| 1. |
- Neuman, Åsa, et al.
(författare)
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Infant wheeze, comorbidities and school age asthma
- 2014
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Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 25:4, s. 380-386
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Tidskriftsartikel (refereegranskat)abstract
- Background: Factors associated with early onset of wheeze have been described, but there is limited knowledge on which of these infant wheezers who will have developed asthma in school age. The aim was to identify clinical risk factors for asthma in the 8-yr-old children that wheezed during infancy in a population-based setting. Methods: Three thousand two hundred and fifty-one children from a population-based birth cohort followed prospectively from infancy until age 8 yr were included in the study. Data were analyzed using multivariate logistic regression analysis. Results: Parents reported any wheeze episode before age 2 yr in 823 subjects (25%). Infant wheezers had an almost fourfold risk of asthma at age 8 [adjusted odds ratio (aOR) 3.68, 95% CI 2.74-4.96], equivalent to an asthma prevalence of 14% compared with 4% among non-wheezers (p < 0.001). After adjustments for sex, exposure to tobacco smoke and indoor dampness/mould, allergic heredity (aOR 1.53, 95% CI 1.02-2.30), increased frequency of wheeze (aOR 3.41, 95% CI 2.09-5.56 for children with >= 3 episodes compared with <= 2 episodes during the first 2 yr of life), infant eczema (aOR 2.31, 95% CI 1.52-3.49), and recurrent abdominal pain (aOR 2.33, 95% CI 1.30-4.16) remained risk factors for school age asthma in the infant wheezing group. Conclusions: Among infant wheezers, allergic heredity, increased severity of wheeze, infant eczema, and recurrent abdominal pain were independent risk factors for asthma at age 8 yr. Among children with three or four of these risk factors, 38% had asthma at school age.
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| 2. |
- Bergstrom, Jan, et al.
(författare)
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Upper lower Cambrian (provisional Cambrian Series 2) trilobites from northwestern Gansu Province, China
- 2014
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Ingår i: Estonian Journal of Earth Sciences. - : Estonian Academy Publishers. - 1736-7557 .- 1736-4728. ; 63:3, s. 123-143
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Tidskriftsartikel (refereegranskat)abstract
- Upper lower Cambrian (provisional Cambrian Series 2) trilobites are described from three sections through the Shuangyingshan Formation in the Beishan area, northwestern Gansu Province, China. The trilobite fauna is dominated by eodiscoid and 'corynexochid' trilobites, together representing at least ten genera: Serrodiscus, Tannudiscus, Calodiscus, Pagetides, Kootenia, Edelsteinaspis, Ptarmiganoides?, Politinella, Dinesus and Subeia. Eleven species are described, of which seven are identified with previously described taxa and four described under open nomenclature. The composition of the fauna suggests biogeographic affinity with Siberian rather than Gondwanan trilobite faunas, and the Cambrian Series 2 faunas described herein and from elsewhere in northwestern China seem to be indicative of the marginal areas of the Siberian palaeocontinent. This suggests that the Middle Tianshan-Beishan Terrane may have been located fairly close to Siberia during middle-late Cambrian Epoch 2.
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| 3. |
- Bergstrom, SM, et al.
(författare)
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The Almelund Shale, a replacement name for the Upper Didymograptus Shale and the Lower Dicellograptus Shale in the lithostratigraphical classification of the Ordovician succession in Scania, Southern Sweden
- 2002
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Ingår i: Bulletin of the Geological Society of Denmark. - 0011-6297. ; 49, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The formation name Almelund Shale is proposed for a lithostratigraphically defined unit to replace the outdated chronostratigraphical designations Upper Didymograptus Shale and Dicellograptus Shale in the Middle and lowermost Upper Ordovician succession in Scania. The Almelund Shale is a lithologically uniform unit of dark-grey to black shales with rare carbonate interbeds between the Komstad Limestone and the Sularp Shale. Apart from a diverse graptolite fauna it yields a few shelly fossils (mostly lingulate brachiopods) and biostratigraphically diagnostic conodonts and chitinozoans. In the type sections of the Almelund Shale along the Sularp Brook in the F (a) over circle gels (a) over circle ng area; W-central Scania, the top of the unit is taken to be the base of the F (a) over circle gels (a) over circle ng Phosphorite, and its basal contact is at the top of the underlying Komstad Limestone. Its total thickness in the F (a) over circle gels (a) over circle ng drill-core is 28.32 m. The unit is widely distributed in the subsurface in a SE-NW belt across Scania.
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| 4. |
- Ekstrom, S., et al.
(författare)
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Body mass index status and peripheral airway obstruction in school-age children: a population-based cohort study
- 2018
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 73:6, s. 538-545
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Tidskriftsartikel (refereegranskat)abstract
- Background Few large prospective studies have investigated the impact of body mass index (BMI) on lung function during childhood. Methods Using data collected between 2002 and 2013, we analysed associations between BMI status and lung function (assessed by spirometry) from 8 to 16 years, as well as cross-sectional associations with small airway function (impulse oscillometry) at 16 years in the BAMSE cohort (n=2889). At 16 years, cross-sectional associations with local and systemic inflammation were investigated by analysing FE NO, blood eosinophils and neutrophils. Results Overweight and obesity at 8 years were associated with higher FVC, but lower FEV 1 /FVC ratio at 8 and 16 years. In boys, but not girls, obesity at 8 years was associated with a further reduction in FEV 1 /FVC between 8 and 16 years. In cross-sectional analyses, overweight and obesity were associated with higher frequency dependence of resistance (R 5-20) and larger area under the reactance curve (AX0.5) at 16 years. Increased blood neutrophil counts were seen in overweight and obese girls, but not in boys. No association was found between BMI status and FE NO. Persistent, but not transient, overweight/obesity between 8 and 16 years was associated with higher R 5-20 and AX0.5 and lower FEV 1 /FVC (-2.8% (95% CI -4.1 to -1.2) in girls and -2.7% (95% CI -4.4 to -1.1) in boys) at 16 years, compared with persistent normal weight. Conclusion I n childhood and adolescence, overweight and obesity, particularly persistent overweight, were associated with evidence of airway obstruction, including the small airways.
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| 5. |
- Eriksson, Lars, et al.
(författare)
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Modeling of a turbocharged SI engine
- 2002
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Ingår i: Annual Reviews in Control. - 1367-5788 .- 1872-9088. ; 26 I, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- Turbocharged SI engines are a major possibility in the current trend of down-sized engines with preserved drivability performance. Considering control and supervision it is favorable to have a mean value model to be used e.g. in observer design. Such models of turbo engines are similar to those of naturally aspirated engines, but there are some special characteristics, e.g. the interconnected gas flows, the intercooler, the difference in relative sizes between the gas volumes (compared to naturally aspirated engines), the turbo, and the waste gate. Here, a model is developed with a strategy to find a model for each engine component (air filter, compressor, after cooler (or intercooler), throttle, engine, turbine, waste gate, and a lumped model for the catalyst and exhaust) as they behave in an engine setting. When investigating agreement with measured data and sensitivity of possible model structures, a number of interesting issues are raised. The experiments and the model validation have been performed on a Saab 2.3 1 production engine.
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| 6. |
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| 7. |
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| 8. |
- Lindberg, Sara, et al.
(författare)
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Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS. - 0360-3016 .- 1879-355X. ; 117:5, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses.Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopul-monary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively.Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Simi-lar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.
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| 9. |
- Lindblad, Per, 1953-, et al.
(författare)
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Diet and risk of renal cell cancer : a population-based case-control study
- 1997
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - Philadelphia, USA : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 6:4, s. 215-223
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Tidskriftsartikel (refereegranskat)abstract
- In a few previous studies on diet and renal cell cancer, an inconsistent positive association with meat, milk, and protein and a negative association with vegetable and fruit consumption have been found. Whereas earlier studies have dealt with recent diet only, our study explored the effect of foods consumed both during the usual adult lifetime and 20 years prior to interview. The study included 379 individuals with incident histologically verified renal cell cancer and 350 control subjects residing in eight counties in Sweden between June 1989 and December 1991. Usual adult dietary intake and dietary habits 20 years prior to interview were assessed by a structured face-to-face interview and a self-administered questionnaire, respectively. Odds ratios were estimated through unconditional logistic regression. We have not observed an association of renal cell cancer with milk or total meat consumption per se; however, frequent intake of fried/sauteed meat increased the risk of renal cell cancer by about 60%; frequent consumption of poultry was also associated with an increased risk (P for trend, 0.05). A significantly protective effect on risk of renal cell cancer was observed with increasing consumption of fruit (P for trend, 0.05). When analyzed by smoking status, total fruit and especially citrus fruit consumption among nonsmokers showed an even stronger protective effect; the highest quartiles of total fruit, apple, and citrus fruit consumption entailed a 50-60% reduction in risk of renal cell cancer compared with the lowest quartiles. There was a suggestion of a protective effect of high total vegetable consumption. A protective effect of vitamin C and alpha-tocopherol was also more pronounced in nonsmokers (P for trend, 0.004 and 0.007, respectively). Our study adds to the evidence that diet may have an important role in the etiology of renal cell cancer.
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| 10. |
- Parrow, Albin, et al.
(författare)
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Drug solubilization in dog intestinal fluids with and without administration of lipid-rich formulations
- 2024
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 371
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Tidskriftsartikel (refereegranskat)abstract
- The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
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| 11. |
- Parrow, Albin, et al.
(författare)
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Molecular Dynamics Simulations of Self-Assembling Colloids in Fed-State Human Intestinal Fluids and Their Solubilization of Lipophilic Drugs
- 2023
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 20:1, s. 451-460
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Tidskriftsartikel (refereegranskat)abstract
- Bioavailability of oral drugs often depends on how soluble the active pharmaceutical ingredient is in the fluid present in the small intestine. For efficient drug discovery and development, computational tools are needed for estimating this drug solubility. In this paper, we examined human intestinal fluids collected in the fed state, with coarse-grained molecular dynamics simulations. The experimentally obtained concentrations in aspirated duodenal fluids from five healthy individuals were used in three simulation sets to evaluate the importance of the initial distribution of molecules and the presence of glycerides in the simulation box when simulating the colloidal environment of the human intestinal fluid. We observed self-assembly of colloidal structures of different types: prolate, elongated, and oblate micelles, and vesicles. Glycerides were important for the formation of vesicles, and their absence was shown to induce elongated micelles. We then simulated the impact of digestion and absorption on the different colloidal types. Finally, we looked at the solubilization of three model compounds of increasing lipophilicity (prednisolone, fenofibrate, and probucol) by calculating contact ratios of drug–colloid to drug–water. Our simulation results of colloidal interactions with APIs were in line with experimental solubilization data but showed a dissimilarity to solubility values when comparing fasted-/fed-state ratios between two of the APIs. This work shows that coarse-grained molecular dynamics simulation is a promising tool for investigation of the intestinal fluids, in terms of colloidal attributes and drug solubility.
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| 12. |
- Pettersson, Gunilla, et al.
(författare)
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Upgrading the strength properties of sheets from hardwood high yield pulps
- 2018
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Ingår i: Pan Pacific Fibre Value Chain Conference 2018, Proceedings. - : Appita Inc.. - 9780975746998 ; , s. 142-147
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Konferensbidrag (refereegranskat)abstract
- In the current paper it is shown that tensile and compression strength of sheets from hardwood high yield pulps (HYP), which has been manufactured at a low energy input in refining, can be multiplied by improving the fibre-fibre bond strength and the number of contact areas between fibre surfaces in the sheet structure. At fibre surface treatment with cationic starch the properties are improved at almost preserved bulk (i.e., preserved density). Remarkable improvements are achieved at densification of the sheet structures by pressing in a hot press nip at temperatures well above the softening temperature of wet lignin. The former technique is above all to prefer in manufacturing of middle plies in paperboard composites, whereas the latter technique is of special interest in manufacturing of packaging papers with high demands upon strength. For instance, it is shown in the paper how tensile index on sheets of CTMP from birch (CSF 480 ml) can be enhanced from 20 to 50 kNm/kg and compression index (SCT) from 10 to 35 kNm/kg by the tested techniques.
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| 13. |
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| 14. |
- Schultz, E. S., et al.
(författare)
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Early life determinants of lung function change from childhood to adolescence
- 2018
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 139, s. 48-54
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Little is known about how perinatal and childhood factors influence lung function change between childhood and adolescence. Objectives: To investigate possible early life predictors of change in FEV1 between age 8 and 16 years. In addition, to investigate possible predictors of having persistently low lung function (FEV1 < 25th percentiles both at age 8 and 16) up to adolescence. Methods: The BAMSE birth cohort study collected data throughout childhood on environmental factors, individual characteristics, and spirometric measures at 8 and 16 years (n = 1425). Associations between early life predictors (n = 31) and FEV1 increase between 8 and 16 years were assessed with linear regression. Predictors of having persistently low lung function were examined. Results: Few factors were consistently associated with altered lung function growth, although low birth weight, asthma heredity (paternal), secondhand smoke in infancy, and season of birth had a significant impact (p-value <= 0.01). The majority of subjects stayed however within the same category of lung function between ages 8 and 16 years (in total 821/1425 = 58%). Predictors associated with having persistently low lung function were gestational age, secondhand smoke (at 2 and 8 years of age), and factors related to lower respiratory tract infections in infancy. Conclusions: In summary, rather few exposures in childhood were identified to have a significant impact on lung function growth between childhood and adolescence. Our data support previous study findings indicating that lung function development is influenced by factors before birth and in infancy, including second hand tobacco smoke.
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| 15. |
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| 16. |
- Tehler, Ulrika, et al.
(författare)
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Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:6, s. 2690-2694
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Tidskriftsartikel (refereegranskat)abstract
- Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.
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| 17. |
- Thacher, J. D., et al.
(författare)
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Tobacco smoke exposure in early life and adolescence in relation to lung function
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 51:6
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Tidskriftsartikel (refereegranskat)abstract
- Maternal smoking during pregnancy is associated with impaired lung function among young children, but less is known about long-term effects and the impact of adolescents' own smoking. We investigated the influence of maternal smoking during pregnancy, secondhand smoke exposure and adolescent smoking on lung function at age 16 years. The BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology) birth cohort collected information on participants' tobacco smoke exposure through repeated questionnaires, and measured saliva cotinine concentrations at age 16 years. Participants performed spirometry and impulse oscillometry (IOS) at age 16 years (n=2295). Exposure to maternal smoking during pregnancy was associated with reduced forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of -1.1% (95% CI -2.0 to -0.2%). IOS demonstrated greater resistance at 5-20 Hz (R5-20) in participants exposed to maternal smoking during pregnancy. Adolescents who smoked had reduced FEV1/FVC ratios of -0.9% (95% CI -1.8 to -0.1%) and increased resistance of 6.5 Pa.L-1.s (95% CI 0.7 to 12.2 Pa.L-1.s) in R5-20. Comparable associations for FEV1/FVC ratio were observed for cotinine concentrations, using. 12 ng.mL(-1) as a cut-off for adolescent smoking. Maternal smoking during pregnancy was associated with lower FEV1/FVC ratios and increased airway resistance. In addition, adolescent smoking appears to be associated with reduced FEV1/FVC ratios and increased peripheral airway resistance.
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| 18. |
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| 19. |
- Toren, Kjell, et al.
(författare)
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Vital capacity and COPD : the Swedish CArdioPulmonary bioImage Study (SCAPIS)
- 2016
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Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - : DOVE MEDICAL PRESS LTD. - 1176-9106 .- 1178-2005. ; 11, s. 927-933
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Tidskriftsartikel (refereegranskat)abstract
- Background: Spirometric diagnosis of chronic obstructive pulmonary disease (COPD) is based on the ratio of forced expiratory volume in 1 second (FEV1)/vital capacity (VC), either as a fixed value <0.7 or below the lower limit of normal (LLN). Forced vital capacity (FVC) is a proxy for VC. The first aim was to compare the use of FVC and VC, assessed as the highest value of FVC or slow vital capacity (SVC), when assessing the FEV1/VC ratio in a general population setting. The second aim was to evaluate the characteristics of subjects with COPD who obtained a higher SVC than FVC. Methods: Subjects (n=1,050) aged 50-64 years were investigated with FEV1, FVC, and SVC after bronchodilation. Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPDFVC was defined as FEV1/FVC <0.7, GOLDCOPD(VC) as FEV1/VC <0.7 using the maximum value of FVC or SVC, LLNCOPDFVC as FEV1/FVC below the LLN, and LLNCOPDVC as FEV1/VC below the LLN using the maximum value of FVC or SVC. Results: Prevalence of GOLDCOPD(FVC) was 10.0% (95% confidence interval [CI] 8.2-12.0) and the prevalence of LLNCOPDFVC was 9.5% (95% CI 7.8-11.4). When estimates were based on VC, the prevalence became higher; 16.4% (95% CI 14.3-18.9) and 15.6% (95% CI 13.5-17.9) for GOLDCOPD(VC) and LLNCOPDVC, respectively. The group of additional subjects classified as having COPD based on VC, had lower FEV1, more wheeze and higher residual volume compared to subjects without any COPD. Conclusion: The prevalence of COPD was significantly higher when the ratio FEV1/VC was calculated using the highest value of SVC or FVC compared with using FVC only. Subjects classified as having COPD when using the VC concept were more obstructive and with indications of air trapping. Hence, the use of only FVC when assessing airflow limitation may result in a considerable under diagnosis of subjects with mild COPD.
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| 20. |
- Winkler, M., et al.
(författare)
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The rich sides of mountain summits - a pan-European view on aspect preferences of alpine plants
- 2016
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Ingår i: Journal of Biogeography. - : Wiley. - 0305-0270. ; 43:11, s. 2261-2273
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Tidskriftsartikel (refereegranskat)abstract
- Aim In the alpine life zone, plant diversity is strongly determined by local topography and microclimate. We assessed the extent to which aspect and its relatedness to temperature affect plant species diversity, and the colonization and disappearance of species on alpine summits on a pan-European scale. Methods Vascular plant species and their percentage cover were recorded in permanent plots in each cardinal direction on 123 summits in 32 regions across Europe. For a subset from 17 regions, resurvey data and 6-year soil temperature series were available. Differences in temperature sum and Shannon index as well as species richness, colonization and disappearance of species among cardinal directions were analysed using linear mixed-effects and generalised mixed-effects models, respectively. Results Temperature sums were higher in east-and south-facing aspects than in the north-facing ones, while the west-facing ones were intermediate; differences were smallest in northern Europe. The patterns of temperature sums among aspects were consistent among years. In temperate regions, thermal differences were reflected by plant diversity, whereas this relationship was weaker or absent on Mediterranean and boreal mountains. Colonization of species was positively related to temperature on Mediterranean and temperate mountains, whereas disappearance of species was not related to temperature. Main conclusions Thermal differences caused by solar radiation determine plant species diversity on temperate mountains. Advantages for plants on eastern slopes may result from the combined effects of a longer diurnal period of radiation due to convection cloud effects in the afternoon and the sheltered position against the prevailing westerly winds. In northern Europe, long summer days and low sun angles can even out differences among aspects. On Mediterranean summits, summer drought may limit species numbers on the warmer slopes. Warmer aspects support a higher number of colonization events. Hence, aspect can be a principal determinant of the pace of climate-induced migration processes.
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| 21. |
- Yngve, Ulrika, et al.
(författare)
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Triazolopyrimidinones as gamma-secretase modulators : structure-activity relationship, modulator profile, and in vivo profiling
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:2, s. 422-431
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Tidskriftsartikel (refereegranskat)abstract
- The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.
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| 22. |
- Zaki, Noha M., et al.
(författare)
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A Modified Physiological BCS for Prediction of Intestinal Absorption in Drug Discovery
- 2010
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Ingår i: Molecular pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 7:5, s. 1478-1487
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 degrees C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.
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