E Lackner

IST Austria, Klosterneuberg, Lower Austria, Austria

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Publications (26)97.39 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: MicroRNAs (miRNAs) are a class of endogenous noncoding RNA and posttranscriptionally modulate gene expression during development and disease. Our study investigated the differential miRNA expression in human Fuchs endothelial corneal dystrophy (FECD) compared to normal endothelium to identify miRNA sequences that are involved in the pathogenesis of FECD. Methods: Comparative miRNA expression profiles of endothelial samples obtained from FECD patients during lamellar corneal transplant surgery and from normal donor globes were generated using OpenArray® plate technology. Differential expression of individual miRNAs was validated in the original and in independent samples using stem-loop RT qPCR assays. Expression of miRNA target genes was assessed using qPCR and tissue microarray (TMA) immunolabeling. Results: Our results demonstrate downregulation of 87 microRNAs in FECD compared to normal endothelium (>3-fold change; p<0.01). Correspondingly, DICER1, (encoding an endoribonuclease critical to miRNA biogenesis) showed a moderate but significant decrease in FECD samples (p<0.05). Significant repression of three miR-29 family members (miR-29a-3p, miR-29b-2-5p, miR-29c-5p) was paralleled by upregulation of their extracellular matrix associated mRNA targets collagen I and collagen IV. TMA immunolabeling showed histologically verifiable subendothelial collagen I and collagen IV deposition and increased endothelial laminin protein expression in FECD samples. Conclusions: The present study provides the first microRNA profile in FECD and normal endothelial cells and demonstrates widespread miRNA down-regulation in FECD. Decreased endothelial expression of miR-29 family members may be associated with increased subendothelial extracellular matrix accumulation in FECD.
    Investigative ophthalmology & visual science 12/2013; 55(1). DOI:10.1167/iovs.13-12689 · 3.66 Impact Factor
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    ABSTRACT: Phakic intraocular lenses (IOLs) are gaining popularity for refractive surgeons, since these IOLs are easy to implant and can correct high ametropia up to 20 D. However, these implants can still lead to reversible and irreversible complications, even years after implantation.This review gives a short overview about the different kinds of phakic IOLs, the advantages and disadvantages of these lenses and the pre- and post-operative examinations.Most of the angle-supported phakic IOLs have been abandoned from the market few years after launching. Two anterior chamber IOLs and one posterior chamber IOL—the iris-clip IOL ‘Artisan/Verisyse’ (Ophtec, Netherlands/Abbott, USA), the angle supported IOL ‘Cachet’ (Alcon, USA) and the ‘implantable collamer lens’ (Staar, USA), are commercially available at the moment.Phakic IOLs are a good option for the treatment of high myopia, but exact preoperative examination of the patient and consistent post-operative controls including endothelial cell count are mandatory to reduce the risk of long-term complications.
    Spektrum der Augenheilkunde 12/2013; 27(6). DOI:10.1007/s00717-013-0190-5 · 0.18 Impact Factor
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    ABSTRACT: The aim was to produce 2 tissue microarrays (TMAs) for keratoconus (KC) corneas and to evaluate the expression of stress-related markers, epidermal growth factor receptor (EGFR), and 8-oxo-2'-deoxyguanosine (8-OHdG), in KC corneas. The corneal buttons of 66 patients with KC were included in both TMAs; 10 Fuchs endothelial corneal dystrophy (FECD), 20 normal autopsy corneas, and 32 nonocular tissue cores served as controls. The expression of immunolabeling for EGFR and 8-OHdG in KC corneas was compared with those of the controls by TMAJ software using an H-score index. To further interpret our findings, pig eyes under different preservation conditions were stained for the same markers. With 2 TMAs, we designed an effective model to investigate KC corneas at the protein level. The EGFR in epithelial cells showed significant upregulation in KC specimens compared with that in FECD controls (P = 0.009), and this was also higher in autopsy controls compared with that in KC corneal samples (P = 0.0002). The 8-OHdG in epithelial cells was elevated in KC samples compared with that in the FECD specimens (P = 0.03), whereas autopsy controls showed higher levels compared with those shown by the KC corneal samples (P < 0.0001). Immunohistochemical staining intensities for both markers in pig corneas correlated with increased time to fixation. TMAs simultaneously enable efficient, high-throughput analysis of tissue samples. The upregulation of EGFR and 8-OHdG protein levels in KC epithelium compared with FECD controls implicates oxidative stress in KC corneas. The expression of these stress markers is increased depending on the time to preservation, which may explain the increased levels of these markers in autopsy control corneas.
    Cornea 11/2013; 33(1). DOI:10.1097/ICO.0000000000000012 · 2.36 Impact Factor
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    ABSTRACT: PURPOSE: To investigate the endothelial gene expression profile in a Col8a2 Q455K mutant knock-in mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD) and identify potential targets which can be correlated to human late-onset FECD. METHODS: Diseased or normal endothelial phenotypes were verified in 12 month-old homozygous Col8a2Q455K/Q455K mutant and wild-type mice by clinical confocal microscopy. An endothelial whole genome expression profile was generated by microarray-based analysis. Result validation was performed by real-time polymerase chain reaction (real-time PCR). Endothelial COX2 and JUN expression was further studied in human late-onset FECD compared to normal samples. RESULTS: Microarray analysis demonstrated endothelial expression of 24,538 genes (162 upregulated and 172 downregulated targets) and identified affected gene ontology terms including Response to Stress, Protein Metabolic Process, Protein Folding, Regulation of Apoptosis and Transporter Activity. Real-time PCR assessment confirmed increased Cox2 (p=0.001) and Jun mRNA (p=0.03) levels in Col8a2Q455K/Q455K mutant compared to wild-type mice. In human FECD samples, real-time PCR demonstrated a statistically significant increase in COX2 mRNA (p<0.0001) and JUN mRNA (p=0.002) and tissue microarray analysis showed increased endothelial COX2 (p=0.02) and JUN protein (p=0.04). CONCLUSIONS: The present study provides the first endothelial whole genome expression analysis in an animal model of FECD and represents a useful resource for future studies of the disease. In particular endothelial COX2 upregulation warrants further investigation of its role in FECD.
    Investigative ophthalmology & visual science 02/2013; 54(3). DOI:10.1167/iovs.12-10898 · 3.66 Impact Factor
  • American Journal of Ophthalmology 02/2013; 155(2):404-5. DOI:10.1016/j.ajo.2012.10.007 · 4.02 Impact Factor
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    ABSTRACT: Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e. one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration versus time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells were determined at days 1 and 3 of treatment as well as 2 and 7 days after end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of AUC(0-24h)/MIC(90) ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects including immuno-modulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.
    Antimicrobial Agents and Chemotherapy 01/2013; 57(4). DOI:10.1128/AAC.02011-12 · 4.45 Impact Factor
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    ABSTRACT: PURPOSE:: To investigate the novel application of tissue microarray (TMA) technology to corneal disease and to report altered protein expression of senescence-associated cyclin-dependent kinase inhibitors p21 and p16 in Fuchs endothelial corneal dystrophy (FECD). METHODS:: A TMA including 208 cores was generated from paraffin-embedded tissues, including corneal buttons of 50 FECD and 5 keratoconus patients retrieved after penetrating keratoplasty, 10 autopsy globes with nonpathologic corneas, and nonocular control specimens. TMA sections were immunolabeled for p21 and p16 and analyzed using a 9-grade scoring system (0-8). Result validation was performed by immunolabeling of individual whole tissue sections. Corneal endothelial p21 and p16 expression levels in FECD specimens compared with controls served as main outcome measures. RESULTS:: TMA immunohistochemical analysis disclosed increased endothelial expression levels of nuclear p21 in FECD specimens (P < 0.05) and an altered endothelial p16 expression pattern. Immunolabeling of whole tissue sections showed statistically significant endothelial overexpression of both proteins (p21 and p16, P < 0.05). CONCLUSIONS:: The present study introduces TMA technology as a valuable tool for molecular high-throughput profiling of corneal tissues. It demonstrates p21 and p16 overexpression in the corneal endothelium of genetically undifferentiated FECD patients supporting a role of cellular senescence in the pathogenesis of FECD.
    Cornea 11/2012; 32(4). DOI:10.1097/ICO.0b013e31826f324e · 2.36 Impact Factor
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    ABSTRACT: To evaluate the onset of posterior vitreous detachment (PVD) including early changes at the vitreoretinal interface after uneventful phacoemulsification in nonmyopic eyes using optical coherence tomography (OCT) and ultrasound. Prospective consecutive study. Patients undergoing cataract surgery at our unit between January and October 2010 were recruited and examined with OCT and ultrasound preoperatively. Inclusion criteria were complete vitreoretinal attachment, no ocular pathology other than cataract, and no previous ocular surgery. All patients underwent phacoemulsification with intraocular lens implantation. Postoperatively, OCT and ultrasound were performed 1 month and 3 months after surgery. Exclusion criteria were axial length≥25 mm, lattice degeneration, intraoperative complications, and incomplete follow-up. Forty-nine eyes of 49 patients could be enrolled in the study. Some degree of PVD was noted in 29 eyes (59.2%) 1 month after surgery and in 35 eyes (71.4%) 3 months after surgery. Moreover, a significant decrease in prevalence of initial PVD and a corresponding increase of more advanced PVD stages throughout the duration of the study was observed. In patients older than 70 years some degree of PVD was diagnosed in 92.3% compared to 47.8% in patients younger than 70 years (P=.002). OCT facilitates the detection of early vitreoretinal separation that indicates initial PVD. After phacoemulsification the prevalence of some degree of PVD is consequently more frequent when supplementary OCT is used. Furthermore, OCT discloses a significant progression of PVD in the postoperative course. Patients older than 70 years are more likely to develop pseudophakic PVD.
    American Journal of Ophthalmology 01/2012; 153(4):705-9. DOI:10.1016/j.ajo.2011.09.009 · 4.02 Impact Factor
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    ABSTRACT: To investigate the early and late stages of posterior vitreous detachment (PVD) in the foveal area in correlation with age and gender. Three hundred and thirty-five emmetropic eyes of 271 Caucasian patients (216 women/119 men) were examined by optical coherence tomography (OCT) and ultrasound (US). Eyes were classified into groups according to the patients age (up to 69.9; 70-74.9; 75-79.9; over 80 years) and to the clinical findings [Vitreous state: Detached in US; Detached in OCT; Foveal adhesion (FA); Attached vitreous]. The mean age was 76 ± 8 ranging from 44 to 89 years in female and 72 ± 10 ranging from 46 to 87 years in male subjects. The vitreous was attached in 32% of all eyes, 18.5% had FA, 18.5% were detached in OCT and 68% were detached in US. While prevalence of FA decreases with increasing age, OCT-diagnosed detachments did not change significantly with age. Between the ages of 70 and 75, an increase in PVD rates occurred. The prevalence of PVD was similar in both genders. Women were significantly older than men in the late-stage PVD in the eyes. The use of OCT and US enabled us to detect a partial or total PVD in 80% of the eyes. A sudden increase in late-stage PVD between the ages of 70 and 75 was observed, correlating with the reported age prevalence of various macular diseases. In contrast to myopics, both genders of elderly emmetropics have a similar prevalence of PVD.
    Acta ophthalmologica 11/2011; 90(3):e179-84. DOI:10.1111/j.1755-3768.2011.02310.x · 2.51 Impact Factor
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    ABSTRACT: For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ± 3.45) and lowest in WBCs (0.27 ± 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin.
    Antimicrobial Agents and Chemotherapy 11/2011; 56(2):1059-64. DOI:10.1128/AAC.05490-11 · 4.45 Impact Factor
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    ABSTRACT: The transversus abdominis plane (TAP) block is a regional anesthetic technique used for pain control following abdominal surgical procedures. While a minimum of systemic side effects is usually expected after local anesthesia, it is unknown to which extent systemic absorption and redistribution to the abdominal wall contributes to the effects of anesthetics. The aim of this study was to determine concentration-time profiles of ropivacaine after the injection of 150 mg of ropivacaine into the lateral abdominal wall in various compartments. The microdialysis technique was used to measure ropivacaine in plasma as well as at abdominal wall sites cranial from the injection site (below the 12th rip) and caudal from the injection site (cranial from the iliac crest) and in the skeletal muscle tissue of the contra lateral thigh of eight healthy volunteers. The mean exposure to ropivacaine measured as the area under the concentration-time curve was significantly higher at the two abdominal sites (240.9 ± 409.1 and 86.18 ± 133.50 μg h/mL, respectively) than in plasma (5.1 ± 1.0 μg h/mL) or in peripheral tissue (1.1 ± 1.2 μg h/mL). While the high mean concentrations of ropivacaine measured at the abdominal wall sites support the topical concept of the TAP block, the observed variability was striking. While the systemic pharmacokinetics was comparable between subjects, the local distribution of ropivacaine was highly variable after TAP block.
    European Journal of Clinical Pharmacology 10/2011; 68(4):419-25. DOI:10.1007/s00228-011-1139-8 · 2.70 Impact Factor
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    Acta ophthalmologica 11/2010; 88(7):e271-2. DOI:10.1111/j.1755-3768.2009.01611.x · 2.51 Impact Factor
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    ABSTRACT: Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹⁴C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹⁴C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹⁴C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-β-glucuronide, were identified.
    Pharmacology 11/2010; 86(5-6):297-305. DOI:10.1159/000321322 · 1.58 Impact Factor
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    ABSTRACT: Cancer progression is often associated with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a major regulator of vascular permeability and has been implicated as mediator of tumor progression. We examined the production and secretion of VEGF(165) in various primary cancer cells derived from malignant effusions, and the role of exogenous VEGF(165) as a mediator of effusion formation. VEGF(165) was constantly secreted by all cultured tumor cells in an mTOR-dependent manner, as it was inhibited by the mTOR inhibitor rapamycin. Secreted VEGF(165) showed functional activity by inducing endothelial leakiness and tumor cell-transendothelial migration in vitro, effects which could be reverted by the anti-VEGF antibody bevacizumab. Thus, mTOR inhibitors as well as bevacizumab should be considered as potential agents in cancer patients suffering from malignant effusions.
    Molecular oncology 04/2010; 4(2):150-60. DOI:10.1016/j.molonc.2010.01.002 · 5.94 Impact Factor
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    ABSTRACT: This randomized, double-blinded volunteer study was designed to evaluate the ED(99) volume of local anaesthetic for sciatic nerve blocks using a step-up/step-down methodology. A maximum of 20 volunteers were included to receive an ultrasound-guided sciatic nerve block with mepivacaine 1.5% and a starting volume of 0.2 ml mm(-2) cross-sectional nerve area. In cases of a complete sensory block, the volume was reduced by 0.02 ml mm(-2) cross-sectional nerve area until the first block failed. Thereafter, the volume of local anaesthetic was increased by 0.02 ml mm(-2) cross-sectional nerve area. After three cycles of successful/failed blocks, the ED(99) volume of local anaesthetic could be calculated by a probability function. The influence of the volumes of local anaesthetics on sensory onset times and duration of sensory block was evaluated by linear regression. The ED(99) volume of local anaesthetic for sciatic nerve block was calculated with 0.10 ml mm(-2) cross-sectional nerve area. The correlation between the volume of local anaesthetic and the sensory onset time was weak (r=0.14), whereas the correlation between the volume of local anaesthetic and the duration of sensory block was moderate (r=0.65). This is the first study where an ED(99) volume of local anaesthetic for sciatic nerve block has been evaluated. The resulting local anaesthetic volume of 0.10 ml mm(-2) cross-sectional nerve area seems to have no impact on sensory onset time, whereas the duration of sensory block is shorter.
    BJA British Journal of Anaesthesia 02/2010; 104(2):239-44. DOI:10.1093/bja/aep368 · 4.35 Impact Factor
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    ABSTRACT: Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.
    Current cancer drug targets 09/2009; 9(5):675-89. · 3.58 Impact Factor
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    ABSTRACT: Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC50 values ranging between 1 and 50 μM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor- and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPPinduced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.
    Current Cancer Drug Targets 07/2009; 9(5):675-689. DOI:10.2174/156800909789057024 · 3.58 Impact Factor
  • European Neuropsychopharmacology 09/2006; 16. DOI:10.1016/S0924-977X(06)70489-8 · 5.40 Impact Factor
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    ABSTRACT: Mesalazine (5-aminosalicylic acid, 5-ASA) containing formulations represent a cornerstone in the treatment of inflammatory bowel diseases. A novel formulation with an Eudragit L/S mixture coating has been developed to provide selective release of 5-ASA to the ileo-caecal region and the colon. To determine the release of 5-ASA during the gastrointestinal transit. A single oral dose of mesalazine EC 500 mg gastroresistant tablets (Asamax) was administered to eight healthy male volunteers. Gastrointestinal transit and tablet disintegration were monitored by scintigraphy. 5-ASA release was verified by assessing plasma pharmacokinetics. Initial tablet disintegration was observed 5.65 +/- 0.86 h after dosing, corresponding to the detection of 5-ASA in plasma. This occurred in the ileo-caecal region in three subjects and the ascending colon in the remaining five. The relative percentage of 5-ASA absorption was more pronounced in the ascending colon (41 +/- 27.4%) than the ileo-caecal region (6.6 +/- 9.2%). This mesalazine EC gastroresistant tablets release locally active 5-ASA specifically in the ileo-caecal region and the ascending colon.
    Alimentary Pharmacology & Therapeutics 02/2006; 23(1):137-44. DOI:10.1111/j.1365-2036.2006.02721.x · 5.48 Impact Factor

Publication Stats

499 Citations
97.39 Total Impact Points

Institutions

  • 2013
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2012–2013
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2010–2013
    • Medical University of Graz
      Gratz, Styria, Austria
  • 1999–2013
    • Medical University of Vienna
      • Department of Clinical Pharmacology
      Wien, Vienna, Austria
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2003
    • University of Vienna
      • Department of Internal Medicine III
      Wien, Vienna, Austria