Publications by authors named "Eckhard Weber"

11 Publications

  • Page 1 of 1

Relationship between tendon structure, stiffness, gait patterns and patient reported outcomes during the early stages of recovery after an Achilles tendon rupture.

Sci Rep 2020 11 27;10(1):20757. Epub 2020 Nov 27.

Translational Medicine Department, Novartis Institute for BioMedical Research, Fabrikstrasse 10-3.40.4, 4002, Basel, Switzerland.

After an Achilles tendon (AT) injury, the decision to return to full weightbearing for the practice of sports or strenuous activities is based on clinical features only. In this study, tendon stiffness and foot plantar pressure, as objective quantitative measures that could potentially inform clinical decision making, were repeatedly measured in 15 patients until 3 months after the AT rupture by using shear wave elastography (SWE) and wearable insoles, respectively. Meanwhile, patient reported outcomes assessing the impact on physical activity were evaluated using the Achilles Tendon Total Rupture Score (ATRS). At week-2 post-injury, stiffness of the injured tendon varied from 6.00 ± 1.62 m/s (mean ± SD) close to the rupture to 8.91 ± 2.29 m/s when measured more distally. While near complete recovery was observed in distal and middle regions at week-8, the shear wave velocity in the proximal region recovered to only 65% of the contralateral value at week-12. In a parallel pre-clinical study, the tendon stiffness measured in vivo by SWE in a rat model was found to be strongly correlated with ex vivo values of the Young's modulus, which attests to the adequacy of SWE for these measures. The insole derived assessment of the plantar pressure distribution during walking showed slight sub-optimal function of the affected foot at week-12, while the ATRS score recovered to a level of 59 ± 16. Significant correlations found between tendon stiffness, insole variables and distinct ATRS activities, suggest clinical relevance of tendon stiffness and foot plantar pressure measurements. These results illustrate how an alteration of the AT structure can impact daily activities of affected patients and show how digital biomarkers can track recovery in function over time.
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http://dx.doi.org/10.1038/s41598-020-77691-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695820PMC
November 2020

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs.

Adv Healthc Mater 2018 05 14;7(9):e1701393. Epub 2018 Feb 14.

John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine.
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http://dx.doi.org/10.1002/adhm.201701393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192424PMC
May 2018

Development and Validation of a Chronic Pancreatitis Prognosis Score in 2 Independent Cohorts.

Gastroenterology 2017 12 14;153(6):1544-1554.e2. Epub 2017 Sep 14.

Department of Medicine A, Universitätsmedizin Greifswald, Ernst-Moritz-Arndt-University Greifswald, Germany; Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. Electronic address:

Background & Aims: The clinical course of chronic pancreatitis is unpredictable. There is no model to assess disease severity or progression or predict patient outcomes.

Methods: We performed a prospective study of 91 patients with chronic pancreatitis; data were collected from patients seen at academic centers in Europe from January 2011 through April 2014. We analyzed correlations between clinical, laboratory, and imaging data with number of hospital readmissions and in-hospital days over the next 12 months; the parameters with the highest degree of correlation were used to develop a 3-stage chronic pancreatitis prognosis score (COPPS). The predictive strength was validated in 129 independent subjects identified from 2 prospective databases.

Results: The mean number of hospital admissions was 1.9 (95% confidence interval [CI], 1.39-2.44) and 15.2 for hospital days (95% CI, 10.76-19.71) for the development cohort and 10.9 for the validation cohort (95% CI, 7.54-14.30) (P = .08). Based on bivariate correlations, pain (numeric rating scale), level of glycated hemoglobin A1c, level of C-reactive protein, body mass index, and platelet count were used to develop the COPPS system. The patients' median COPPS was 8.9 points (range, 5-14). The system accurately discriminated stages of disease severity (low to high): A (5-6 points), B (7-9), and C (10-15). In Pearson correlation analysis of the development cohort, the COPPS correlated with hospital admissions (0.39; P < .01) and number of hospital days (0.33; P < .01). The correlation was validated in the validation set (Pearson correlation values of 0.36 and 0.44; P < .01). COPPS did not correlate with results from the Cambridge classification system.

Conclusions: We developed and validated an easy to use dynamic multivariate scoring system, similar to the Child-Pugh-Score for liver cirrhosis. The COPPS allows objective monitoring of patients with chronic pancreatitis, determining risk for readmission to hospital and potential length of hospital stay.
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http://dx.doi.org/10.1053/j.gastro.2017.08.073DOI Listing
December 2017

1-Aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats.

Drug Metab Dispos 2014 Jul 11;42(7):1117-24. Epub 2014 Apr 11.

Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (R.A.S., E.W., P.L., S.M., B.S.); and Global Imaging Group, Novartis Pharma AG, Basel, Switzerland (B.T.).

The simultaneous effects of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying were evaluated with the test compound 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole(NVS-CRF38), a novel corticotropin releasing factor receptor 1 (CRF1) antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pretreatment of rats with 100 mg/kg oral ABT administered 2 hours before a semisolid caloric test meal markedly delayed gastric emptying. ABT increased stomach weights by 2-fold; this is likely attributable to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of coadministered compounds can be expected due to a disturbance of gastrointestinal transit.
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http://dx.doi.org/10.1124/dmd.113.056408DOI Listing
July 2014

Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotropin-releasing factor receptor 1 antagonist.

Xenobiotica 2014 Oct 3;44(10):902-12. Epub 2014 Apr 3.

Novartis Institutes for Biomedical Research , Horsham, West Sussex , UK.

1. The pharmacokinetic properties and metabolism of NVS-CRF38 [7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole], a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist, were determined in vitro and in animals. 2.  NVS-CRF38 undergoes near complete absorption in rats and dogs. In both species the compound has low hepatic extraction and is extensively distributed to tissues. 3. In rat and human hepatic microsomes and cryopreserved hepatocytes from rat, dog, monkey and human, NVS-CRF38 was metabolised to form O-desmethyl NVS-CRF38 (M7) and several oxygen adducts (M1, M3, M4, M5 and M6). In hepatocytes further metabolites were observed, specifically the carboxylic acid (M2) and conjugates (sulphate and glucuronide) of M7. 4.  Formation of primary metabolites in hepatocytes was blocked by the cytochrome P450 enzyme (P450) suicide inhibitor 1-aminobenzotriazole, implicating P450 enzymes in the primary metabolism of this compound. 5. NVS-CRF38 is weakly bound to plasma proteins from rat (fub = 0.19), dog (fub = 0.25), monkey (fub = 0.20) and humans (fub = 0.23). Blood-to-plasma partition for NVS-CRF38 approaches unity in rat and human blood. 6.  The hepatic clearance of NVS-CRF38 in humans is predicted to be low (extraction ratio ∼ 0.2) based on scaling from drug depletion profiles in hepatic microsomes.
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http://dx.doi.org/10.3109/00498254.2014.907458DOI Listing
October 2014

Pre-study protocol MagPEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis.

BMC Gastroenterol 2013 Jan 15;13:11. Epub 2013 Jan 15.

Central Endoscopy and Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, Greifswald, 17475, Germany.

Background: Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement.

Methods: We designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated.

Conclusions: If magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis.

Trial Registration: Current Controlled Trials ISRCTN46556454.
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http://dx.doi.org/10.1186/1471-230X-13-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599317PMC
January 2013

L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)--a randomized multicentre trial.

Nutr J 2012 Jul 23;11:52. Epub 2012 Jul 23.

Department of Medicine A, University Medicine Greifswald, Friedrich Löffler Straße 23a, Greifswald 17475, Germany.

Background: Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia.

Findings: We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2.5 (SEM) kg. During treatment body-mass-index increased by 3.4 ± 1.4% under L-Carnitine and decreased (-1.5 ± 1.4%) in controls (p < 0.05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.).

Conclusion: While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.
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http://dx.doi.org/10.1186/1475-2891-11-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439338PMC
July 2012

Large-scale prediction and testing of drug activity on side-effect targets.

Nature 2012 Jun 10;486(7403):361-7. Epub 2012 Jun 10.

Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.

Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 μM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.
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http://dx.doi.org/10.1038/nature11159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383642PMC
June 2012

Environmental risk factors for chronic pancreatitis and pancreatic cancer.

Dig Dis 2011 5;29(2):235-42. Epub 2011 Jul 5.

Department of Medicine A, Klinikum der Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

Chronic pancreatitis has long been thought to be mainly associated with immoderate alcohol consumption. The observation that only ∼10% of heavy drinkers develop chronic pancreatitis not only suggests that other environmental factors, such as tobacco smoke, are potent additional risk factors, but also that the genetic component of pancreatitis is more common than previously presumed. Either disease-causing or protective traits have been indentified for mutations in different trypsinogen genes, the gene for the trypsin inhibitor SPINK1, chymotrypsinogen C, and the cystic fibrosis transmembane conductance regulator (CFTR). Other factors that have been proposed to contribute to pancreatitis are obesity, diets high in animal protein and fat, as well as antioxidant deficiencies. For the development of pancreatic cancer, preexisting chronic pancreatitis, more prominently hereditary pancreatitis, is a risk factor. The data on environmental risk factors for pancreatic cancer are, with the notable exception of tobacco smoke, either sparse, unconfirmed or controversial. Obesity appears to increase the risk of pancreatic cancer in the West but not in Japan. Diets high in processed or red meat, diets low in fruits and vegetables, phytochemicals such as lycopene and flavonols, have been proposed and refuted as risk or protective factors in different trials. The best established and single most important risk factor for cancer as well as pancreatitis and the one to clearly avoid is tobacco smoke.
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http://dx.doi.org/10.1159/000323933DOI Listing
November 2011

Optimal timing of oral refeeding in mild acute pancreatitis: results of an open randomized multicenter trial.

Pancreas 2010 Oct;39(7):1088-92

Internistische Gemeinschaftspraxis für Verdauungs- und Stoffwechselkrankheiten, Leipzig.

Objectives: The aim of this study was to compare 2 protocols regarding the initiation of oral nutrition in patients with mild acute pancreatitis.

Methods: We randomized 143 patients to the Lipase directed (LIP) (n = 74) and the self selected PAT (n = 69) group. In the (PAT) group, the patients restarted eating through self-selection. In the LIP group, serum lipase had to normalize before eating.

Results: The mean time between admission and oral nutrition was 2 days (interquartile range [IQR], 1-3) in the PAT group and 3 days (IQR, 2-4) in the LIP group (P < 0.005). Before and after the first meal, the mean Δ visual analogue scale (VAS) was +3.14 mm (±11.5 mm) in the PAT group and +2.85 mm (±16.4) in the LIP group (P = 0.597). The length of hospital stay was 7 days (median; IQR, 5-10.5) in the PAT group and 8 days (median; IQR, 5.75-12) in the LIP group (P = 0.315).

Conclusions: We were not able to demonstrate a difference in postprandial abdominal pain or in the length of hospital stay. Patients with self-selected eating, however, were able to restart eating 1 day earlier, and this difference was found to be significant. Our data suggest that normalization of serum lipase is not obligatory for enteral nutrition in mild acute pancreatitis.
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http://dx.doi.org/10.1097/MPA.0b013e3181d3ce05DOI Listing
October 2010

Noninvasive assessment of gastric emptying by near-infrared fluorescence reflectance imaging in mice: pharmacological validation with tegaserod, cisapride, and clonidine.

Mol Imaging 2004 Oct;3(4):303-11

Novartis Institutes for BioMedical Research, Novartis Pharma AG, WSJ-386.14.48, CH-4002 Basel, Switzerland.

Noninvasive near-infrared fluorescence reflectance imaging (FRI) is an in vivo technique to assess physiological and molecular processes in the intact organism. Here we describe a method to assess gastric emptying in mice. TentaGel beads with covalently bound cyanine dye (Cy5.5) conjugates as fluorescent probe were administered by oral gavage. The amount of intragastric beads/label was derived from the fluorescence signal intensity measured in a region of interest corresponding to the mouse stomach. The FRI signal intensity decreased as a function of time reflecting gastric emptying. In control mice, the gastric half-emptying time was in agreement with literature data. Pharmacological modulation of gastric motility allowed the evaluation of the sensitivity of the FRI-based method. Gastric emptying was either stimulated or inhibited by treatment with the 5-HT(4) receptor agonists tegaserod (Zelnorm) and cisapride or the alpha(2)-receptor agonist clonidine, respectively. Tegaserod and cisapride dose-dependently accelerated gastric emptying. In contrast, clonidine dose-dependently delayed gastric emptying. In conclusion, FRI using fluorescently labeled beads allows the reliable determination of gastric emptying as well as the assessment of pharmacological interventions. The technique thus offers the potential to characterize molecular targets and pathways involved in physiological regulation and pharmacological modulation of gastric emptying.
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http://dx.doi.org/10.1162/1535350042973490DOI Listing
October 2004