| 1. |
- Ahlin, Gustav, et al.
(författare)
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Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
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Tidskriftsartikel (refereegranskat)abstract
- The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
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| 2. |
- Berg, Staffan, et al.
(författare)
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Evaluation in pig of an intestinal administration device for oral peptide delivery
- 2023
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 353, s. 792-801
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Tidskriftsartikel (refereegranskat)abstract
- The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
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| 3. |
- Bergström, Christel A S, 1973-, et al.
(författare)
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Computational prediction of drug solubility in water-based systems : qualitative and quantitative approaches used in the current drug discovery and development setting
- 2018
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 540:1-2, s. 185-193
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Forskningsöversikt (refereegranskat)abstract
- In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation.
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| 4. |
- Clulow, Andrew J., et al.
(författare)
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Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid
- 2017
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 121:48, s. 10869-10881
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Tidskriftsartikel (refereegranskat)abstract
- The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small angle X-ray scattering (SAXS), cryogenic -transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.
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| 5. |
- Contreras, Mariela, 1979-
(författare)
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Child nutrition in rural Nicaragua : Population-based studies in a transitional society
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Emerging favourable as well as unfavourable nutrition patterns are observed in societies undergoing rapid social and economic change. The aim of this thesis is to analyse the associations between household and maternal resources and infant and young child feeding habits and nutritional status in rural Nicaragua, a low-income transitional society.All households (n=1,500) in Los Cuatro Santos with at least one child (0-3 y) were visited to collect information on feeding of the youngest child. Children´s anthropometry was also measured using standardised World Health Organisation (WHO) techniques. Validated instruments were used to assess household and maternal resources. All instruments had been adapted to the local context and piloted in a nearby community. The education of the mother showed more independent variation in the studied outcomes. The odds for exclusive breastfeeding were highest in infants aged 0 to 5 months of mothers with the lowest education. Further, children aged 6 to 35 months with lowest educated mothers were less likely to consume highly processed snacks (HP snacks) and sugar-sweetened beverages (SSBs). They were also less likely to be exposed to a double burden of suboptimal feeding (concurrent unmet WHO recommended feeding practices and consumption of HP snacks or SSBs). However, children aged 6 to 35 months were more prone to infrequently meet dietary diversity and to more shortness. Children in the same age group with lower educated mothers were also shorter in households with the lowest housing quality.Higher level of maternal education contributed both favourably and unfavourably to child feeding and nutrition. This was reflected in more and less frequent practice of the WHO feeding indicators, but also in more frequent children´s consumption of HP snacks and SSBs. Higher maternal education was associated with taller children, even in households with the lowest housing quality.
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| 6. |
- Doring, Nora, et al.
(författare)
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Primary prevention of childhood obesity through counselling sessions at Swedish child health centres : design, methods and baseline sample characteristics of the PRIMROSE cluster-randomised trial
- 2014
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 14:335
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood obesity is a growing concern in Sweden. Children with overweight and obesity run a high risk of becoming obese as adults, and are likely to develop comorbidities. Despite the immense demand, there is still a lack of evidence-based comprehensive prevention programmes targeting pre-school children and their families in primary health care settings. The aims are to describe the design and methodology of the PRIMROSE cluster-randomised controlled trial, assess the relative validity of a food frequency questionnaire, and describe the baseline characteristics of the eligible young children and their mothers. Methods/Design: The PRIMROSE trial targets first-time parents and their children at Swedish child health centres (CHC) in eight counties in Sweden. Randomisation is conducted at the CHC unit level. CHC nurses employed at the participating CHC received training in carrying out the intervention alongside their provision of regular services. The intervention programme, starting when the child is 8-9 months of age and ending at age 4, is based on social cognitive theory and employs motivational interviewing. Primary outcomes are children's body mass index and waist circumference at four years. Secondary outcomes are children's and mothers' eating habits (assessed by a food frequency questionnaire), and children's and mothers' physical activity (measured by accelerometer and a validated questionnaire), and mothers' body mass index and waist circumference. Discussion: The on-going population-based PRIMROSE trial, which targets childhood obesity, is embedded in the regular national (routine) preventive child health services that are available free-of-charge to all young families in Sweden. Of the participants (n = 1369), 489 intervention and 550 control mothers (75.9%) responded to the validated physical activity and food frequency questionnaire at baseline (i.e., before the first intervention session, or, for children in the control group, before they reached 10 months of age). The food frequency questionnaire showed acceptable relative validity when compared with an 8-day food diary. We are not aware of any previous RCT, concerned with the primary prevention of childhood obesity through sessions at CHC that addresses healthy eating habits and physical activity in the context of a routine child health services programme.
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| 7. |
- Döringer, Nora, et al.
(författare)
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Motivational Interviewing to Prevent Childhood Obesity: A Cluster RCT
- 2016
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Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 137:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective was to evaluate a manualized theory-driven primary preventive intervention aimed at early childhood obesity. The intervention was embedded in Swedish child health services, starting when eligible children were 9 to 10 months of age and continuing until the children reached age 4. METHODS: Child health care centers in 8 Swedish counties were randomized into intervention and control units and included 1355 families with 1369 infants. Over similar to 39 months, families in the intervention group participated in 1 group session and 8 individual sessions with a nurse trained in motivational interviewing, focusing on healthy food habits and physical activity. Families in the control group received care as usual. Primary outcomes were children's BMI, overweight prevalence, and waist circumference at age 4. Secondary outcomes were children's and mothers' food and physical activity habits and mothers' anthropometrics. Effects were assessed in linear and log-binominal regression models using generalized estimating equations. RESULTS: There were no statistically significant differences in children's BMI (beta = -0.11, 95% confidence interval [CI]: -0.31 to 0.08), waist circumference (beta = -0.48, 95% CI: -0.99 to 0.04), and prevalence of overweight (relative risk = 0.95, 95% CI: 0.69 to 1.32). No significant intervention effects were observed in mothers' anthropometric data or regarding mothers' and children's physical activity habits. There was a small intervention effect in terms of healthier food habits among children and mothers. CONCLUSIONS: There were no significant group differences in children's and mothers' anthropometric data and physical activity habits. There was, however, some evidence suggesting healthier food habits, but this should be interpreted with caution.
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| 8. |
- Edueng, Khadijah, et al.
(författare)
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Mechanism-based selection of stabilization strategy for amorphous formulations : Insights into crystallization pathways
- 2017
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Ingår i: Journal of Controlled Release. - : ELSEVIER SCIENCE BV. - 0168-3659 .- 1873-4995. ; 256, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (mu DISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.
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| 9. |
- Franklin, Karl A., et al.
(författare)
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Effects of a palaeolithic diet on obstructive sleep apnoea occurring in females who are overweight after menopause-a randomised controlled trial
- 2022
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 46, s. 1833-1839
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Tidskriftsartikel (refereegranskat)abstract
- Background/Objectives Obesity is the main risk factor for obstructive sleep apnoea, commonly occurring in females who are overweight after menopause. We aimed to study the effect of a palaeolithic diet on sleep apnoea in females with overweight after menopause from the population. Methods Seventy healthy, non-smoking females with a mean age of 60 years and a mean BMI of 33 kg/m(2) were randomised to a palaeolithic diet or to a control low-fat diet according to Nordic Nutritional Recommendations, for 2 years. The apnoea-hypopnoea index was measured and daytime sleepiness was estimated during the intervention. Results The mean apnoea-hypopnoea index at baseline was 11.6 (95% CI 8.6-14.5). The mean weight loss was 7.2 kg (95% CI 5.3-9.2 kg) in the palaeolithic diet group and 3.9 kg in the control group (95% CI 1.9-5.9 kg); p < 0.021 for the group difference. The reduction in weight corresponded to a reduction in the apnoea-hypopnoea index in the palaeolithic diet group (r = 0.38, p = 0.034) but not in the control group (r = 0.08, p = 0.69). The apnoea-hypopnoea index was reduced in the palaeolithic diet group when the weight was reduced by more than 8 kg. Daytime sleepiness according to the Epworth Sleepiness Scale score and the Karolinska Sleepiness Scale score was unaffected by dietary group allocation. Conclusions A substantial decrease in body weight of 8 kg was needed to achieve a reduction in sleep apnoea in this small trial of women who are overweight after menopause. The palaeolithic diet was more effective for weight reduction than a control low-fat diet and the reduction in sleep apnoea was related to the degree of weight decrement within this diet group.
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| 10. |
- Hammarström, Anne, et al.
(författare)
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Experiences of barriers and facilitators to weight-loss in a diet intervention : a qualitative study of women in Northern Sweden
- 2014
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Ingår i: BMC Women's Health. - : BioMed Central. - 1472-6874. ; 14, s. 59-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is a lack of research about the experiences of participating in weight-reducing interventions. The aim of this study was to explore barriers and facilitators to weight-loss experienced by participants in a diet intervention for middle-aged to older women in the general population in Northern Sweden.METHOD: In the intervention the women were randomised to eat either a Palaeolithic-type diet or a diet according to Nordic Nutrition recommendations for 24 months. A strategic selection was made of women from the two intervention groups as well as from the drop-outs in relation to social class, civil status and age. Thematic structured interviews were performed with twelve women and analysed with qualitative content analyses.RESULTS: The results showed that the women in the dietary intervention experienced two main barriers - struggling with self (related to difficulties in changing food habits, health problems, lack of self-control and insecurity) and struggling with implementing the diet (related to social relations and project-related difficulties) - and two main facilitators- striving for self-determination (related to having clear goals) and receiving support (from family/friends as well as from the project) - for weight-loss. There was a greater emphasis on barriers than on facilitators.CONCLUSION: It is important to also include drop-outs from diet interventions in order to fully understand barriers to weight-loss. A gender-relational approach can bring new insights into understanding experiences of barriers to weight-loss.
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