Publications by authors named "Christoph Ladel"

24 Publications

  • Page 1 of 1

Baseline clinical characteristics of predicted structural and pain progressors in the IMI-APPROACH knee OA cohort.

RMD Open 2021 Aug;7(3)

Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Objectives: To describe the relations between baseline clinical characteristics of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) participants and their predicted probabilities for knee osteoarthritis (OA) structural (S) progression and/or pain (P) progression.

Methods: Baseline clinical characteristics of the IMI-APPROACH participants were used for this study. Radiographs were evaluated according to Kellgren and Lawrence (K&L grade) and Knee Image Digital Analysis. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Numeric Rating Scale (NRS) were used to evaluate pain. Predicted progression scores for each individual were determined using machine learning models. Pearson correlation coefficients were used to evaluate correlations between scores for predicted progression and baseline characteristics. T-tests and χ tests were used to evaluate differences between participants with high versus low progression scores.

Results: Participants with high S progressions score were found to have statistically significantly less structural damage compared with participants with low S progression scores (minimum Joint Space Width, minJSW 3.56 mm vs 1.63 mm; p<0.001, K&L grade; p=0.028). Participants with high P progression scores had statistically significantly more pain compared with participants with low P progression scores (KOOS pain 51.71 vs 82.11; p<0.001, NRS pain 6.7 vs 2.4; p<0.001).

Conclusions: The baseline minJSW of the IMI-APPROACH participants contradicts the idea that the (predicted) course of knee OA follows a pattern of inertia, where patients who have progressed previously are more likely to display further progression. In contrast, for pain progressors the pattern of inertia seems valid, since participants with high P score already have more pain at baseline compared with participants with a low P score.
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http://dx.doi.org/10.1136/rmdopen-2021-001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383877PMC
August 2021

Response letter to the Editor.

Semin Arthritis Rheum 2021 May 8. Epub 2021 May 8.

University of Maryland School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.semarthrit.2021.05.001DOI Listing
May 2021

Making the patient voice heard in a research consortium: experiences from an EU project (IMI-APPROACH).

Res Involv Engagem 2021 May 10;7(1):24. Epub 2021 May 10.

Lygature, Jaarbeursplein 6, Utrecht, 3521 AL, The Netherlands.

APPROACH is an EU-wide research consortium with the goal to identify different subgroups of knee osteoarthritis to enable future differential diagnosis and treatment. During a 2-year clinical study images, biomarkers and clinical data are collected from people living with knee osteoarthritis and data are analyzed to confirm patterns that can indicate such different subgroups. A Patient Council (PC) has been set up at project initiation and consists of five people from Norway, The Netherlands and UK. Initially, this group of individuals had to learn how to effectively work with each other and with the researchers. Today, the PC is a strong team that is fully integrated in the consortium and acknowledged by researchers as an important sounding board. The article describes this journey looking at formal processes of involvement - organizational structure, budget, meetings - and more informal processes such as building relationships and changing researcher perceptions. It describes how the PC helped improve the experience and engagement of study participants by providing input to the clinical protocol and ensuring effective communication (e.g. through direct interactions with participants and newsletters). Furthermore, the PC is helping with dissemination of results and project advocacy, and overall provides the patient perspective to researchers. Additionally, the authors experienced and describe the intangible benefits such as a shift in researcher attitudes and a sense of community and purpose for PC members. Importantly, learnings reported in this article also include the challenges, such as effective integration of the PC with researchers' work in the early phase of the project. TRIAL REGISTRATION: US National Library of Medicine, NCT03883568 , retrospectively registered 21 March 2019.
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http://dx.doi.org/10.1186/s40900-021-00267-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107424PMC
May 2021

Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study.

Ann Rheum Dis 2021 May 7. Epub 2021 May 7.

Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.

Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression.

Results: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53).

Conclusion: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.

Trial Registration Number: NCT01919164.
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http://dx.doi.org/10.1136/annrheumdis-2020-219181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292562PMC
May 2021

Serum C-reactive protein metabolite (CRPM) is associated with incidence of contralateral knee osteoarthritis.

Sci Rep 2021 03 22;11(1):6583. Epub 2021 Mar 22.

Immuno-Science, Nordic Bioscience, Biomarkers and Research, Herlev Hovedgade, 2730, Herlev, Denmark.

The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We investigated the level of blood CRPM in OA compared to RA using data from two phase III knee OA and two RA studies (N = 1591). Moreover, the association between CRPM levels and radiographic progression was investigated. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3-8.8] ng/mL, n = 781) compared to the RA patients (12.8 [9.5-16.0] ng/mL, n = 60); however, a significant subset of OA patients (31%) had CRPM levels (≥ 9 ng/mL) comparable to RA. Furthermore, OA patients (n = 152) with CRPM levels ≥ 9 ng/mL were more likely to develop contra-lateral knee OA assessed by X-ray over a two-year follow-up period with an odds ratio of 2.2 [1.0-4.7]. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.
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http://dx.doi.org/10.1038/s41598-021-86064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985384PMC
March 2021

The effects of sprifermin on symptoms and structure in a subgroup at risk of progression in the FORWARD knee osteoarthritis trial.

Semin Arthritis Rheum 2021 04 11;51(2):450-456. Epub 2021 Mar 11.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK. Electronic address:

Objective: To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin.

Methods: Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40-90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint.

Results: The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07]).

Conclusions: Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials.

Clinical Trial Registration: NCT01919164.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.005DOI Listing
April 2021

The Anti-ADAMTS-5 Nanobody M6495 Protects Cartilage Degradation Ex Vivo.

Int J Mol Sci 2020 Aug 20;21(17). Epub 2020 Aug 20.

Merck KGaA, 64293 Darmstadt, Germany.

Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody (M6495) on cartilage turnover ex vivo. Bovine cartilage (BEX, = 4), human osteoarthritic - (HEX, = 8) and healthy-cartilage (hHEX, = 1) explants and bovine synovium and cartilage were cultured up to 21 days in medium alone (/), with pro-inflammatory cytokines (oncostatin M (10 ng/mL) + TNFα (20 ng/mL) (O + T), IL-1α (10 ng/mL) or oncostatin M (50 ng/mL) + IL-1β (10 ng/mL)) with or without M6495 (1000-0.46 nM). Cartilage turnover was assessed in conditioned medium by GAG (glycosaminoglycan) and biomarkers of ADAMTS-5 driven aggrecan degradation (huARGS and exAGNxI) and type II collagen degradation (C2M) and formation (PRO-C2). HuARGS, exAGNxI and GAG peaked within the first culture week in pro-inflammatory stimulated explants. C2M peaked from day 14 by O + T and day 21 in co-culture experiments. M6495 dose dependently decreased huARGS, exAGNxI and GAG after pro-inflammatory stimulation. In HEX C2M was dose-dependently reduced by M6495. M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures.
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http://dx.doi.org/10.3390/ijms21175992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503673PMC
August 2020

Cohort profile: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) study: a 2-year, European, cohort study to describe, validate and predict phenotypes of osteoarthritis using clinical, imaging and biochemical markers.

BMJ Open 2020 07 28;10(7):e035101. Epub 2020 Jul 28.

Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Purpose: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development.

Participants: APPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression.

Findings To Date: Selection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: p<0.001, for selected versus excluded patients, respectively. Based on the selection model, this cohort has a predicted higher chance of progression.

Future Plans: Patients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests.After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy.

Trial Registration Number: NCT03883568.
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http://dx.doi.org/10.1136/bmjopen-2019-035101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389775PMC
July 2020

Multi-classifier prediction of knee osteoarthritis progression from incomplete imbalanced longitudinal data.

Sci Rep 2020 05 21;10(1):8427. Epub 2020 May 21.

School of Computing Science, Newcastle University, 1 Science Square, Newcastle, NE4 5TG, UK.

Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class classification task, with classes based on clinically relevant measures of progression (over a time scale typical for clinical trials). Using data from two long-term knee osteoarthritis studies OAI and CHECK, we tested multiple algorithms and learning process configurations (including multi-classifier approaches, cost-sensitive learning, and feature selection), to identify the best performing machine learning models. We examined the behaviour of the best models, with respect to prediction errors and the impact of used features, to confirm their clinical relevance. We found that the model-based selection outperforms the conventional inclusion criteria, reducing by 20-25% the number of patients who show no progression. This result might lead to more efficient clinical trials.
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http://dx.doi.org/10.1038/s41598-020-64643-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242357PMC
May 2020

Uptake of the OMERACT-OARSI Hip and Knee Osteoarthritis Core Outcome Set: Review of Randomized Controlled Trials from 1997 to 2017.

J Rheumatol 2019 08 1;46(8):976-980. Epub 2019 Mar 1.

From the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford; School of Health and Social Care, London South Bank University, London; Institute of Translational Medicine, University of Liverpool, Liverpool; Faculty of Health and Medical Sciences, University of Surrey, Guildford; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds; National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds, UK; Department of Medicine, Faculty of Medicine, and Institute of Health Policy, Management, and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto; Division of Rheumatology, Department of Medicine, and School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Institute of Bone and Joint Research, Department of Rheumatology, School of Medicine, University of Sydney and Royal North Shore Hospital, Sydney, Australia; Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, location VUmc; Amsterdam University Medical Centre, Department of Medical Humanities, Amsterdam Public Health, Amsterdam; Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands; Musculoskeletal Statistics Unit, the Parker Institute, Bispebjerg and Frederiksberg Hospital and Department of Rheumatology, Odense University Hospital; Center for Muscle and Joint Health, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; Université de Lorraine, APEMAC, Nancy, France; Division of Rheumatology, Allergy and Immunology, Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago; Sections of Clinical Epidemiology and Rheumatology, Boston University School of Medicine, Boston; TissueGene Inc., Rockville; Division of Rheumatology and Clinical Immunology, Department of Medicine and Division of Gerontology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Merck Biopharma, Merck KGaA, Darmstadt; University Pain Centre, University Hospital Carl Gustav Carus, Dresden, Germany; Inner West Psychology; Institute of Bone and Joint Research, Department of Rheumatology, School of Medicine, University of Sydney and Royal North Shore Hospital; School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, Australia; Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Faculty of Humanities and Social Sciences, University of Lucerne, Lucerne, Switzerland.

Objective: To assess the uptake of the OMERACT-OARSI (Outcome Measures in Rheumatology- Osteoarthritis Research Society International) core outcome set (COS) domains in hip and/or knee osteoarthritis (OA) trials.

Methods: There were 382 trials of hip and/or knee OA identified from the ClinicalTrial.gov registry from 1997 to 2017. Frequency of COS adoption was assessed by year and per 5-yearly phases.

Results: COS adoption decreased from 61% between 1997 and 2001 to 38% between 2012 and 2016. Pain (95%) and physical function (86%) were most consistently adopted. Patient's global assessment (48%) was the principal missing domain.

Conclusion: Limited adoption of the COS domains indicates that further consideration to improve uptake is required.
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http://dx.doi.org/10.3899/jrheum.181066DOI Listing
August 2019

The OMERACT-OARSI Core Domain Set for Measurement in Clinical Trials of Hip and/or Knee Osteoarthritis.

J Rheumatol 2019 08 15;46(8):981-989. Epub 2019 Jan 15.

From the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, and UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford; Institute of Translational Medicine, University of Liverpool, Liverpool; Faculty of Health and Medical Sciences, University of Surrey, Guildford; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds; NIHR Leeds Biomedical Research Centre, Leeds, UK; Department of Medicine, Faculty of Medicine, and Institute of Health Policy, Management, and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto; Division of Rheumatology, Department of Medicine, and School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Institute of Bone and Joint Research, Department of Rheumatology, School of Medicine, University of Sydney and Royal North Shore Hospital; Inner West Psychology; School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, Australia; Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, location VUmc; Amsterdam University Medical Centre, Department of Medical Humanities, Amsterdam Public Health, Amsterdam; Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands; Musculoskeletal Statistics Unit, the Parker Institute, Bispebjerg and Frederiksberg Hospital, and Department of Rheumatology, Odense University Hospital; Center for Muscle and Joint Health, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; Université de Lorraine, Approches Épidémiologiques et Psychologiques (APEMAC), Nancy, France; Division of Rheumatology, Allergy and Immunology, Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Sections of Clinical Epidemiology and Rheumatology, Boston University School of Medicine, Boston, Massachusetts; TissueGene Inc., Rockville; Division of Rheumatology and Clinical Immunology, Department of Medicine and Division of Gerontology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA; Merck Biopharma, Merck KGaA, Darmstadt; University Pain Centre, University Hospital Carl Gustav Carus, Dresden, Germany; Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Faculty of Humanities and Social Sciences, University of Lucerne, Lucerne, Switzerland.

Objective: To update the 1997 OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) core domain set for clinical trials in hip and/or knee osteoarthritis (OA).

Methods: An initial review of the COMET database of core outcome sets (COS) was undertaken to identify all domains reported in previous COS including individuals with hip and/or knee OA. These were presented during 5 patient and health professionals/researcher meetings in 3 continents (Europe, Australasia, North America). A 3-round international Delphi survey was then undertaken among patients, healthcare professionals, researchers, and industry representatives to gain consensus on key domains to be included in a core domain set for hip and/or knee OA. Findings were presented and discussed in small groups at OMERACT 2018, where consensus was obtained in the final plenary.

Results: Four previous COS were identified. Using these, and the patient and health professionals/researcher meetings, 50 potential domains formed the Delphi survey. There were 426 individuals from 25 different countries who contributed to the Delphi exercise. OMERACT 2018 delegates (n = 129) voted on candidate domains. Six domains gained agreement as mandatory to be measured and reported in all hip and/or knee OA clinical trials: pain, physical function, quality of life, and patient's global assessment of the target joint, in addition to the mandated core domain of adverse events including mortality. Joint structure was agreed as mandatory in specific circumstances, i.e., depending on the intervention.

Conclusion: The updated core domain set for hip and/or knee OA has been agreed upon. Work will commence to determine which outcome measurement instrument should be recommended to cover each core domain.
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http://dx.doi.org/10.3899/jrheum.181194DOI Listing
August 2019

A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation.

Int J Mol Sci 2018 Nov 6;19(11). Epub 2018 Nov 6.

Department of Rheumatology, Nordic Bioscience, Biomarkers and Research, 2730 Herlev, Denmark.

N-terminal propeptide of type II collagen (PIINP) is a biomarker reflecting cartilage formation. PIINP exists in two main splice variants termed as type IIA and type IIB collagen NH₂-propeptide (PIIANP, PIIBNP). PIIANP has been widely recognized as a cartilage formation biomarker. However, the utility of PIIBNP as a marker in preclinical and clinical settings has not been fully investigated yet. In this study, we aimed to characterize an antibody targeting human PIIBNP and to develop an immunoassay assessing type II collagen synthesis in human blood samples. A high sensitivity electrochemiluminescence immunoassay, hsPRO-C2, was developed using a well-characterized antibody against human PIIBNP. Human cartilage explants from replaced osteoarthritis knees were cultured for ten weeks in the presence of growth factors, insulin-like growth factor 1 (IGF-1) or recombinant human fibroblast growth factor 18 (rhFGF-18). The culture medium was changed every seven days, and levels of PIIBNP, PIIANP, and matrix metalloproteinase 9-mediated degradation of type II collagen (C2M) were analyzed herein. Serum samples from a cross-sectional knee osteoarthritis cohort, as well as pediatric and rheumatoid arthritis samples, were assayed for PIIBNP and PIIANP. Western blot showed that the antibody recognized PIIBNP either as a free fragment or attached to the main molecule. Immunohistochemistry demonstrated that PIIBNP was predominately located in the extracellular matrix of the superficial and deep zones and chondrocytes in both normal and osteoarthritic articular cartilage. In addition, the hsPRO-C2 immunoassay exhibits acceptable technical performances. In the human cartilage explants model, levels of PIIBNP, but not PIIANP and C2M, were increased (2 to 7-fold) time-dependently in response to IGF-1. Moreover, there was no significant correlation between PIIBNP and PIIANP levels when measured in knee osteoarthritis, rheumatoid arthritis, and pediatric serum samples. Serum PIIBNP was significantly higher in controls (KL0/1) compared to OA groups (KL2/3/4, = 0.012). The hsPRO-C2 assay shows completely different biological and clinical patterns than PIIANP ELISA, suggesting that it may be a promising biomarker of cartilage formation.
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http://dx.doi.org/10.3390/ijms19113485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275061PMC
November 2018

Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo.

J Transl Med 2017 Dec 12;15(1):250. Epub 2017 Dec 12.

Biomarkers and Research Rheumatology, Nordic Bioscience A/S, Herlev Hovedgade 205-207, 2730, Herlev, Denmark.

Background: Sprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix (ECM) production. To gain further insight into the process of sprifermin in the cartilage tissue, this study aimed at investigating the ECM turnover of articular cartilage explants in a longitudinal manner.

Methods: Bovine full-depth articular cartilage explants were stimulated with sprifermin or placebo at weekly intervals, similar to the dosing regimen used in clinical trials. Pre-culturing with oncostatin M and tumour necrosis factor-α, was also used to induce an inflammatory state before treatment. Metabolic activity was measured using AlamarBlue, and chondrocyte proliferation was visualized by immuno-histochemical detection of proliferating cell nuclear antigen. ECM turnover was quantified by biomarker ELISAs; ProC2 reflecting type II collagen formation, CS846 reflecting aggrecan formation, active MMP9, C2M and AGNx2 reflecting matrix metalloproteinase activity, and AGNx1 reflecting aggrecanase activity.

Results: Sprifermin was able to reach the chondrocytes through the extracellular matrix, as it increased cell proliferation and metabolic activity of explants. ProC2 and CS846 was dose-dependently increased (P < 0.05) by sprifermin compared to placebo, while C2M and AGNx2 were unaffected, active MMP9 was slightly decreased, and AGNx1 was slightly increased. Over the course of treatment, the temporal order of ECM turnover responses was AGNx1, then ProC2, followed by CS846 and MMP9. Pro-inflammatory activation of the explants diminished the ECM turnover responses otherwise observed under non-inflammatory conditions.

Conclusions: The data suggest that sprifermin has chondrogenic effects on articular cartilage ex vivo, exerted through a sequential process of ECM turnover; aggrecan degradation seems to occur first, while type II collagen and aggrecan production increased at a later time point. In addition, it was observed that these chondrogenic effects are dependent on the inflammatory status of the cartilage prior to treatment.
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http://dx.doi.org/10.1186/s12967-017-1356-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727954PMC
December 2017

Association Between Biochemical Markers of Bone Turnover and Bone Changes on Imaging: Data From the Osteoarthritis Initiative.

Arthritis Care Res (Hoboken) 2017 08 10;69(8):1179-1191. Epub 2017 Jul 10.

Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia.

Objective: To determine the relationship between biochemical markers involved in bone turnover and bone features on imaging in knees with osteoarthritis (OA).

Methods: We analyzed data from the Foundation for the National Institutes of Health OA Biomarkers Consortium within the Osteoarthritis Initiative (n = 600). Bone marrow lesions (BMLs), osteophytes, and subchondral bone area (mm ) and shape (position on 3-D vector) were assessed on magnetic resonance images, and bone trabecular integrity (BTI) was assessed on radiographs. Serum and urinary markers (serum C-terminal crosslinked telopeptide of type I collagen [CTX-I], serum crosslinked N-telopeptide of type I collagen [NTX-I], urinary NTX-I, urinary C-terminal crosslinked telopeptide of type II collagen [CTX-II], and urinary CTX-Iα and CTX-Iβ) were measured. The associations between biochemical and imaging markers at baseline and over 24 months were assessed using regression models adjusted for covariates.

Results: At baseline, most biochemical markers were associated with BMLs, with C statistics for the presence/absence of any BML ranging from 0.675 to 0.688. At baseline, urinary CTX-II was the marker most consistently associated with BMLs (with odds of having ≥5 subregions affected compared to no BML increasing by 1.92-fold [95% confidence interval (95% CI) 1.25, 2.96] per 1 SD of urinary CTX-II), large osteophytes (odds ratio 1.39 [95% CI 1.10, 1.77]), bone area and shape (highest partial R  = 0.032), and changes in bone shape over 24 months (partial R range 0.008 to 0.024). Overall, biochemical markers were not predictive of changes in BMLs or osteophytes. Serum NTX-I was inversely associated with BTI of the vertical trabeculae (quadratic slope) in all analyses (highest partial R  = 0.028).

Conclusion: We found multiple significant associations, albeit mostly weak ones. The role of systemic biochemical markers as predictors of individual bone anatomic features of single knees is limited based on our findings.
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http://dx.doi.org/10.1002/acr.23121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385286PMC
August 2017

A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis.

Clin Exp Rheumatol 2016 May-Jun;34(3):445-50. Epub 2016 Mar 23.

Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.

Objectives: To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA).

Methods: This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 μg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks.

Results: Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 μg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected.

Conclusions: This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.
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August 2016

Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis.

Biomarkers 2015 10;20(8):547-56. Epub 2016 Feb 10.

a Department of Rheumatology , Biomarkers and Research , Nordic Bioscience , Herlev , Denmark and.

Objective: Characterize biomarkers measuring extracellular matrix turnover of inflamed osteoarthritis synovium.

Methods: Human primary fibroblast-like synoviocytes and synovial membrane explants (SMEs) treated with various cytokines and growth factors were assessed by C1M, C3M, and acMMP3 in the conditioned medium.

Results: TNFα significantly increased C1M up to seven-fold (p = 0.0002), C3M up to 24-fold (p = 0.0011), and acMMP3 up to 14-fold (p < 0.0001) in SMEs. IL-1β also significantly increased C1M up to five-fold (p = 0.00094), C3M four-fold (p = 0.007), and acMMP3 18-fold (p < 0.0001) in SMEs.

Conclusion: The biomarkers C1M, C3M, and acMMP-3 were synovitis biomarkers ex vivo and provide a translational tool together with the SME model.
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http://dx.doi.org/10.3109/1354750X.2015.1105497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819844PMC
November 2016

Comparison of radiographic joint space width and magnetic resonance imaging for prediction of knee replacement: A longitudinal case-control study from the Osteoarthritis Initiative.

Eur Radiol 2016 Jun 16;26(6):1942-51. Epub 2015 Sep 16.

Division of Rheumatology and the University of Arizona Arthritis Center, University of Arizona, Tucson, AZ, USA.

Objective: To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement.

Methods: Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression.

Results: One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement.

Conclusions: Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement.

Key Points: • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.
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http://dx.doi.org/10.1007/s00330-015-3977-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794411PMC
June 2016

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study.

Arthritis Care Res (Hoboken) 2015 Oct;67(10):1481-6

Paracelsus Medical University, Salzburg, Austria, and Chondrometrics, Ainring, Germany.

Objective: To explore whether baseline to 12-month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non-TKA).

Methods: In this prospective cohort study, 531 right knees from Osteoarthritis Initiative participants with definite radiographic knee osteoarthritis (Kellgren/Lawrence [K/L] grades 2-4) were studied. Segmentation was applied to coronal fast low-angle shot magnetic resonance images, to quantitatively determine cartilage thickness in 16 femorotibial subregions. Unadjusted P values (t-tests) and P values adjusted for age, baseline body mass index (BMI), K/L grade, and sex (generalized estimating equation models) were used to evaluate differences in longitudinal 1-year rates of cartilage thickness between TKAs and non-TKAs, with total knee arthroplasty status as fixed effect.

Results: Of the 531 participants (mean ± SD ages 63 ± 9 years, BMI 30 ± 4.8 kg/m(2)), 40 received a femorotibial TKA within 4 years. At baseline, TKAs had thinner medial and lateral femorotibial cartilage (-15%; P < 0.001) than non-TKAs. Longitudinal cartilage thickness change was significantly greater in TKAs than in non-TKAs in the total femorotibial joint (area under the curve [AUC] 0.64), the lateral compartment (AUC 0.66), both tibiae (AUC ≥ 0.61), and the first 9 (of 16) ordered values of subregion change (AUC 0.64-0.69). Discrimination was stronger for TKAs that occurred at 24 and 36 months (n = 18) than for those at 48 and 60 months (n = 22).

Conclusion: Knees with incident TKA displayed smaller baseline cartilage thickness and greater lateral as well as location-independent ordered value femorotibial cartilage loss than non-TKAs. Discrimination of cartilage loss was greater for TKAs occurring within 2 years after the measurement than for those occurring later.
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http://dx.doi.org/10.1002/acr.22608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580517PMC
October 2015

Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.

Front Immunol 2014 22;5:233. Epub 2014 May 22.

Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.
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http://dx.doi.org/10.3389/fimmu.2014.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033217PMC
June 2014

Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling.

J Biol Chem 2014 Apr 27;289(14):10192-200. Epub 2014 Feb 27.

From Sensory and Motor System Medicine.

To identify genes that maintain the homeostasis of adult articular cartilage and regenerate its lesions, we initially compared four types of chondrocytes: articular (AA) versus growth plate (AG) cartilage chondrocytes in adult rats, and superficial layer (IS) versus deep layer (ID) chondrocytes of epiphyseal cartilage in infant rats. Microarray analyses revealed that 40 and 186 genes had ≥10-fold higher expression ratios of AA/AG and IS/ID, respectively, and 16 genes showed ≥10-fold of both AA/AG and IS/ID ratios. The results were validated by real-time RT-PCR analysis. Among them, Hoxd1, Fgf18, and Esm1 were expressed more strongly in AA than in IS. Fgf18 was the extracellular and secreted factor that decreased glycosaminoglycan release and depletion from the cartilage, and enhanced proliferation of articular chondrocytes. Fgf18 was strongly expressed in the articular cartilage chondrocytes of adult rats. In a surgical rat osteoarthritis model, a once-weekly injection of recombinant human FGF18 (rhFGF18) given 3 weeks after surgery prevented cartilage degeneration in a dose-dependent manner at 6 and 9 weeks after surgery, with significant effect at 10 μg/week of rhFGF18. As the underlying mechanism, rhFGF18 strongly up-regulated Timp1 expression in the cell and organ cultures, and inhibition of aggrecan release by rhFGF18 was restored by addition of an antibody to Timp1. In conclusion, we have identified Fgf18 as a molecule that protects articular cartilage by gene expression profiling, and the anticatabolic effects may at least partially be mediated by the Timp1 expression.
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http://dx.doi.org/10.1074/jbc.M113.524090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974988PMC
April 2014

Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis.

Arthritis Rheum 2011 Nov;63(11):3323-32

Merck Serono SA RBM SpA Istituto di Ricerche Biomediche Antoine Marxer, Turin, Italy.

Objective: To assess the therapeutic potential of a P2X purinergic receptor antagonist, namely, periodate oxidized ATP, in collagen-induced arthritis (CIA).

Methods: Arthritis was induced in male DBA/1J mice by immunization with type II collagen (CII). Animals showing digit inflammation and paw swelling were treated intraperitoneally with 100 μl of 3 mM oxidized ATP daily for 10 days. At the end of the treatment period, animals were killed and paws were removed for histologic analysis and evaluation of T cell infiltration. Humoral response to CII was analyzed, and specific serum autoantibody levels were correlated with the clinical scores observed in the different treatment groups.

Results: Treatment with oxidized ATP resulted in a sustained reduction in disease activity, which was associated with a significant decrease in CD3+ T cell infiltration in arthritic lesions and a significant amelioration of cartilage erosion. Peripheral Treg cells were significantly increased upon P2X blockade in mouse lymph nodes. Moreover, a marked reduction in circulating autoantibodies directed against mouse CII was detected. There was a significant correlation between serum autoantibody levels and the clinical efficacy of oxidized ATP.

Conclusion: Our findings indicate that P2X receptor antagonism has important therapeutic potential in chronic inflammatory rheumatic disorders. Taken together, our results underscore the value of the P2X receptor signaling pathway as a potential pharmacologic target for the modulation of adaptive immunity in CIA.
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http://dx.doi.org/10.1002/art.30556DOI Listing
November 2011

New DNA polymerase IIIC inhibitors: 3-subtituted anilinouracils with potent antibacterial activity in vitro and in vivo.

ChemMedChem 2008 Oct;3(10):1604-15

Global Drug Discovery, Bayer Schering Pharma, Bayer HealthCare AG, 42096 Wuppertal, Germany.

The development of resistance has rendered several antibiotics clinically ineffective, and there is an urgent medical need for potent and safe antibacterials with a novel and valid mode of action. To avoid cross-resistance, they should preferably inhibit targets that are not addressed by established antibiotics. In this respect, 6-anilinouracils represent a promising lead structure. They target the Gram-positive DNA polymerase IIIC, a target that is associated with a bactericidal mode of action. Moreover, they have no cross-resistance to marketed antibiotics. This paper describes the synthesis and biological characterization of structurally novel anilinouracils, some of which display potent in vivo efficacy in murine models of bacterial septicemia.
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http://dx.doi.org/10.1002/cmdc.200800117DOI Listing
October 2008

Dysregulation of bacterial proteolytic machinery by a new class of antibiotics.

Nat Med 2005 Oct 2;11(10):1082-7. Epub 2005 Oct 2.

Department of Anti-infectives, Bayer HealthCare AG, Pharma Research, Aprather Weg 18a, D-42096 Wuppertal, Germany.

Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
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http://dx.doi.org/10.1038/nm1306DOI Listing
October 2005

Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.

Antimicrob Agents Chemother 2005 Mar;49(3):987-95

Bayer HealthCare AG, Pharma Research EU, D-42096 Wuppertal, Germany.

Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 microg/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.
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http://dx.doi.org/10.1128/AAC.49.3.987-995.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC549236PMC
March 2005
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