Biomedical subjects

T Andersson

Publications and source records attributed to T Andersson.

At least 37 records · Page 2Linked to original sources

PubMed2001

Role of p190RhoGAP in beta 2 integrin regulation of RhoA in human neutrophils.

We found that engagement of beta(2) integrins on human neutrophils induced activation of RhoA, as indicated by the increased ratio of GTP:GTP + GDP recovered on RhoA and translocation of RhoA to a membrane fraction. The clustering of beta(2) integrins also induced a time-dependent increase in GDP bound to RhoA, which correlated with beta(2) integrin-induced activation of p190RHOGAP: The activation of p190RhoGAP was completely blocked by [4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] (PP1), a selective inhibitor of Src family tyrosine kinases. However, clustering of beta(2) integrins did not increase the basal tyrosine phosphorylation of p190RhoGAP, nor did it affect the amount of p120RasGAP bound to p190RHOGAP: Instead, the beta(2) integrin-induced activation of p190RhoGAP was accompanied by increased tyrosine phosphorylation of a p190RhoGAP-associated protein, p120RasGAP, and accumulation of both p120RasGAP and p190RhoGAP in a membrane fraction. PP1 blocked the beta(2) integrin-induced phosphorylation of p120RasGAP, as well as the translocation of p190RhoGAP and p120RasGAP, but it did not affect the accumulation of RhoA in the membrane fraction. In agreement with the mentioned findings, PP1 also increased the GTP:GTP + GDP ratio recovered on RhoA immunoprecipitated from beta(2) integrin-stimulated cells. Thus, in neutrophils, beta(2) integrin-induced activation of p190RhoGAP requires a signal from a Src family tyrosine kinase, but it does not occur via the signaling pathway responsible for activation of RHOA:

CD18 Antigens↗

PubMed2001

Image quality vs. radiation dose for a flat-panel amorphous silicon detector: a phantom study.

The aim of this study was to investigate the image quality for a flat-panel amorphous silicon detector at various radiation dose settings and to compare the results with storage phosphor plates and a screen-film system. A CDRAD 2.0 contrast-detail phantom was imaged with a flat-panel detector (Philips Medical Systems, Eindhoven, The Netherlands) at three different dose levels with settings for intravenous urography. The same phantom was imaged with storage phosphor plates at a simulated system speed of 200 and a screen-film system with a system speed of 160. Entrance surface doses were recorded for all images. At each setting, three images were read by four independent observers. The flat-panel detector had equal image quality at less than half the radiation dose compared with storage phosphor plates. The difference was even larger when compared with film with the flat-panel detector having equal image quality at approximately one-fifth the dose. The flat-panel detector has a very favourable combination of image quality vs radiation dose compared with storage phosphor plates and screen film.

Humans↗

PubMed2001

Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole.

BACKGROUND: Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor developed as a single isomer for the treatment of acid-related diseases. AIM: To examine the pharmacokinetics and pharmacodynamics of esomeprazole. METHODS: In a crossover study, 12 healthy males received 5, 10 or 20 mg of esomeprazole, or 20 mg of omeprazole, once daily over 5 days. The pharmacokinetics and effects on pentagastrin-stimulated peak acid output of esomeprazole and omeprazole were studied on days 1 and 5. RESULTS: The area under the curve (AUC) of both esomeprazole and omeprazole increased from day 1 to day 5. The correlation between acid inhibition and AUC for esomeprazole could be well described with a sigmoid Emax model. The mean inhibition values of the pentagastrin-stimulated peak acid output on day 1 for 5, 10 and 20 mg of esomeprazole were 15%, 29% and 46%, respectively; the corresponding day 5 values were 28%, 62% and 90%. The mean inhibition values of the pentagastrin-stimulated peak acid output for omeprazole were 35% (day 1) to 79% (day 5). CONCLUSIONS: The pharmacokinetics of esomeprazole are time and dose dependent. There was a good correlation between AUC and effect for esomeprazole. These data suggest an increased acid inhibitory effect of esomeprazole compared to omeprazole.

Administration, Oral↗

PubMed2001

Geographical differences in the incidence of acute myocardial infarction in Sweden. Analyses of possible causes using two parallel case-control studies.

OBJECTIVES: To analyse differences in myocardial infarction incidence between two Swedish counties and to evaluate the importance of major risk factors for the observed differences. DESIGN: The incidence of first myocardial infarction was studied using information from registers. For a number of risk factors of myocardial infarction, the prevalence as well as the relative risk was estimated from population controls of case-control studies in the two areas. SUBJECTS: Men and women aged 45-64 years in Stockholm and Västernorrland County 1993-94. MAIN OUTCOME MEASURES: Relative risks (RRs) and impact fractions were used to evaluate the importance of differences in risk factor prevalence for differences in myocardial infarction incidence between the two areas. RESULTS: The incidence of first myocardial infarction was higher in Västernorrland than in Stockholm amongst both men (RR = 1.23; 95% CI = 1.08-1.40) and women (RR = 1.41; 95% CI = 1.11-1.79). Obesity and increased levels of blood serum lipids were more prevalent in Västernorrland than in Stockholm amongst men with impact fractions of 6 and 9-11%, respectively. Amongst women, corresponding differences were not seen, but job strain and shift work tended to be more common in the more northern area. Current smoking was more frequent in Stockholm, particularly for women. CONCLUSIONS: The incidence of first myocardial infarction was higher in Västernorrland than in Stockholm in both genders. A higher prevalence of obesity and elevated blood serum lipids may explain, in part, this excess incidence amongst men, but amongst women the causes of the higher incidence in the more northern area remain largely unclear.

Aged↗

PubMed2001

Digital radiography of scoliosis with a scanning method: initial evaluation.

PURPOSE: To evaluate the radiation dose, image quality, and Cobb angle measurements obtained with a digital scanning method of scoliosis radiography. MATERIALS AND METHODS: Multiple images were reconstructed into one image at a workstation. A low-dose alternative was to use digital pulsed fluoroscopy. Dose measurements were performed with thermoluminescent dosimeters in an Alderson phantom. At the same time, kerma area-product values were recorded. A Monte Carlo dose calculation also was performed. Image quality was evaluated with a contrast-detail phantom and visual grading system. Angle measurements were evaluated with an angle phantom and measurements obtained on patient images. RESULTS: The effective radiation dose was 0.087 mSv for screen-film imaging, 0.16 mSv for digital exposure imaging, and 0.017 mSv for digital fluoroscopy; the corresponding kerma area-product values were 0.43, 0.87, and 0.097 Gy. cm(2), respectively. The image quality of the digital exposure and screen-film images was about equal at visual grading, whereas fluoroscopy had lower image quality. The angle phantom had lower angle values with digital fluoroscopy, although the difference in measured angles was less than 0.5 degrees. The patient images showed no difference in angles. CONCLUSION: The described digital scanning method has acceptable image quality and adequate accuracy in angle measurements. The radiation dose required for digital exposure imaging is higher than that required for screen-film imaging, but that required for digital fluoroscopy is much lower.

Fluoroscopy↗

PubMed2001

Novel candidate genes for atherosclerosis are identified by representational difference analysis-based transcript profiling of cholesterol-loaded macrophages.

OBJECTIVES: To analyze the early gene expression in macrophages accompanying the phenotypic changes into foam cells upon exposure to oxidized low-density lipoprotein. To identify candidate genes and markers for further studies into the pathogenesis of atherosclerosis. METHODS: Cells of the monocytic cell line THP-1 were activated by PMA and exposed to oxidized low-density lipoprotein. Gene expression profiles were investigated after 24 h, using a solid phase cDNA representational difference analysis (RDA) method and shotgun sequencing. Results were verified by microarray hybridization, and analyzed in the virtual chip display of a novel software tool for transcript profile exploration. RESULTS: By comparing transcript profiles of exposed/unexposed cells, 1,984 transcript sequences, representing a total of 921 genes with altered expression levels in response to oxidized low-density lipoprotein exposure, were identified. Genes that are central to cell cycle control and proliferation, inflammatory response, and of pathways not previously implicated in atherosclerosis were identified. The data obtained is also made available on-line at http:// biobase.biotech.kth.se/thp1a for further exploration. CONCLUSION: The identification of new candidate genes for atherosclerotic disease through RDA-based transcript profiling facilitates further functional genomic studies in coronary artery disease. Candidate genetic polymorphism markers of potential clinical relevance can be identified by filtering information in genome variation databases through the virtual chip analysis of the transcript profiles and subsequently tested in association studies.

Arteriosclerosis↗

PubMed2001

Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells.

The Wnt-5a gene encodes a secreted protein that controls several normal processes during embryogenesis and development of adult tissues by as yet unknown mechanisms. Endogenous expression of Wnt-5a mRNA is known to occur in both mouse and human mammary cell lines. To investigate the biological role of Wnt-5a in the human mammary epithelial cell line HB2, we used an antisense approach to repress endogenous expression of Wnt-5a protein. We also generated a cell population that constitutively overexpresses this protein. We found that overexpression of Wnt-5a protein enhanced cell-to-collagen binding and abolished hepatocyte growth factor-stimulated migration of HB2 transfectants through collagen matrices. Conversely, repression of Wnt-5a protein led to cell scattering, impaired cell-collagen interaction and enhanced cell motility. As we were searching for modified collagen receptors in antisense cells, we discovered that the collagen-binding discoidin domain receptor 1 (DDR1) failed to undergo phosphorylation. In reciprocal experiments, phosphorylation of DDR1 was consistently enabled by expression of Wnt-5a-HA protein in non-Wnt-5a-producing MCF-7 breast cancer cells. Activation of the Wnt/beta-catenin signalling pathway did not influence or mimic the Wnt-5a-mediated effect on DDR1 phosphorylation. These data demonstrate that Wnt-5a protein participates in regulation of adhesion to and migration through collagen and is also a co-factor necessary for collagen-induced activation of DDR1 receptors in mammary epithelial cells.

Breast↗

PubMed2001

Pharmacokinetic study of esomeprazole in the elderly.

OBJECTIVE: Esomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of patients with acid-related diseases. The aim of this study was to examine the pharmacokinetics and tolerability of esomeprazole in the elderly, relative to middle-aged patients with gastro-oesophageal reflux disease (GORD). DESIGN: Nonblinded single-centre pharmacokinetic study with historical control group. PATIENTS AND PARTICIPANTS: 14 healthy elderly volunteers [mean age 74 (range 71 to 80) years]. METHODS: Participants received treatment with esomeprazole 40 mg once daily for 5 days, with 24-hour blood sampling on days 1 and 5. The total area under the plasma concentration-time curve (AUCinfinity), maximum plasma drug concentration (Cmax), terminal elimination half-life (t(1/2z)) and time to Cmax (tmax) were determined for the parent drug and its hydroxy and sulphone metabolites. AUCinfinity and Cmax data were compared with those in an historical group of 36 middle-aged patients [mean age 45 (range 29 to 58) years] with GORD, treated with an identical dosage of esomeprazole for 5 days. RESULTS: A total of 13 volunteers completed the study. On day 5, the mean plasma AUCinfinity of esomeprazole was 16.0 micromol x h/L, Cmax was 5.6 micromol/L, tmax was 1.5 hours and t(1/2z) was 1.7 hours. The AUCinfinity and Cmax values for the parent drug were 2- and 1.5-fold higher on day 5 compared with day 1. AUCinfinity and Cmax values for the sulphone metabolite increased to a slightly greater extent, and values for the hydroxy metabolite were unchanged. Ratios of the AUCinfinity and Cmax values between elderly volunteers and patients with GORD were 1.25 [95% confidence interval (CI) 0.94, 1.67] and 1.18 (0.91, 1.52), respectively. Esomeprazole was well tolerated and there were no safety concerns. CONCLUSIONS: The AUCinfinity and Cmax values in the elderly were not significantly different from those obtained in a group of middle-aged patients. The difference for AUCinfinity was 25% (95% CI -6% to +67%). Esomeprazole has a wide therapeutic window and our results do not indicate that dosage adjustment should be necessary in the elderly.

Administration, Oral↗

PubMed2001

Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole.

This article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single isomer PPI developed for the treatment of patients with acid-related diseases. In vitro experiments in human liver microsomes demonstrated that the formation of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cytochrome P450 (CYP) 2C19, whereas that of the sulphone metabolite is via CYP3A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabo- lites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower clearance of esomeprazole in vivo. In vivo investigations demonstrated that esomeprazole is chirally stable after administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolised more slowly than omeprazole, resulting in a higher area under the concentration-time curve (AUC) after administration of the same dose. This is more pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazole, contributing to less overall interindividual variability for esomeprazole than for omeprazole. In general, esomeprazole and omeprazole are subject to the same metabolic transformations. Almost complete recoveries were reported and the ratio between urinary and faecal excretion is about 4:1 for both compounds. The dose-dependent increase in AUC of esomeprazole with repeated administration results from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas elderly individuals exhibited a slightly lower metabolism rate. Patients with a severe deficit in their liver function had a lower rate of metabolism, as would be expected, whereas those with mild to moderate liver disease did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of esomeprazole in individuals with impaired renal function is unlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC and peak plasma drug concentration were slightly, but not statistically significantly, higher in females than in males.

Animals↗

PubMed2001

Drug interaction studies with esomeprazole, the (S)-isomer of omeprazole.

Esomeprazole, the (S)-isomer of omeprazole, is the first proton pump inhibitor (PPI) developed as a single isomer for the treatment of patients with acid related diseases. Because of the extensive use of PPIs, the documentation of the potential for drug interactions with esomeprazole is of great importance. Altered absorption or metabolism are 2 of the major mechanisms for drug-drug interactions. Since intragastric pH will increase with esomeprazole treatment, it can be hypothesised that the absorption of drugs with pH-sensitive absorption (e.g. digoxin and ketoconazole) may be affected. Esomeprazole does not seem to have any potential to interact with drugs that are metabolised by cytochrome P450 (CYP) 1 A2, 2A6, 2C9, 2D6 or 2E1. In drug interaction studies with diazepam, phenytoin and (R)-warfarin, it was shown that esomeprazole has the potential to interact with CYP2C19. The slightly altered metabolism of cisapride was also suggested to be the result of inhibition of a minor metabolic pathway for cisapride mediated by CYP2C19. Esomeprazole did not interact with the CYP3A4 substrates clarithromycin (2 studies) or quinidine. Since the slightly increased area under the concentration-time curve (AUC) of cisapride could be explained as an inhibition of CYP2C19, the data on these 3 CYP3A4 substrates indicate that esomeprazole does not have the potential to inhibit this enzyme. The minor effects reported for diazepam, phenytoin, (R)-warfarin, and cisapride are unlikely to be of clinical relevance. Clarithromycin interacts with the metabolism of esomeprazole resulting in a doubling of the AUC of esomeprazole. The increased plasma concentrations of esomeprazole are unlikely to have any safety implications. It can be concluded that the potential for drug-drug interactions with esomeprazole is low, and similar to that reported for omeprazole.

Anti-Ulcer Agents↗

PubMed2000

Can chronic disability be prevented? A randomized trial of a cognitive-behavior intervention and two forms of information for patients with spinal pain.

STUDY DESIGN: A randomized controlled design superimposed on treatment as usual was used to compare the effects of a cognitive-behavior intervention aimed at preventing chronicity with two different forms of information. OBJECTIVE: To develop a coping-oriented preventive intervention applicable in primary care, and to compare its impact with educational information. SUMMARY OF BACKGROUND DATA: Preventing long-term disability resulting from spinal pain has proved difficult. The information provided by health care professions and early interventions aimed at preventing long-term disability may be important, but little scientific evidence exists concerning their use. METHODS: A protocol for a six-session cognitive-behavior group intervention was developed on the basis of earlier research. The main focus was to prevent long-term disability by changing patients' behaviors and beliefs so they can cope better with their problems. Comparison groups received either a pamphlet shown earlier to have an effect, or a more extensive information package consisting of six installments. All the groups continued to receive treatment as usual in primary care. There were 243 patients with acute or subacute spinal pain who perceived that they were at risk for developing a chronic problem. These patients were randomized to the cognitive-behavioral intervention or one of the two information groups. Because the aim was to prevent long-term disability, the key outcome variables at the 1-year follow-up assessment were sick absenteeism and health care use. Other variables were pain, function, fear-avoidance beliefs, and cognitions. RESULTS: The comparison groups reported benefits. However, the risk for a long-term sick absence developing was lowered ninefold for the cognitive-behavior intervention group as compared with the risk for the information groups (relative risk, 9.3). Participants in the cognitive-behavior group also reported a significant decrease in perceived risk. In addition, the cognitive-behavior group demonstrated a significant decrease in physician and physical therapy use as compared with two groups receiving information, in which such use increased. All three groups tended to improve on the variables of pain, fear-avoidance, and cognitions. CONCLUSIONS: This study demonstrates that a cognitive-behavior group intervention can lower the risk of a long-term disability developing. These findings underscore the significance of early interventions that specifically aim to prevent chronic problems. This approach might be applied to primary care settings.

Absenteeism↗

PubMed2000

Analysis of phenols in pyrolysis oils by gel permeation chromatography and multidimensional liquid chromatography.

A simple method with minimal manual sample preparation was developed for the analysis of phenols in pyrolysis oils. Sample pre-treatment was done by gel permeation chromatography (GPC), where the high-molecular-mass lignins were separated from the phenols. Multidimensional liquid chromatography (LC-LC) was used in the analysis of the phenolic fraction. The pre-column was used for sample clean-up and pre-fractionation before introduction of the phenolic fraction to the analytical column. The repeatability and linearity of the total GPC and LC-LC methods were excellent. The results were in accordance with the reference method in which the sample pre-treatment was done by precipitating the lignins with water, and the phenols were extracted with toluene and analysed by GC-MS.

Chromatography, Gel↗

PubMed2000

Pressurized hot water extraction coupled on-line with LC-GC: determination of polyaromatic hydrocarbons in sediment.

Pressurized hot water extraction (PHWE) was directly combined with a LC-GC system for the determination of polyaromatic hydrocarbons (PAHs) in sediment. The sediment sample was first extracted with pressurized hot water, and the analytes were adsorbed into a solid-phase trap. The trap also functioned as a LC column, which removed most of the interfering matrix components. The 780-microL LC fraction containing the analytes was directly transferred to the GC using an on-column interface. The whole PHWE-LC-GC analysis took place in a closed system, and no sample pretreatment was required. The sensitivity of the method was excellent due to the efficient concentration in the LC-GC system. Sensitivity was approximately 800 times better than in traditional systems. In addition, only a small amount of sample (10 mg) was required for the analysis. The PHWE-LC-GC method proved to be linear in the concentration range of 0.01-2 microg/g, the limits of quantification were below 0.01 microg/g for all the analytes, and the relative standard deviations were between 3 and 28%. LC cleanup and the improved sensitivity made detection with FID sufficient for the determination of analytes. The results were comparable to those obtained in an interlaboratory comparison study as well as to the results obtained with off-line SFE-GC-MS.

Chromatography, Gas↗

PubMed2000

Clustering of beta(2)-integrins on human neutrophils activates dual signaling pathways to PtdIns 3-kinase.

The beta(2)-integrins on leukocytes can serve as a signaling unit during cell adhesion and locomotion, and to further clarify this important property we investigated the possible mechanisms of beta(2)-integrin-induced activation of PtdIns 3-kinase. It has previously been demonstrated that clustering of beta(2)-integrins activates p21(ras) by a tyrosine kinase-dependent pathway, and here we show that active p21(ras) interacts with its downstream target, PtdIns 3-kinase. Engagement of beta(2)-integrins also activates the tyrosine kinases p58(c-fgr) and p59/61(hck) and causes them to associate with the p85 subunit of PtdIns 3-kinase. These findings suggest a mechanism whereby p58(c-fgr) and p59/61(hck) are directly involved in the activation of PtdIns 3-kinase. No coupling between p58(c-fgr) and p59/61(hck) could be detected; hence these kinases probably trigger independent but parallel signals to PtdIns 3-kinase. The effect of beta(2)-integrin clustering on PtdIns 3-kinase activity was monitored as the activation of protein kinase B (PKB). Stimulation of PKB by beta(2)-integrins was abolished by genistein and wortmannin but not by using methyl transferase inhibitors to abrogate the influence of p21(ras)-related proteins. Thus, even if PtdIns 3-kinase is not activated by p21(ras), it can maintain full enzyme activity due to the mentioned interaction with p58(c-fgr) or p59/61(hck). These tyrosine kinases apparently activate similar pathways that operate in parallel and therefore have the potential to substitute for each other in mediating adhesion and regulating cell locomotion.

Antibodies, Monoclonal↗

PubMed2000

Relative and absolute configurations of ganefromycin alpha.

The full structure of ganefromycin alpha has been determined. The relative configurations were determined from 3JH,H coupling constants and NOE data, while the absolute configurations in moleties A and B were determined separately by difference CD of their acylate derivatives, which showed typical exciton couplets. The configurations of the stereogenic centers in ganefromycin alpha are 8S, 9S, 11R, 12S, 13S, 21S, 22R, 23R, 24R, and 26S.

Aminoglycosides↗

PubMed2000

Stable isotopes examined across a migratory divide in Scandinavian willow warblers (Phylloscopus trochilus trochilus and Phylloscopus trochilus acredula) reflect their African winter quarters.

The C and N isotopes of feathers from two subspecies of willow warblers Phylloscopus trochilus trochilus and Phylloscopus trochilus acredula) are isotopically distinct. Our analysis of 138 adult males from 14 sites distributed across Sweden shows that the mean delta15N and delta13C values of subspecies acredula (from latitudes above 63 degrees N) were significantly higher than the mean delta15N and delta13C values of subspecies trochilus (from latitudes below 61 degrees N). The analysed willow warbler feathers had been moulted in the winter quarters and the observed isotopic signatures should thus reflect the isotopic pattern of food assimilated in Africa. The isotopic data observed in Sweden match the cline in morphology, both showing abrupt changes around 62 degrees N. This result agrees with data from ringing recoveries indicating that the two subspecies occupy geographically and isotopically distinct wintering grounds in Africa. Our isotopic data suggest that analysis of stable isotopes of C and N is a promising method to track wintering quarters of European birds that migrate to Africa.

Africa↗

PubMed2000

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects.

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.

Administration, Oral↗

PubMed2000

The lymphoid-specific cofactor OBF-1 is essential for the expression of a V(H) promoter/HS1,2 enhancer-linked transgene in late B cell development.

Mice deficient for the lymphoid-specific cofactor OBF-1 display reduced levels of IgG, IgA and IgE. To examine whether the lowered immunoglobulin expression is linked to reduced activity of IgH cis-regulatory elements, OBF-1(-/-) mice were crossed with mice expressing transgenes driven by a V(H) or beta-globin promoter linked to the HS1,2 enhancer. Here we show that OBF-1 is essential for the induced expression of a V(H) promoter-linked transgene, in contrast to a beta-globin promoter-dependent transgene, in LPS/IL-4 or CD40-stimulated splenic B cells. Furthermore, impaired transgene expression is observed in OBF-1(-/-) peritoneal B cells. This deficiency may be linked to OBF-1, as peritoneal cells from normal mice express OBF-1 protein constitutively. Our data link OBF-1 to IgH gene expression in late B lymphoid development.

Animals↗