CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee ...osteoarthritis (OA) and different phenotypes.
This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0–100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes.
213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12–18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache.
Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions.
EudraCT 2015-001136-37.
Laser-diode self-mixing interferometry is a noncontact technique widely used both in industries and laboratories. In this paper, we propose to extend the self-mixing approach to low-coherence sources ...such as superluminescent diodes. In particular, we present a fiber-based common-path interferometer exploiting a single-mode-pigtailed superluminescent diode. The developed measuring system has been demonstrated to be able to directly measure the flow in pipes. To the best of our knowledge, it is the first time that flow measurements have been performed by a single-arm self-mixing pigtailed superluminescent-diode. The measuring system exploits the Doppler interference pattern produced by the light back-reflected from the inner facet of the pipe wall and the light back-diffused by the moving particles. Then, the use of a low-coherence source allows to measure the velocity of the scattering particles in a fixed and well-defined region located close to the pipe wall, thus providing good robustness to variations of scatterers concentration and allowing to easily estimate the flow under the laminar flow assumption. Experimental results demonstrated a high linearity (Pearson coefficient of about 99%) and sensitivity of about 16.62 ± 1.1 cm -3 , with flows ranging from 1 to 15 cm 3 /s and scatterers volume concentration ranging from 0.015 to 0.36%.
Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the ...oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man.
Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1500, and 3000
mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48
h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state.
Endogenous plasma levels of glucosamine were detected (10.4–204
ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750–1500
mg, but not at 3000
mg, where the plasma concentration–time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10
μM with the standard 1500
mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15
h.
Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1500
mg were in line with those found to be effective in selected
in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available.
Summary Objective ADAMTS5 (aggrecanase-2) has been demonstrated to be crucial in the development of osteoarthritis (OA), by use of several mouse mutants carrying either truncated, catalytically ...inactive enzymes or aggrecanase-resistant mutant aggrecan. We have selected recombinant monoclonal antibodies directed against ADAMTS5, by using Intracellular Antibody Capture Technology (IACT). CRB0017 revealed very high affinity for the enzyme in Biacore analyses and very good specificity in a panel of binding assays. Therefore, we tested CRB0017 in a relevant spontaneous OA model, the STR/ort mouse. Design STR/ort male mice were recruited at 5 months of age, and treated intra-articularly in each knee with CRB0017 1.2 μg, CRB0017 12 μg, or vehicle. After 6 weeks, the intra-articular administration of CRB0017 was repeated with the same doses. After 3 months from recruitment, the animals were sacrificed and the femorotibial joints processed for histology and scored in a blind fashion according to both Mankin's and the OARSI methods. Results and conclusions All histological scores were significantly decreased in the CRB0017 12 μg/knee group compared to vehicle, while administration of CRB0017 1.2 μg was associated with a trend to a decrease in the same parameters. Therefore, CRB0017 administered twice in 3 months could modify the course of OA in the STR/ort mouse, by delaying cartilage breakdown as assessed histologically. The procedure of blind scoring of the histological samples clearly showed that knee intra-articular administration of CRB0017, an anti-ADAMTS5 antibody, dose-dependently improved disease progression in a relevant animal model of OA.
Summary Objective To assess the incidence of Total Joint Replacement (TJR) during the long-term follow-up of patients with knee osteoarthritis (OA) formerly receiving treatment with glucosamine ...sulphate or placebo. Methods Knee OA patients participating in two previous randomised, placebo-controlled, double-blind, 3-year trials of glucosamine sulphate and receiving treatment for at least 12 months, were systematically contacted to participate in a long-term follow-up retrospective assessment of the incidence of total knee replacement. Results Out of 340 patients with at least 12 months of treatment, 275 (i.e., 81%) could be retrieved and interviewed for the present evaluation: 131 formerly on placebo and 144 on glucosamine sulphate. There were no differences in baseline disease characteristics between groups or with the patients lost to follow-up. The mean duration of follow-up was approximately 5 years after trial termination and treatment discontinuation, making up a total of 2178 patient-years of observation (including treatment and follow-up). Total knee replacement had occurred in over twice as many patients from the placebo group, 19/131 (14.5%), than in those formerly receiving glucosamine sulphate, 9/144 (6.3%) ( P = 0.024, chi-square test), with a Relative Risk that was therefore 0.43 (95% confidence interval (CI): 0.20–0.92), i.e., a 57% decrease compared with placebo. The Kaplan Meier/Log–Rank test survival analysis confirmed a significantly decreased ( P = 0.026) cumulative incidence of total knee replacements in patients who had received glucosamine sulphate. A pharmacoeconomic analysis in a subgroup of subjects suggested that patients formerly on glucosamine sulphate had recurred to less symptomatic medications and use of other health resources than those from the placebo group during the last year of follow-up. Conclusions Treatment of knee OA with glucosamine sulphate for at least 12 months and up to 3 years may prevent TJR in an average follow-up of 5 years after drug discontinuation.
The development and testing of innovative technologies and automated data analysis methodologies offer tools for the monitoring of complex marine ecosystems and the direct and indirect effects of ...climate change on natural heritage. Photogrammetric methods allow precise mapping of the underwater landscape as well as detailed three-dimensional (3D) reconstruction of marine structures, improving the study of complex marine ecosystems. Moreover, fluorescence analyses can provide critical information about the health status of marine organisms. Analysing the variations in their self-fluorescence, allow for early detect changes in their physiological state. These applications provide very useful data to evaluate the health state of biodiversity-rich 3D biogenic structures and make measurements of fine-scale changes, with greater precision than existing methodologies. This contribution shows a multidisciplinary approach to the design, development, and implementation of a technological solution based on the above-mentioned optical measuring systems. Such a system is characterized by a reflex camera, LED-based light sources, and filters to allow the analysis of the self-fluorescence signal. The proposed solution aspires to improve the standardization of monitoring plans through non-destructive fine-scale accurate data collection for image analysis and multi-temporal comparisons, providing challenging stepping-stones for habitat-forming anthozoan management and restoration activities. Initial results of tests carried out in controlled conditions are shown. The photogrammetric approach resulted in 3D reconstructions that allow the monitoring of deformations at millimetre scale. The fluorimetry methodology allowed to obtain high-resolution images with great repeatability, which enabled the identification of stressful status even in absence of geometric deformations. The proposed approaches and obtained results are discussed, together with potential issues related to their implementation in a real-world context adopting remotely operative vehicles.
Summary Objective We investigated the synovial and plasma glucosamine concentrations in osteoarthritic patients following oral administration of crystalline glucosamine sulphate at the therapeutic ...dose of 1500 mg once-a-day for 14 days. Design Twelve osteoarthritic patients (six males and six females) received 14 consecutive once-daily oral administrations of crystalline glucosamine sulphate soluble powder (1500 mg), in an open fashion. Plasma and synovial fluid were collected simultaneously from the same patient, at baseline and, at steady state (3 h after the last dose). Glucosamine was determined in plasma and synovial fluid by liquid chromatography–tandem mass spectrometry. Results Median endogenous glucosamine concentrations in plasma and synovial fluid were 52.0 ng/ml (0.29 μM) and 36.5 ng/ml (0.21 μM), respectively ( P = 0.001), and varied substantially among patients (41–121 ng/ml and <10–67 ng/ml, respectively). Three hours after the last dose, glucosamine concentrations resulted increased from baseline in all patients with median increases of 20.5 and 21.5 folds in plasma and synovial fluid, respectively, the difference being not statistically significant ( P = 0.11). In plasma, the median post-treatment value was 1282 ng/ml (7.17 μM) and ranged from 600 to 4061 ng/ml (3.35–22.7 μM). The median post-treatment synovial glucosamine concentration was 777 ng/ml (4.34 μM), i.e., significantly lower than in plasma ( P = 0.001), and ranged from 577 to 3248 ng/ml (3.22–18.1 μM). Plasma and synovial glucosamine concentrations were highly correlated and were in the 10 μM range. Conclusions Glucosamine is bioavailable both systemically and at the site of action (the joint) after oral administration of crystalline glucosamine sulphate in ostaeoarthritis patients. Steady state glucosamine concentrations in plasma and synovial fluid were correlated and in line with those effective in selected in vitro studies.
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