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- Tavelin, Staffan
(author)
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New Approaches to Studies of Paracellular Drug Transport in Intestinal Epithelial Cell Monolayers
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Studies of intestinal drug permeability have traditionally been performed in the colon-derived Caco-2 cell model. However, the permeability of these cell monolayers resembles that of the colon rather than that of the small intestine, which is the major site of drug absorption following oral administration. One aim of this thesis was therefore to develop a new cell culture model that mimics the permeability of the small intestine. 2/4/A1 cells are conditionally immortalized with a temperature sensitive mutant of SV40T. These cells proliferate and form multilayers at 33°C. At cultivation temperatures of 37 – 39°C, they stop proliferating and form monolayers. 2/4/A1 cells cultivated on permeable supports expressed functional tight junctions. The barrier properties of the tight junctions such as transepithelial electrical resistance and permeability to hydrophilic markers resembled those of the human small intestine in vivo. These cells lacked functional expression of drug transport proteins and can therefore be used as a model to study passive drug permeability unbiased by active transport. The permeability to diverse sets of drugs in 2/4/A1 was comparable to that of the human jejunum for both incompletely and completely absorbed drugs, and the prediction of human intestinal permeability was better in 2/4/A1 than in Caco-2 for incompletely absorbed drugs. The small intestinal-like paracellular permeability of 2/4/A1 thus enables better predictions of drug permeability in the small intestine than does Caco-2. The studies of the paracellular route and its importance for intestinal drug permeability was also in focus in the second part of this thesis, in which a new principle for tight junction modulation was developed, based on the primary structure of the extracellular tight junction protein occludin. Peptides corresponding to the N-terminus of the first extracellular loop increased the permeability of the tight junctions, but lacked apical effect. This problem was solved by conjugation of one peptide to a lipoamino acid, resulting in two diastereomers with different effects. The L-isomer had a sustained apical effect, while that of the D-isomer was transient. In conclusion, conjugated occludin peptides constitute a new class of tight junction modulators that can enhance the tight junction permeability.
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| 2. |
- Al-Hayali, Amani Ibraheem Younis, et al.
(author)
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Dissolution and precipitation behavior of ternary solid dispersions of Ezetimibe in biorelevant media : AAPS annual meeting and Exposition2014 USA
- 2014
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Conference paper (other academic/artistic)abstract
- PurposeTo prepare ternary solid dispersions of Ezetimibe (EZ) and investigate their powder dissolution and precipitation behavior(supersaturation) in simulated gastric and intestinal fluidsMethodsTernary solid dispersions of EZ were prepared with PVPK30 and Poloxamer 188 at different ratios. Spray drying and meltquenching methods were used for the preparation of these solid dispersions. The solid dispersions were characterized bybasic to advanced solid-state tools including Modulated differential scanning calorimetry (MDSC), Powder X-ray diffractionand Fourier transform infrared spectroscopy .Biorelevant simulated media (FaSSIF pH 6.5 and FaSSGF pH1.6) were used tostudy the supersaturating solubility of the ternary solid dispersions. HPLC was used to determine the drug concentrationsResultsTernary solid dispersions were successfully prepared by spray drying and melt quench methods. All prepared soliddispersions showed broadening of the XRD peaks indicating amorphous nature. MDSC analysis revealed disappearance ofthe melting peak of Ezetimibe indicating that molecular dispersion of the drug in polymer matrix. The solid dispersions withhigher PVPK30 content showed single Tg at 158.54 °C (spray drying) and 169.32 °C (melt quench). About 10 folds increasein the apparent solubility was observed for solid dispersions prepared by both methods. However, melt quenched soliddispersions had maintained the supersaturation solubility in FaSSIF longer than spray dried solid dispersions. Dissolutionstudies in FaSSGF are ongoingConclusionAmorphous ternary solid dispersions of Ezetimibe containing PVP K30 and Poloxamer 188 could be prepared by spraydrying and melt quenching methods. These solid dispersions showed improved solubility and prolonged supersaturation inbiorelevant media
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| 3. |
- Al-Hayali, Amani Ibraheem Younis, et al.
(author)
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Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media
- 2017
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 43:1, s. 79-88
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Journal article (peer-reviewed)abstract
- The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work.Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions.All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures.Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.
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| 4. |
- Avdeef, Alex, et al.
(author)
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Caco-2 permeability of weakly basic drugs predicted with the Double-Sink PAMPA method :
- 2005
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 24:4, s. 333-49
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Journal article (peer-reviewed)abstract
- The aim of this study was to analyze pH-dependent permeability of cationic drugs in Caco-2 cell monolayers using the method and to correlate the results with those obtained in PAMPA (parallel artificial membrane permeability assay). The pH-dependent permeability of verapamil and propranolol was studied in Caco-2 cell monolayers. The data were subsequently processed using software developed for the PAMPA method. Literature values for an additional nine cationic drugs were also analyzed. Double-Sink PAMPA data were also obtained for the same cationic drugs, to compare with the Caco-2 data. The Algorithm Builder program was then used to develop a predictive model of Caco-2 permeability based on PAMPA permeability and calculated Abraham molecular descriptors. From the relationship between permeability and pH it was shown that in PAMPA only the uncharged form of the drugs permeated across the membrane barrier, while charged and ionized forms of the drugs were significantly permeable in Caco-2. The charged-form permeability, Pi, was therefore determined and subsequently subtracted from all permeability coefficients in Caco-2 prior to the comparison with PAMPA. The resulting intrinsic permeability coefficients (Po) obtained in Caco-2 were successfully related to those derived from the PAMPA model. In this study we have shown that permeability coefficients obtained in PAMPA can predict the passive transcellular permeability in Caco-2.
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| 6. |
- Elmstedt, Sixten, et al.
(author)
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Cancer patients hospitalised in the last week of life risk insufficient care quality : a population-based study from the Swedish Register of Palliative Care
- 2019
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In: Acta Oncologica. - : Taylor & Francis Group. - 0284-186X .- 1651-226X. ; 58:4, s. 432-438
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Journal article (peer-reviewed)abstract
- Background: One-quarter of all cancer deaths in Sweden occur in hospitals. If the place of death affects the quality of end-of-life (EOL) is largely unknown.Methods: This population-based, retrospective study included all adults cancer deaths reported to the Swedish Register of Palliative Care in 2011-2013 (N = 41,729). Hospital deaths were compared to deaths occurring in general or specialised palliative care, or in nursing homes with respect to care quality indicators in the last week of life. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with specialised palliative home care as reference.Results: Preferred place of death was unknown for 63% of hospitalised patients and consistent with the actual place of death in 25% compared to 97% in palliative home care. Hospitalised patients were less likely to be informed when death was imminent (OR: 0.3; CI: 0.28-0.33) as were their families (OR: 0.51; CI: 0.46-0.57). Validated screening tools were less often used in hospitals for assessment of pain (OR: 0.32; CI: 0.30-0.34) or other symptoms (OR: 0.31; CI: 0.28-0.34) despite similar levels of EOL symptoms. Prescriptions of as needed drugs against anxiety (OR: 0.27; CI: 0.24-0.30), nausea (OR: 0.19; CI: 0.17-0.21), or pulmonary secretions (OR: 0.29; CI: 0.26-0.32) were less prevalent in hospitals. Bereavement support was offered after 57% of hospital deaths compared to 87-97% in palliative care units and 72% in nursing homes.Conclusions: Dying in hospital was associated with inferior end-of-life care quality among cancer patients in Sweden.
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| 7. |
- Filippov, Andrei, et al.
(author)
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Interaction of a Poly(acrylic acid) Oligomer with Dimyristoylphosphatidylcholine Bilayers
- 2011
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In: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 27:7, s. 3754-3761
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Journal article (peer-reviewed)abstract
- We studied the influence of 5 kDa poly(acrylic acid) (PAA) on the phase state, thermal properties, and lateral diffusion in bilayered systems of dimyristoylphosphatidylcholine (DMPC) using 31P NMR spectroscopy, differential scanning calorimetry (DSC), 1H NMR with a pulsed field gradient, and 1H nuclear Overhauser enhancement spectroscopy (NOESY). The presence of PAA does not change the lamellar structure of the system. 1H MAS NOESY cross-peaks observed for the interaction between lipid headgroups and polyion protons demonstrated only surface PAA−biomembrane interaction. Small concentrations of PAA (up to 4 mol %) lead to the appearance of a new lateral phase with a higher main transition temperature, a lower cooperativity, and a lower enthalpy of transition. Higher concentrations lead to the disappearance of measurable thermal effects. The lateral diffusion coefficient of DMPC and the apparent activation energy of diffusion gradually decreased at PAA concentrations up to around 4 mol %. The observed effects were explained by the formation of at least two types of PAA−DMPC lateral complexes as has been described earlier (Fujiwara, M.; Grubbs, R. H.; Baldeschwieler, J. D. J. Colloid Interface Sci., 1997, 185, 210). The first one is characterized by a stoichiometry of around 28 lipids per polymer, which corresponds to the adsorption of the entire PAA molecule onto the membrane. Lipid molecules of the complex are exchanged with the “pure” lipid bilayer, with the lifetime of the complex being less than 0.1 s. The second type of DMPC−PAA complex is characterized by a stoichiometry of 6 to 7 lipids per polymer and contains PAA molecules that are only partially adsorbed onto the membrane. A decrease in the DMPC diffusion coefficient and activation energy for diffusion in the presence of PAA was explained by the formation of a new cooperative unit for diffusion, which contains the PAA molecule and several molecules of lipids.
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| 8. |
- Lindskog, Magnus, et al.
(author)
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Fluid therapy is associated with lower care quality and higher symptom burden during last days of life of patients with cancer : a population-based register study
- 2024
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In: BMC Palliative Care. - : BioMed Central (BMC). - 1472-684X. ; 23:1
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Journal article (peer-reviewed)abstract
- Background: Parenteral fluid (PF) therapy of patients in end-of-life (EOL) is controversial. The purpose of this study was to assess associations between PF, quality of the EOL care process and symptom burden in dying cancer patients, using a population-based approach.Methods: This was a nationwide retrospective register study of all adult cancer deaths with documented information on PF in the last 24 h of life as reported to the Swedish Register of Palliative Care during a three-year period (n = 41,709). Prevalence and relief of symptoms during the last week of life as well as EOL care process quality indicators were assessed in relation to PF in those patients who had a documented decision to focus on EOL care (immediately dying, n = 23,112). Odds ratios were calculated, adjusting for place of death (hospital vs. non-hospital).Results: PF was administered to 30.9% of immediately dying patients in hospitals compared to 6.5% outside of hospitals. PF was associated with a higher likelihood for breathlessness and nausea. In patients screened for EOL symptoms with a validated instrument, PF was inversely associated with the likelihood of complete relief of breathlessness, respiratory secretions, anxiety, nausea and pain. Several palliative care quality indicators were inversely associated with PF, including EOL conversations and prescriptions of injectable drugs as needed. These associations were more pronounced in hospitals.Conclusions: Parenteral fluid therapy in the last 24 h of life was associated with inferior quality of the EOL care process and with increased symptom burden in imminently dying cancer patients.
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| 9. |
- Lindskog, Magnus, et al.
(author)
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Old age as risk indicator for poor end-of-life care quality : a population-based study of cancer deaths from the Swedish Register of Palliative Care
- 2015
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 51:10, s. 1331-1339
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Journal article (peer-reviewed)abstract
- Background: If patient age affects the quality of end-of-life care in cancer is unknown. Using data from a population-based register of palliative care in Sweden, we addressed this question. Methods: This nation-wide study focused on the last week of life of adults dying from cancer in 2011-2012, based on data reported to a national quality register for end-of-life care (N = 26,976). We specifically investigated if age-dependent differences were present with respect to thirteen indicators of palliative care quality. Patients were categorised in one out of five pre-defined age groups. Odds ratios (OR) with 95% confidence intervals (CIs), adjusted for type of end-of-life care unit, were calculated using logistic regression, with the oldest group as reference. Findings: Age-dependent differences in implementation rate were detected for ten out of thirteen end-of-life care quality indicators, most of which were progressively less well met with each increment in age group. Compared to elderly cancer patients, young patients were more often informed about imminent death, (OR, 3.9; 95% CI 2.5-5.9, p < 0.001), were more often systematically assessed for the presence and severity of pain (OR, 1.6; 95% CI 1.2-2.1, p < 0.001) or other symptoms (OR, 1.4; 95% CI 1.0-1.9, p = 0.044), were more likely to be assessed by palliative care consultation services (OR, 4.3; 95% CI 3.3-5.7, p < 0.001) and to have injections prescribed as needed against pain (OR, 3.4; 95% CI 1.3-9.4, p = 0.016), anxiety (OR, 3.8; 95% CI 2.0-7.1, p < 0.001) or nausea (OR, 3.6; 95% CI 2.3-5.7, p < 0.001). The families of young patients were more likely to be informed about imminent death ( OR, 2.6; 95% CI 1.5-4.3, p = 0.001) and to be offered bereavement support ( OR, 4.6; 95% CI 2.7-7.8, p < 0.001). Interpretation: Old age is a risk indicator for poor end-of-life care quality among cancer patients in Sweden. Funding: The executive committee of the National Quality Registries in Sweden.
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