The influence of the preparation methods on the inclusion of model drugs in a β-cyclodextrin cavity

NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmaceutics and Biopharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Eur J Pharm Biopharm. 2009 Feb;71(2):377-386. Epub 2008 Oct 17.The work aims to prove the complexation of two model drugs (ibuprofen, IB and indomethacin, IN) by bcyclodextrin (bCD), and the effect of water in such a process, and makes a comparison of their complexation yields. Two methods were considered: kneading of a binary mixture of the drug, bCD, and inclusion of either IB or IN in aqueous solutions of bCD. In the latter method water was removed by air stream, spray-drying and freeze-drying. To prove the formation of complexes in final products, optical microscopy, UV spectroscopy, IR spectroscopy, DSC, X-ray and NMR were considered. Each powder was added to an acidic solution (pH = 2) to quantify the concentration of the drug inside bCD cavity. Other media (pH = 5 and 7) were used to prove the existence of drug not complexed in each powder, as the drugs solubility increases with the pH. It was observed that complexation occurred in all powders, and that the fraction of drug inside the bCD did not depend neither on the method of complexation nor on the processes of drying considered

Comparison of ibuprofen release from minitablets and capsules containing ibuprofen: β-Cyclodextrin complex

NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmaceutics and Biopharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Eur J Pharm Biopharm. 2011 May;78(1):58-66. Epub 2010 Dec 30.Mixtures containing ibuprofen (IB) complexed with b-cyclodextrin (bCD) obtained by two complexation methods [suspension/solution (with water removed by air stream, spray- and freeze-drying) and kneading technique] were processed into pharmaceutical dosage forms (minitablets and capsules). Powders (IB, bCD and IBbCD) were characterized for moisture content, densities (true and bulk), angle of repose and Carr’s index, X-ray and NMR. From physical mixtures and IBbCD complexes without other excipients were prepared 2.5-mm-diameter minitablets and capsules. Minitablets were characterized for the energy of compaction, tensile strength, friability, density and IB release (at pH 1.0 and 7.2), whereby capsules were characterized for IB release. The results from the release of IB were analyzed using different parameters, namely, the similarity factor (f2), the dissolution efficiency (DE) and the amounts released at a certain time (30, 60 and 180 min) and compared statistically (a = 0.05). The release of IB from the minitablets showed no dependency on the amount of water used in the formation of the complexes. Differences were due to the compaction force used or the presence of a shell for the capsules. The differences observed were mostly due to the characteristics of the particles (dependent on the method considered on the formation of the complexes) and neither to the dosage form nor to the complex of the IB

Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier

Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1-/- mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1-/- mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis

The mechano-ubiquitinome of articular cartilage: differential ubiquitination and activation of a group of ER-associated DUBs and ER stress regulators

Understanding how connective tissue cells respond to mechanical stimulation is important to human health and disease processes in musculoskeletal diseases. Injury to articular cartilage is a key risk factor in predisposition to tissue damage and degenerative osteoarthritis. Recently, we have discovered that mechanical injury to connective tissues including murine and porcine articular cartilage causes a significant increase in Lysine 63- polyubiquitination. Here we identified the ubiquitin signature that is unique to injured articular cartilage tissue post mechanical injury (the “mechano-ubiquitinome”). A total of 463 ubiquitinated peptides were identified, with an enrichment of ubiquitinated peptides of proteins involved in protein processing in the endoplasmic reticulum (ER), also known as the ER-associated degradation (ERAD) response, including YOD1, BRCC3, ATXN3 and USP5 as well as the ER stress regulators, RAD23B, VCP/p97 and Ubiquilin 1. Enrichment of these proteins suggested an injury-induced ER stress response and, for instance, ER stress markers DDIT3/CHOP and BIP/GRP78 were upregulated following cartilage injury on the protein and gene expression levels. Similar ER stress induction was also observed in response to tail fin injury in zebrafish larvae, suggesting a generic response to tissue injury. Furthermore, a rapid increase in global DUB activity following injury and significant activity in human osteoarthritic cartilage was observed using DUB specific activity probes. Combined, these results implicate the involvement of ubiquitination events and activation of a set of DUBs and ER stress regulators in cellular responses to cartilage tissue injury and in osteoarthritic cartilage tissues. This link through the ERAD pathway makes this protein set attractive for further investigation in in vivo models of tissue injury and for targeting in osteoarthritis and related musculoskeletal diseases

Radioactivity Backgrounds in ZEPLIN-III

We examine electron and nuclear recoil backgrounds from radioactivity in the ZEPLIN-III dark matter experiment at Boulby. The rate of low-energy electron recoils in the liquid xenon WIMP target is 0.75$\pm$0.05 events/kg/day/keV, which represents a 20-fold improvement over the rate observed during the first science run. Energy and spatial distributions agree with those predicted by component-level Monte Carlo simulations propagating the effects of the radiological contamination measured for materials employed in the experiment. Neutron elastic scattering is predicted to yield 3.05$\pm$0.5 nuclear recoils with energy 5-50 keV per year, which translates to an expectation of 0.4 events in a 1-year dataset in anti-coincidence with the veto detector for realistic signal acceptance. Less obvious background sources are discussed, especially in the context of future experiments. These include contamination of scintillation pulses with Cherenkov light from Compton electrons and from $\beta$ activity internal to photomultipliers, which can increase the size and lower the apparent time constant of the scintillation response. Another challenge is posed by multiple-scatter $\gamma$-rays with one or more vertices in regions that yield no ionisation. If the discrimination power achieved in the first run can be replicated, ZEPLIN-III should reach a sensitivity of $\sim 1 \times 10^{-8}$ pb$\cdot$year to the scalar WIMP-nucleon elastic cross-section, as originally conceived.Peer Reviewe

Erythropoietin doping as cause of sudden death in athletes: an experimental study

Aims: To evaluate the cardiovascular (CV) effects of rhEPO treatment in rats under chronic aerobic exercise and to assess the probable cause of sudden death in one rat. Protocol: Male Wistar rats: control - sedentary; rhEPO - 50 IU/Kg/3xwk; swimming (EX) -1 hr, 3x/wk; EX+EPO. Hematology, catecholamines and serotonin, redox status and inflammation, were assessed. One rat of EX+EPO group suffered a sudden death episode. Results: rhEPO treatment in trained rats promoted several markers of increased CV risk. The sudden death rat tissues presented: lungs without signs of drowning; brain with vascular congestion; LV hypertrpphy and deregulations of cardiac fibers, together with a "cardiac liver", suggesting the hypothesis of heart failure as cause of death. Conclusion: The sudden death of a EX+EPO rat, due to a cardiac episode, together with the increased CV risk profile, strongly suggest a high life risk associated to the continuous rhEPO doping. The anatomo-pathological studies were determinant to establish the cause of death

Gloeothece sp. as a nutraceutical source-an improved method of extraction of carotenoids and fatty acids

The nutraceutical potential of microalgae boomed with the exploitation of new species and sustainable extraction systems of bioactive compounds. Thus, a laboratory-made continuous pressurized solvent extraction system (CPSE) was built to optimize the extraction of antioxidant compounds, such as carotenoids and PUFA, from a scarcely studied prokaryotic microalga, Gloeothece sp. Following "green chemical principles" and using a GRAS solvent (ethanol), biomass amount, solvent flow-rate/pressure, temperature and solvent volume-including solvent recirculation-were sequentially optimized, with the carotenoids and PUFA content and antioxidant capacity being the objective functions. Gloeothece sp. bioactive compounds were best extracted at 60?C and 180 bar. Recirculation of solvent in several cycles (C) led to an 11-fold extraction increase of ß-carotene (3C) and 7.4-fold extraction of C18:2 n6 t (5C) when compared to operation in open systems. To fully validate results CPSE, this system was compared to a conventional extraction method, ultrasound assisted extraction (UAE). CPSE proved superior in extraction yield, increasing total carotenoids extraction up 3-fold and total PUFA extraction by ca. 1.5-fold, with particular extraction increase of 18:3 n3 by 9.6-fold. Thus, CPSE proved to be an efficient and greener extraction method to obtain bioactive extract from Gloeothece sp. for nutraceutical purposes-with low levels of resources spent, while lowering costs of production and environmental impacts. © 2018 by the authors.Funding: This work was financially co-supported by: ZEBRALGRE (PTDC/CVT-WEL/5207/2014), founded by national funds through FCT supported by COMPETE 2020: Programa Operacional Competitividade e Internacionalização (POCI)-01-0145-FEDER-016797; by the Structured Program of R&D&I INNOVMAR—Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035, namely within the Research Line NOVELMAR—Novel marine products with biotechnological applications, within the R&D Institution CIIMAR (Interdisciplinary Centre of Marine and Environmental Research), supported by the Northern Regional Operational Programme (NORTE2020), through the ERDF; and by DINOSSAUR—PTDC/BBB-EBB/1374/2014-POCI-01-0145-FEDER-016640, funded by FEDER funds through COMPETE2020—POCI and by national funds through FCT—Fundacão para a Ciência e a Tecnologia, I.P

Measurement of single electron emission in two-phase xenon

We present the first measurements of the electroluminescence response to the emission of single electrons in a two-phase noble gas detector. Single ionization electrons generated in liquid xenon are detected in a thin gas layer during the 31-day background run of the ZEPLIN-II experiment, a two-phase xenon detector for WIMP dark matter searches. Both the pressure dependence and magnitude of the single-electron response are in agreement with previous measurements of electroluminescence yield in xenon. We discuss different photoionization processes as possible cause for the sample of single electrons studied in this work. This observation may have implications for the design and operation of future large-scale two-phase systems.Comment: 11 pages, 6 figure

Interacting Kasner-type cosmologies

It is well known that Kasner-type cosmologies provide a useful framework for analyzing the three-dimensional anisotropic expansion because of the simplification of the anisotropic dynamics. In this paper relativistic multi-fluid Kasner-type scenarios are studied. We first consider the general case of a superposition of two ideal cosmic fluids, as well as the particular cases of non-interacting and interacting ones, by introducing a phenomenological coupling function $q(t)$. For two-fluid cosmological scenarios there exist only cosmological scaling solutions, while for three-fluid configurations there exist not only cosmological scaling ones, but also more general solutions. In the case of triply interacting cosmic fluids we can have energy transfer from two fluids to a third one, or energy transfer from one cosmic fluid to the other two. It is shown that by requiring the positivity of energy densities there always is a matter component which violates the dominant energy condition in this kind of anisotropic cosmological scenarios.Comment: Accepted for publication in Astrophysics &Space Science, 8 page

The ZEPLIN II dark matter detector: data acquisition system and data reduction

ZEPLIN-II is a two-phase (liquid/gas) xenon dark matter detector searching for WIMP-nucleon interactions. In this paper we describe the data acquisition system used to record the data from ZEPLIN-II and the reduction procedures which parameterise the data for subsequent analysis.Comment: 11 pages, 10 figure