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- Persson, Eva M, et al.
(författare)
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A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine
- 2006
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 23:4, s. 742-751
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. Methods Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. Results The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. Conclusions There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.
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- Bergman, Ebba, 1977-, et al.
(författare)
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Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers
- 2010
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 50:9, s. 1039-1049
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Tidskriftsartikel (refereegranskat)abstract
- The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.
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- Bergman, Ebba, et al.
(författare)
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Pharmacokinetics of gefitinib in humans : the influence of gastrointestinal factors
- 2007
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 341:1-2, s. 134-142
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t1/2 > 20 h) and altered (A; t1/2 < 20 h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine. Methods One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250 mg gefitinib dispersion preparation (IRESSA®, AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy. Results There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified. Conclusions There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.
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- Bergman, Ebba, 1977-, et al.
(författare)
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The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil
- 2009
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:12, s. 2349-2358
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Tidskriftsartikel (refereegranskat)abstract
- The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin was administered as an intrajejunal bolus dose in Treatments I, II and III (TI, TII, and TIII, respectively; n=6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH) and femoral veins and bile from the common hepatic duct. The biliary recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50-values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI; 0.89±0.06, TII; 0.46±0.13) and increased the AUCVP and AUCVH by 1.6 and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the OATP-family, rather than canalicular transporters.
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- Knutson, Kaj, et al.
(författare)
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The Swedish knee arthroplasty register. A nation-wide study of 30,003 knees 1976-1992
- 1994
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Ingår i: Acta Orthopaedica Scandinavica. - : Medical Journals Sweden AB. - 0001-6470 .- 1745-3674. ; 65:4, s. 375-386
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Tidskriftsartikel (refereegranskat)abstract
- 1976 through 1992, 30,003 primary knee arthroplasties and their revisions have been recorded in a nation-wide Swedish study. We report on the structure of the register, demographic data and survivorship. We found that operations for osteoarthrosis (OA) counted for the increase in number of arthroplasties in contrast to rheumatoid arthritis (RA), where the number had slightly declined. For primary operations, the total knee prostheses have practically eliminated other types in RA and are steadily gaining popularity in OA at the expense of the unicompartmental prostheses. Total knee replacements showed gradually improving survival even in unchanged designs while the unicompartmental prostheses don't, partly because of newly introduced inferior designs. We also found that failed unicompartmental prostheses were best replaced with a tricompartmental prosthesis and that a total revision was to be preferred when a tricompartmental tibial component failed. The risk of the most devastating complications, e.g., infection, leading to extraction of the prosthesis or arthrodesis has decreased considerably also in the last years.
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