Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats

Background and purpose: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg-1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg-1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT = LT0/(1 + MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 mg·mL-1. Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics

Electrophysiological and morphological heterogeneity of slow firing neurons in medial septal/diagonal band complex as revealed by cluster analysis

Slow firing septal neurons modulate hippocampal and neocortical functions. Electrophysiologically, it is unclear whether slow firing neurons belong to a homogeneous neuronal population. To address this issue, whole-cell patch recordings and neuronal reconstructions were performed on rat brain slices containing the medial septum/diagonal band complex (MS/DB). Slow firing neurons were identified by their low firing rate at threshold (\u3c 5Hz) and lack of time-dependent inward rectification (Ih). Unsupervised cluster analysis was used to investigate whether slow firing neurons could be further classified into different subtypes. The parameters used for the cluster analysis included latency for first spike, slow afterhyperpolarizing potential, maximal frequency and action potential (AP) decay slope. Neurons were grouped into three major subtypes. The majority of neurons (55%) were grouped as cluster I. Cluster II (17% of neurons) exhibited longer latency for generation of the first action potential (246.5±20.1 ms). Cluster III (28% of neurons) exhibited higher maximal firing frequency (25.3±1.7 Hz) when compared to cluster I (12.3±0.9 Hz) and cluster II (11.8±1.1 Hz) neurons. Additionally, cluster III neurons exhibited faster action potentials at suprathreshold. Interestingly, cluster II neurons were frequently located in the medial septum whereas neurons in cluster I and III appeared scattered throughout all MS/DB regions. Sholl’s analysis revealed a more complex dendritic arborization in cluster III neurons. Cluster I and II neurons exhibited characteristics of “true” slow firing neurons whereas cluster III neurons exhibited higher frequency firing patterns. Several neurons were labeled with a cholinergic marker, Cy3-conjugated 192 IgG (p75NTR), and cholinergic neurons were found to be distributed among the three clusters. Our findings indicate that slow firing medial septal neurons are heterogeneous and that soma location is an important determinant of their electrophysiological properties. Thus, slow firing neurons from different septal regions have distinct functional properties, most likely related to their diverse connectivity

Results of the engineering run of the coherent neutrino nucleus interaction experiment (CONNIE)

The CONNIE detector prototype is operating at a distance of 30 m from the core of a 3.8 GWth nuclear reactor with the goal of establishing Charge-Coupled Devices (CCD) as a new technology for the detection of coherent elastic neutrino-nucleus scattering. We report on the results of the engineering run with an active mass of 4 g of silicon. The CCD array is described, and the performance observed during the first year is discussed. A compact passive shield was deployed around the detector, producing an order of magnitude reduction in the background rate. The remaining background observed during the run was stable, and dominated by internal contamination in the detector packaging materials. The in-situ calibration of the detector using X-ray lines from fluorescence demonstrates good stability of the readout system. The event rates with the reactor ON and OFF are compared, and no excess is observed coming from nuclear fission at the power plant. The upper limit for the neutrino event rate is set two orders of magnitude above the expectations for the standard model. The results demonstrate the cryogenic CCD-based detector can be remotely operated at the reactor site with stable noise below2 e RMS and stable background rates. The success of the engineering test provides a clear path for the upgraded 100 g detector to be deployed during 2016.Fil: Aguilar Arevalo, A.. Universidad Nacional Autónoma de México; MéxicoFil: Bertou, Xavier Pierre Louis. Comisión Nacional de Energía Atómica; Argentina. Comisión Nacional de Energía Atómica. Fundación José A. Balseiro; ArgentinaFil: Bonifazi, C.. Universidade Federal do Rio de Janeiro; BrasilFil: Butner, M.. Fermi National Accelerator Laboratory; Estados UnidosFil: Cancelo, G.. Fermi National Accelerator Laboratory; Estados UnidosFil: Castañeda Vazquez, A.. Universidad Nacional Autónoma de México; MéxicoFil: Cervantes Vergara, B.. Universidad Nacional Autónoma de México; MéxicoFil: Chavez, C. R.. Universidad Nacional de Asunción; ParaguayFil: Da Motta, H.. Centro Brasileiro de Pesquisas Físicas; BrasilFil: D'Olivo, J. C.. Universidad Nacional Autónoma de México; MéxicoFil: Dos Anjos, J.. Centro Brasileiro de Pesquisas Físicas; BrasilFil: Estrada, J.. Fermi National Accelerator Laboratory; Estados UnidosFil: Fernández Moroni, Guillermo. Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ford, R.. Fermi National Accelerator Laboratory; Estados UnidosFil: Foguel, A.. Centro Brasileiro de Pesquisas Físicas; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Hernandez Torres, K. P.. Universidad Nacional Autónoma de México; MéxicoFil: Izraelevitch, F.. Fermi National Accelerator Laboratory; Estados UnidosFil: Kavner, A.. University of Michigan; Estados UnidosFil: Kilminster, B.. Universitat Zurich; SuizaFil: Kuk, K.. Fermi National Accelerator Laboratory; Estados UnidosFil: Lima Jr, H. P.. Centro Brasileiro de Pesquisas Físicas; BrasilFil: Makler, M.. Centro Brasileiro de Pesquisas Físicas; BrasilFil: Molina, J.. Universidad Nacional de Asunción; ParaguayFil: Moreno Granados, G.. Universidad Nacional Autónoma de México; MéxicoFil: Moro, Juan Manuel. Universidad Nacional del Sur. Departamento de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paolini, Eduardo Emilio. Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto ; ArgentinaFil: Sofo Haro, Miguel Francisco. Comision Nacional de Energia Atomica. Gerencia D/area de Energia Nuclear; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tiffenberg, Javier Sebastian. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Trillaud, F.. Universidad Nacional Autónoma de México; MéxicoFil: Wagner, S.. Centro Brasileiro de Pesquisas Físicas; Brasil. Pontificia Universidade Católica do Rio Grande do Sul; Brasi

Pharmacokinetic/Pharmacodynamic Modeling of Antipyretic and Anti-Inflammatory Effects of Naproxen in the Rat

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively

A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line

<p>Abstract</p> <p>Background</p> <p>Enhancement of tumor cell sensitivity may help facilitate a reduction in drug dosage using conventional chemotherapies. Consequently, it is worthwhile to search for adjuvants with the potential of increasing chemotherapeutic drug effectiveness and improving patient quality of life. Natural products are a very good source of such adjuvants.</p> <p>Methods</p> <p>The biological activity of a fraction enriched in hydrolysable polyphenols (P2Et) obtained from <it>Caesalpinia spinosa </it>was evaluated using the hematopoietic cell line K562. This fraction was tested alone or in combination with the conventional chemotherapeutic drugs doxorubicin, vincristine, etoposide, camptothecin and taxol. The parameters evaluated were mitochondrial depolarization, caspase 3 activation, chromatin condensation and clonogenic activity.</p> <p>Results</p> <p>We found that the P2Et fraction induced mitochondrial depolarization, activated caspase 3, induced chromatin condensation and decreased the clonogenic capacity of the K562 cell line. When the P2Et fraction was used in combination with chemotherapeutic drugs at sub-lethal concentrations, a fourfold reduction in doxorubicin inhibitory concentration 50 (IC₅₀) was seen in the K562 cell line. This finding suggested that P2Et fraction activity is specific for the molecular target of doxorubicin.</p> <p>Conclusions</p> <p>Our results suggest that a natural fraction extracted from <it>Caesalpinia spinosa </it>in combination with conventional chemotherapy in combination with natural products on leukemia cells may increase therapeutic effectiveness in relation to leukemia.</p

VAMOS: a Pathfinder for the HAWC Gamma-Ray Observatory

VAMOS was a prototype detector built in 2011 at an altitude of 4100m a.s.l. in the state of Puebla, Mexico. The aim of VAMOS was to finalize the design, construction techniques and data acquisition system of the HAWC observatory. HAWC is an air-shower array currently under construction at the same site of VAMOS with the purpose to study the TeV sky. The VAMOS setup included six water Cherenkov detectors and two different data acquisition systems. It was in operation between October 2011 and May 2012 with an average live time of 30%. Besides the scientific verification purposes, the eight months of data were used to obtain the results presented in this paper: the detector response to the Forbush decrease of March 2012, and the analysis of possible emission, at energies above 30 GeV, for long gamma-ray bursts GRB111016B and GRB120328B.Comment: Accepted for pubblication in Astroparticle Physics Journal (20 pages, 10 figures). Corresponding authors: A.Marinelli and D.Zaboro

Hysteresis in Pressure-Driven DNA Denaturation

In the past, a great deal of attention has been drawn to thermal driven denaturation processes. In recent years, however, the discovery of stress-induced denaturation, observed at the one-molecule level, has revealed new insights into the complex phenomena involved in the thermo-mechanics of DNA function. Understanding the effect of local pressure variations in DNA stability is thus an appealing topic. Such processes as cellular stress, dehydration, and changes in the ionic strength of the medium could explain local pressure changes that will affect the molecular mechanics of DNA and hence its stability. In this work, a theory that accounts for hysteresis in pressure-driven DNA denaturation is proposed. We here combine an irreversible thermodynamic approach with an equation of state based on the Poisson-Boltzmann cell model. The latter one provides a good description of the osmotic pressure over a wide range of DNA concentrations. The resulting theoretical framework predicts, in general, the process of denaturation and, in particular, hysteresis curves for a DNA sequence in terms of system parameters such as salt concentration, density of DNA molecules and temperature in addition to structural and configurational states of DNA. Furthermore, this formalism can be naturally extended to more complex situations, for example, in cases where the host medium is made up of asymmetric salts or in the description of the (helical-like) charge distribution along the DNA molecule. Moreover, since this study incorporates the effect of pressure through a thermodynamic analysis, much of what is known from temperature-driven experiments will shed light on the pressure-induced melting issue

GW190412: Observation of a Binary-Black-Hole Coalescence with Asymmetric Masses

We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M_⊙ black hole merged with a ∼8 M_⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs

Properties and Astrophysical Implications of the 150 M_⊙ Binary Black Hole Merger GW190521

The gravitational-wave signal GW190521 is consistent with a binary black hole (BBH) merger source at redshift 0.8 with unusually high component masses, 85⁺²¹₋₁₄ M_⊙ and 66⁺¹⁷₋₁₈ M_⊙, compared to previously reported events, and shows mild evidence for spin-induced orbital precession. The primary falls in the mass gap predicted by (pulsational) pair-instability supernova theory, in the approximate range 65–120 M_⊙. The probability that at least one of the black holes in GW190521 is in that range is 99.0%. The final mass of the merger 142⁺²⁸₋₁₆ M_⊙) classifies it as an intermediate-mass black hole. Under the assumption of a quasi-circular BBH coalescence, we detail the physical properties of GW190521's source binary and its post-merger remnant, including component masses and spin vectors. Three different waveform models, as well as direct comparison to numerical solutions of general relativity, yield consistent estimates of these properties. Tests of strong-field general relativity targeting the merger-ringdown stages of the coalescence indicate consistency of the observed signal with theoretical predictions. We estimate the merger rate of similar systems to be 0.13_(-0.11)^(+0.30) Gpc⁻³ yr⁻¹. We discuss the astrophysical implications of GW190521 for stellar collapse and for the possible formation of black holes in the pair-instability mass gap through various channels: via (multiple) stellar coalescences, or via hierarchical mergers of lower-mass black holes in star clusters or in active galactic nuclei. We find it to be unlikely that GW190521 is a strongly lensed signal of a lower-mass black hole binary merger. We also discuss more exotic possible sources for GW190521, including a highly eccentric black hole binary, or a primordial black hole binary