to ee \bar{e}$ are induced from the mass generation mechanism. This last type of contributions may compete with the above one, depending on the masses of the scalars which participate in the diagrams which generate radiatively the masses of the charged leptons. Using the experimental data we compute some bounds for the mixings parameters and for the masses of the scalars.Comment: 12 pages, Latex, 7 figures. Accepted for publication in Int. Journ. of Mod. Phys.

'Asking the right question'. A comparison of two approaches to gathering data on 'herbals' use in survey based studies

BACKGROUND:Over the last decade academic interest in the prevalence and nature of herbal medicines use by pregnant women has increased significantly. Such data are usually collected by means of an administered questionnaire survey, however a key methodological limitation using this approach is the need to clearly define the scope of 'herbals' to be investigated. The majority of published studies in this area neither define 'herbals' nor provide a detailed checklist naming specific 'herbals' and CAM modalities, which limits inter-study comparison, generalisability and the potential for meta-analyses. The aim of this study was to compare the self-reported use of herbs, herbal medicines and herbal products using two different approaches implemented in succession. METHODS:Cross-sectional questionnaire surveys of women attending for their mid-trimester scan or attending the postnatal unit following live birth at the Royal Aberdeen Maternity Hospital, North-East Scotland. The questionnaire utilised two approaches to collect data on 'herbals' use, a single closed yes/no answer to the question "have you used herbs, herbal medicines and herbal products in the last three months"; and a request to tick which of a list of 40 'herbals' they had used in the same time period. RESULTS:A total of 889 responses were obtained of which 4.3% (38) answered 'yes' to herbal use via the closed question. However, using the checklist 39% (350) of respondents reported the use of one or more specific 'herbals' (p<0.0001). The 312 respondents who reported 'no' to 'herbals' use via the closed question but "yes" via the checklist consumed a total of 20 different 'herbals' (median 1, interquartile range 1-2, range 1-6). CONCLUSIONS:This study demonstrates that the use of a single closed question asking about the use of 'herbals', as frequently reported in published studies, may not yield valid data resulting in a gross underestimation of actual use

Visualization of the modeled degradation of building flooring systems in building maintenance

The development of a maintenance programme for construction projects is a highly complex and data intensive undertaking. This exercise is characterised by the lack of relevant data on the one hand and the overwhelming amount of extraneous data on the other. The uncertainties and complexities have resulted in increased conservatism in the development of lifecycle evaluation of building maintenance programing, subsequently, these programmes tend to display the symptoms of either the maintenance actions being uneconomical or fall short of providing the appropriate service to the users of the building. The current research project is based on the premise that the visual approach will facilitate a just-in-time solution to maintenance scheduling, hence, the use of virtual simulation of the building is proposed. The broader aim of this research is to develop a complete building maintenance programme through visualisation of buildings as they degrade over time. Here, the focus is on the flooring system and the manner they degrade over time. This requires a better understanding of their pattern and rate of usage. To this end, Anthroposophy and Anthropocentric descriptions of human movement pattern have been used to describe the behaviour of 'subjects' and subsequently represent the pattern and density of the degradation of flooring systems. The mathematics representing this behaviour has been developed which enables it to be embedded into the proposed overall visual building maintenance model

Effect of Cellular Quiescence on the Success of Targeted CML Therapy

Similar to tissue stem cells, primitive tumor cells in chronic myelogenous leukemia have been observed to undergo quiescence; that is, the cells can temporarily stop dividing. Using mathematical models, we investigate the effect of cellular quiescence on the outcome of therapy with targeted small molecule inhibitors.According to the models, the initiation of treatment can result in different patterns of tumor cell decline: a biphasic decline, a one-phase decline, and a reverse biphasic decline. A biphasic decline involves a fast initial phase (which roughly corresponds to the eradication of cycling cells by the drug), followed by a second and slower phase of exponential decline (corresponding to awakening and death of quiescent cells), which helps explain clinical data. We define the time when the switch to the second phase occurs, and identify parameters that determine whether therapy can drive the tumor extinct in a reasonable period of time or not. We further ask how cellular quiescence affects the evolution of drug resistance. We find that it has no effect on the probability that resistant mutants exist before therapy if treatment occurs with a single drug, but that quiescence increases the probability of having resistant mutants if patients are treated with a combination of two or more drugs with different targets. Interestingly, while quiescence prolongs the time until therapy reduces the number of cells to low levels or extinction, the therapy phase is irrelevant for the evolution of drug resistant mutants. If treatment fails as a result of resistance, the mutants will have evolved during the tumor growth phase, before the start of therapy. Thus, prevention of resistance is not promoted by reducing the quiescent cell population during therapy (e.g., by a combination of cell activation and drug-mediated killing).The mathematical models provide insights into the effect of quiescence on the basic kinetics of the response to targeted treatment of CML. They identify determinants of success in the absence of drug resistant mutants, and elucidate how quiescence influences the emergence of drug resistant mutants

Dark Matter Sees The Light

We construct a Dark Matter (DM) annihilation module that can encompass the predictions from a wide array of models built to explain the recently reported PAMELA and ATIC/PPB-BETS excesses. We present a detailed analysis of the injection spectrums for DM annihilation and quantitatively demonstrate effects that have previously not been included from the particle physics perspective. With this module we demonstrate the parameter space that can account for the aforementioned excesses and be compatible with existing high energy gamma ray and neutrino experiments. However, we find that it is relatively generic to have some tension between the results of the HESS experiment and the ATIC/PPB-BETS experiments within the context of annihilating DM. We discuss ways to alleviate this tension and how upcoming experiments will be able to differentiate amongst the various possible explanations of the purported excesses.Comment: 47 pages, 17 figure