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- Caccavo, D., et al.
(författare)
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Mathematical modelling of the drug release from an ensemble of coated pellets
- 2017
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 174:12, s. 1797-1809
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Tidskriftsartikel (refereegranskat)abstract
- Background and PurposeCoated pellets are widely used as oral drug delivery systems, being highly accepted by patients and with several advantages compared to single unit devices. However, their behaviour needs to be elucidated so as to improve the effectiveness of the formulations and reduce production costs. In spite of this important issue, few mathematical modelling studies have been attempted, mostly due to the complexities arising from the system's polydispersity (non-homogeneous multiple-unit particulate systems), which has been scarcely investigated using mechanistic models. Experimental approachA mechanistic mathematical model was developed that was able to describe the single pellet behaviour in terms of hydration, drug dissolution, diffusion and release and particle size. This model was then extended to describe and predict the behaviour of mono- and polydispersed ensembles of pellets. Key ResultsThe polydispersity arising from the size and distribution of the inert core was shown to have a minimal effect on the drug release profile, whereas the thickness and distribution of the polymeric film was found to be the key parameter determining the drug release. Conclusions and ImplicationsThe mechanistic model developed, which is capable of determining the polydispersity of the drug delivery system, was able to predict the release kinetics from ensembles of pellets and to highlight the key parameters that need to be controlled in the production of pellet-based drug delivery systems, demonstrating its use as a powerful predictive tool.
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- Kazlauske, Jurgita, 1981, et al.
(författare)
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Determination of the release mechanism of Theophylline from pellets coated with Surelease (R)-A water dispersion of ethyl cellulose
- 2017
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 528:1-2, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease (R) and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease (R) films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51 mm) of the coating layer controlling the drug release rate.
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- Ajore, Ram, et al.
(författare)
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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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- Ambite, Ines, et al.
(författare)
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Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets
- 2016
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration: The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).
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- Morero, B., et al.
(författare)
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Integrated Waste Management : Adding Value to Oil and Gas Industry Residues Through Co-processing
- 2023
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Ingår i: Waste and Biomass Valorization. - : Springer Science and Business Media LLC. - 1877-2641 .- 1877-265X. ; 14:4, s. 1391-1412
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Tidskriftsartikel (refereegranskat)abstract
- In developing countries, the sustainable management of materials into a circular economy framework is conditioned by several constraints, being economic limitations one of the most relevant. Integrated waste management could effectively aid in overcoming them. This work presents an exhaustive analysis from both economic and environmental points of view addressing the selection and design of treatment alternatives for the integrated management of urban and industrial wastes. We propose a mixed-integer mathematical programming formulation to determine the optimal set of treatments to convert wastes into energy, marketable products or innocuous materials, and we endorse the environmental performance through a life cycle analysis. In our case study, urban wastes include sewage sludge and municipal solid waste, while industrial wastes come from two sources: drill cuttings (an important oil and gas industry residue) and seasonal pomace waste from fruit processing. Treatment alternatives comprise anaerobic digestion, composting, recycling, bioremediation, compost amendment, thermal desorption and final disposal in landfill. Results for different scenarios show that even though the most profitable alternative is to dispose drill cuttings in landfills while processing organic wastes by anaerobic digestion, integrated management using biological treatment alternatives provides a more sustainable and still profitable strategy. We also demonstrate that the process integration increases the profitability and reduces the environmental impact significantly when compared with separate treatment alternatives for waste streams. Graphical abstract: [Figure not available: see fulltext.]
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- Ponticelli, Francesco, et al.
(författare)
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Safety and efficacy of coronary sinus narrowing in chronic refractory angina: Insights from the RESOURCE study.
- 2021
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 337, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- Refractory angina (RA) is considered the end-stage of coronary artery disease, and often has no interventional treatment options. Coronary sinus Reducer (CSR) is a recent addition to the therapeutic arsenal, but its efficacy has only been evaluated on small populations. The RESOURCE registry provides further insights into this therapy.The RESOURCE is an observational, retrospective registry that includes 658 patients with RA from 20 centers in Europe, United Kingdom and Israel. Prespecified endpoints were the amelioration of anginal symptoms evaluated with the Canadian Cardiovascular Society (CCS) score, the rates of procedural success and complications, and MACEs as composite of all-cause mortality, acute coronary syndromes, and stroke.At a median follow-up of 502days (IQR 225-1091) after CSR implantation, 39.7% of patients improved by ≥2 CCS classes (primary endpoint), and 76% by ≥1 class. Procedural success was achieved in 96.7% of attempts, with 3% of procedures aborted mostly for unsuitable coronary sinus anatomy. Any complication occurred in 5.7% of procedures, but never required bailout surgery nor resulted in intra- or periprocedural death or myocardial infarction. One patient developed periprocedural stroke after inadvertent carotid artery puncture. At the last available follow-up, overall mortality and MACE were 10.4% and 14.6% respectively. At one, three and five years, mortality rate at Kaplan-Meier analysis was 4%, 13.7%, and 23.4% respectively.CSR implantation is safe and reduces angina in patients with refractory angina.
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