Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Rôle du strontium en ingénierie tissulaire osseuse pour le développement d’une matrice composite de polysaccharides : application à la technique de Masquelet

Reconstruction of large and complex bone defects remains a challenge for orthopaedic and maxillo-facial surgery. The gold standard strategy for bone reconstruction is the autologous bone graft. However, this approach still exhibits some limitations (infection risks, morbidity at the donor site). In this context, tissue engineering can provide innovative solutions for bone reconstruction. Indeed, the use of osteoconductives and osteoinductives matrices could replace autograft. Based on previous data obtained by our laboratory, the first objective of this work was to develop a composite matrix of polysaccharides containing hydroxyapatite (HA) particles doped with strontium (Sr), to stimulate both bone formation and angiogenesis. In vitro and in vivo results allow us to optimize the amount of HA particules and the ratio of Sr-substitution within the polysaccharide-based matrix. The second part of this work was to apply this biomaterial in the context of Masquelet approach. These two time procedure surgery, based on the formation of an induced membrane, is commonly used in orthopaedic and maxillo-facial surgery. The first chirurgical step uses a surgical cement (poly(methyl)methalcrylate, PMMA) to promote around it the formation of a vascularized membrane. Our work was to replace this cement by silicone and to study the influence of radiotherapy treatment on the quality and the function of this induced membrane. The first preclinical evaluation of this matrix has been performed on a rat femoral segmental bone defect, followed by a radiotherapy procedure. The perspectives of this work are to evaluate the performances of this matrix on irradiated segmental mandibular bone defect in large animal.La reconstruction de lésions osseuses complexes reste un défi dans le domaine de la chirurgie orthopédique et maxillo-faciale. A ce jour, la technique de référence reste la greffe d’os autologue. Cependant cette technique présente de nombreuses limites (risque d’infection, morbidité au site de prélèvement). Dans ce contexte, l’ingénierie tissulaire peut apporter des solutions de reconstruction innovantes. En effet l’utilisation de matrices ostéoconductrices et ostéoinductrices permettrait de remplacer l’autogreffe. Le premier objectif de ce travail a été de mettre au point une matrice de polysaccharides, contenant des particules d’hydroxyapatite (HA) dopées avec du strontium (Sr), afin de stimuler à la fois la régénération osseuse, mais également l’angiogenèse. Les résultats obtenus in vitro et in vivo nous ont permis d’optimiser la formulation de cette matrice, en termes de quantités de particules d’hydroxyapatite dopées par différents taux de substitution en strontium, dispersées au sein de la matrice. La deuxième partie de ce travail a été consacrée à l’application de cette matrice à la technique de Masquelet afin de remplacer l’utilisation de l’autogreffe. Cette procédure chirurgicale en deux temps, basée sur la formation d’une membrane induite, est utilisée fréquemment en chirurgie orthopédique et maxillo-faciale. Le premier temps opératoire utilise un ciment chirurgical, le (poly(méthyl)méthalcrylate, PMMA) qui entraîne la formation d’une membrane induite vascularisée. Notre travail a été de remplacer ce ciment par du silicone et d’étudier l’influence de la radiothérapie sur la qualité et la fonction de la membrane ainsi formée. Les premiers essais d’évaluation de cette matrice ont été réalisés chez le rat après résection segmentaire du fémur, suivie d’une procédure de radiothérapie. Les perspectives de ce travail sont d’évaluer la performance de cette matrice dans une lésion mandibulaire de grand volume, après irradiation, chez le gros animal

Role of strontium for bone tissue engineering and the development of a polysaccharide-based composite matrix : application to Masquelet’s technique

La reconstruction de lésions osseuses complexes reste un défi dans le domaine de la chirurgie orthopédique et maxillo-faciale. A ce jour, la technique de référence reste la greffe d’os autologue. Cependant cette technique présente de nombreuses limites (risque d’infection, morbidité au site de prélèvement). Dans ce contexte, l’ingénierie tissulaire peut apporter des solutions de reconstruction innovantes. En effet l’utilisation de matrices ostéoconductrices et ostéoinductrices permettrait de remplacer l’autogreffe. Le premier objectif de ce travail a été de mettre au point une matrice de polysaccharides, contenant des particules d’hydroxyapatite (HA) dopées avec du strontium (Sr), afin de stimuler à la fois la régénération osseuse, mais également l’angiogenèse. Les résultats obtenus in vitro et in vivo nous ont permis d’optimiser la formulation de cette matrice, en termes de quantités de particules d’hydroxyapatite dopées par différents taux de substitution en strontium, dispersées au sein de la matrice. La deuxième partie de ce travail a été consacrée à l’application de cette matrice à la technique de Masquelet afin de remplacer l’utilisation de l’autogreffe. Cette procédure chirurgicale en deux temps, basée sur la formation d’une membrane induite, est utilisée fréquemment en chirurgie orthopédique et maxillo-faciale. Le premier temps opératoire utilise un ciment chirurgical, le (poly(méthyl)méthalcrylate, PMMA) qui entraîne la formation d’une membrane induite vascularisée. Notre travail a été de remplacer ce ciment par du silicone et d’étudier l’influence de la radiothérapie sur la qualité et la fonction de la membrane ainsi formée. Les premiers essais d’évaluation de cette matrice ont été réalisés chez le rat après résection segmentaire du fémur, suivie d’une procédure de radiothérapie. Les perspectives de ce travail sont d’évaluer la performance de cette matrice dans une lésion mandibulaire de grand volume, après irradiation, chez le gros animal.Reconstruction of large and complex bone defects remains a challenge for orthopaedic and maxillo-facial surgery. The gold standard strategy for bone reconstruction is the autologous bone graft. However, this approach still exhibits some limitations (infection risks, morbidity at the donor site). In this context, tissue engineering can provide innovative solutions for bone reconstruction. Indeed, the use of osteoconductives and osteoinductives matrices could replace autograft. Based on previous data obtained by our laboratory, the first objective of this work was to develop a composite matrix of polysaccharides containing hydroxyapatite (HA) particles doped with strontium (Sr), to stimulate both bone formation and angiogenesis. In vitro and in vivo results allow us to optimize the amount of HA particules and the ratio of Sr-substitution within the polysaccharide-based matrix. The second part of this work was to apply this biomaterial in the context of Masquelet approach. These two time procedure surgery, based on the formation of an induced membrane, is commonly used in orthopaedic and maxillo-facial surgery. The first chirurgical step uses a surgical cement (poly(methyl)methalcrylate, PMMA) to promote around it the formation of a vascularized membrane. Our work was to replace this cement by silicone and to study the influence of radiotherapy treatment on the quality and the function of this induced membrane. The first preclinical evaluation of this matrix has been performed on a rat femoral segmental bone defect, followed by a radiotherapy procedure. The perspectives of this work are to evaluate the performances of this matrix on irradiated segmental mandibular bone defect in large animal

Role of strontium for bone tissue engineering and the development of a polysaccharide-based composite matrix : application to Masquelet’s technique

La reconstruction de lésions osseuses complexes reste un défi dans le domaine de la chirurgie orthopédique et maxillo-faciale. A ce jour, la technique de référence reste la greffe d’os autologue. Cependant cette technique présente de nombreuses limites (risque d’infection, morbidité au site de prélèvement). Dans ce contexte, l’ingénierie tissulaire peut apporter des solutions de reconstruction innovantes. En effet l’utilisation de matrices ostéoconductrices et ostéoinductrices permettrait de remplacer l’autogreffe. Le premier objectif de ce travail a été de mettre au point une matrice de polysaccharides, contenant des particules d’hydroxyapatite (HA) dopées avec du strontium (Sr), afin de stimuler à la fois la régénération osseuse, mais également l’angiogenèse. Les résultats obtenus in vitro et in vivo nous ont permis d’optimiser la formulation de cette matrice, en termes de quantités de particules d’hydroxyapatite dopées par différents taux de substitution en strontium, dispersées au sein de la matrice. La deuxième partie de ce travail a été consacrée à l’application de cette matrice à la technique de Masquelet afin de remplacer l’utilisation de l’autogreffe. Cette procédure chirurgicale en deux temps, basée sur la formation d’une membrane induite, est utilisée fréquemment en chirurgie orthopédique et maxillo-faciale. Le premier temps opératoire utilise un ciment chirurgical, le (poly(méthyl)méthalcrylate, PMMA) qui entraîne la formation d’une membrane induite vascularisée. Notre travail a été de remplacer ce ciment par du silicone et d’étudier l’influence de la radiothérapie sur la qualité et la fonction de la membrane ainsi formée. Les premiers essais d’évaluation de cette matrice ont été réalisés chez le rat après résection segmentaire du fémur, suivie d’une procédure de radiothérapie. Les perspectives de ce travail sont d’évaluer la performance de cette matrice dans une lésion mandibulaire de grand volume, après irradiation, chez le gros animal.Reconstruction of large and complex bone defects remains a challenge for orthopaedic and maxillo-facial surgery. The gold standard strategy for bone reconstruction is the autologous bone graft. However, this approach still exhibits some limitations (infection risks, morbidity at the donor site). In this context, tissue engineering can provide innovative solutions for bone reconstruction. Indeed, the use of osteoconductives and osteoinductives matrices could replace autograft. Based on previous data obtained by our laboratory, the first objective of this work was to develop a composite matrix of polysaccharides containing hydroxyapatite (HA) particles doped with strontium (Sr), to stimulate both bone formation and angiogenesis. In vitro and in vivo results allow us to optimize the amount of HA particules and the ratio of Sr-substitution within the polysaccharide-based matrix. The second part of this work was to apply this biomaterial in the context of Masquelet approach. These two time procedure surgery, based on the formation of an induced membrane, is commonly used in orthopaedic and maxillo-facial surgery. The first chirurgical step uses a surgical cement (poly(methyl)methalcrylate, PMMA) to promote around it the formation of a vascularized membrane. Our work was to replace this cement by silicone and to study the influence of radiotherapy treatment on the quality and the function of this induced membrane. The first preclinical evaluation of this matrix has been performed on a rat femoral segmental bone defect, followed by a radiotherapy procedure. The perspectives of this work are to evaluate the performances of this matrix on irradiated segmental mandibular bone defect in large animal

L'intérêt des méthodes non-médicamenteuses dans la gestion systématique de la douleur chez le nouveau-né prématuré : diplôme d'État de sage-femme

MédecineLongtemps considérés insensibles et exemptés d’une mémoire de la douleur, les nouveau-nés à terme ou prématurés subissaient des procédures invasives sans thérapeutique antalgique. Actuellement toutes les procédures ne sont pas encore accompagnées d’une analgésie alors que la prise en charge de la douleur est un droit fondamental humain. Se pose alors la question de l’efficacité des moyens non-médicamenteux seuls ou en association lors des actes douloureux et de l’importance de leur usage systématique. Une revue de la littérature a été réalisée à partir des bases de données Pubmed et la Cochrane Library en ciblant le nouveau-né prématuré où la littérature est plus floride. L’étude des différents moyens non-médicamenteux existants a permis d’identifier les plus efficaces d’entre eux, à savoir le glucose/ le saccharose, la succion non-nutritive et le Kangaroo Mother Care. D’autres moyens existent mais semblent avoir une efficacité plus limitée, notamment s’ils sont utilisés seuls comme le peau-à-peau, le repli facilité, le massage et le soutien postural. Le toucher, l’emmaillotage, l’allaitement au sein et l’acupuncture/ l’acupressure utilisés isolément, semblent être moins efficaces. L’administration de lait maternel ainsi que la musicothérapie requièrent des études complémentaires. Les méthodes de faible efficacité ne sont surtout pas à exclure dans la mesure où l’association des différentes méthodes entre elles potentialise l’effet antalgique afin d’optimiser la prise en charge de la douleur du nouveau-né. Les méthodes non-médicamenteuses sont nombreuses et faciles à mettre en place. Les études réalisées sur la population des nouveau-nés prématurés ont permis de démontrer l’efficacité et la sécurité de ces méthodes qui devraient être systématiquement utilisées en pratique en maternité et en néonatologi

Controlled ingestion of kaolinite (5%) modulates enteric nitrergic innervation in rats

International audienceWe have previously shown that kaolinite slowed down gastric emptying and intesti- nal transit and induced changes in enteric mechanical activities. As gastric emptying and intestinal transit have been shown to be regulated by nitric oxide (NO), the effect of an imposed ingestion of kaolinite on enteric nitrergic innervation was determined. Kaolinite has also been shown to increase plasmatic levels of leptin. Therefore, the responses of enteric neurons in the presence of leptin after kaolinite ingestion were determined, and a possible role of nitrergic neurons was evaluated in rats using organ bath technique. Our results showed that kaolinite modulates activities of enteric nerves at 14 days of ingestion. Exogenous L-NNA produced a decrease in nerve stimulation (NS)-induced relaxation in both jejunum and colon of control groups. At 14 days of kaolinite ingestion, this effect of L-NNA was significantly reduced only in the jejunum. Although L-NNA did not affect NS-induced contraction in jejunum and colon of control animals, it increased the amplitude of the NS- induced contraction in the colon of rats at 14 days of kaolinite ingestion. Leptin inhibitory effects on ENS in the jejunum were also altered at 14 days of ingestion. These differences were masked in the presence of L-NNA. Our data give evidence that changes in mechanical activities induced by kaolinite might be due to alterations in inhibitory (nitrergic and/or other) innervation at 14 days of kaolinite ingestion and to modifications of leptin effects on the responses to intramural nerve stimulation

Influence of External Beam Radiotherapy on the Properties of Polymethyl Methacrylate-Versus Silicone-Induced Membranes in a Bilateral Segmental Bone Defect in Rats

Introduction: Standard care for malignant tumors arising next to a bone structure is surgical removal with safety margins, followed by external beam radiotherapy (EBRT). Complete tumor removal can result in large bone defects. A two-step bone reconstruction technique using the induced membrane (IM) technique has proven its efficacy to bridge gap nonunion. During the first step, a spacer is placed in the bone gap. The spacer then is removed and the IM around it is filled with autologous cancellous bone graft. However, the feasibility of this technique with the addition of adjuvant EBRT between the two reconstruction steps has not yet been studied. Polymethyl methacrylate (PMMA) used to be the standard spacer material for the first step. Silicone spacers could replace them owing to their good behavior when submitted to EBRT and their easier removal from the surgical site during the second step. The aim of this study was to evaluate the influence of EBRT on the histological and biochemical properties of IM induced using PMMA or silicone as spacer.Materials and methods: The analyses were performed on PMMA- or silicone-IM with and without EBRT in a 6-mm bilateral femoral defect in 32 rats. Thickness and vessel content were measured in both groups. Bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) content in lysates of the crushed membranes were measured by enzyme immunoassay. Finally, alkaline phosphatase activity was analyzed in human bone marrow stromal cell cultures in contact with the same lysates.Results: EBRT did not change the histological structure of the cellular internal layer or the fibrous outer layer. The nature of the spacer only influenced IM thickness, PMMA-IM with external radiotherapy being significantly thicker. EBRT decreased the vascular density of IM but was less effective on VEGF/BMP2 production. In vitro, IM could have an osteoinductive potential on human bone marrow stem cells.Conclusion: EBRT did not modify the histological properties of IMs but decreased their vascular density. VEGF and BMP2 production within IMs was not affected by EBRT. Silicone spacers are able to induce membranes with similar histological characteristics to PMMA-IM

Bone Regeneration in Small and Large Segmental Bone Defect Models after Radiotherapy Using Injectable Polymer-Based Biodegradable Materials Containing Strontium-Doped Hydroxyapatite Particles

International audienceThe reconstruction of bones following tumor excision and radiotherapy remains a challenge. Our previous study, performed using polysaccharide-based microbeads that contain hydroxyapatite, found that these have osteoconductivity and osteoinductive properties. New formulations of composite microbeads containing HA particles doped with strontium (Sr) at 8 or 50% were developed to improve their biological performance and were evaluated in ectopic sites. In the current research, we characterized the materials by phase-contrast microscopy, laser dynamic scattering particle size-measurements and phosphorus content, before their implantation into two different preclinical bone defect models in rats: the femoral condyle and the segmental bone. Eight weeks after the implantation in the femoral condyle, the histology and immunohistochemistry analyses showed that Sr-doped matrices at both 8% and 50% stimulate bone formation and vascularization. A more complex preclinical model of the irradiation procedure was then developed in rats within a critical-size bone segmental defect. In the non-irradiated sites, no significant differences between the non-doped and Sr-doped microbeads were observed in the bone regeneration. Interestingly, the Sr-doped microbeads at the 8% level of substitution outperformed the vascularization process by increasing new vessel formation in the irradiated sites. These results showed that the inclusion of strontium in the matrix-stimulated vascularization in a critical-size model of bone tissue regeneration after irradiation

Effects of controlled ingestion of kaolinite (5%) on food intake, gut morphology and in vitro motility in rats.

International audienceGeophagia is found in various animal species and in humans. We have previously shown that spontaneously ingested kaolinite interacts with the intestinal mucosa modifies nutrient absorption and slows down gastric emptying and intestinal transit in rats in vivo. However, the precise mechanisms involved are not elucidated. The aim of this work was to investigate the effects of controlled kaolinite ingestion on food intake, gut morphology and in vitro motility in rats. Male Wistar rats were fed with 5% kaolinite in standard food pellets during 7, 14 and 28 days. Body mass and food consumption were measured daily. Intestinal morphological and proteomic analyses were conducted. The length of mucosal lacteals was evaluated. Plasmatic levels of leptin and adiponectin were determined. Finally, organ bath studies were conducted to evaluate smooth muscle contractility. Food consumption was significantly increased during the first two weeks of kaolinite ingestion without any mass gain compared to controls. Kaolinite induced weak variations in proteins that are involved in various biological processes. Compared to control animals, the length of intestinal lacteals was significantly reduced in kaolinite group whatever the duration of the experiment. Leptin and adiponectin plasmatic levels were significantly increased after 14 days of kaolinite consumption. Changes in spontaneous motility and responses to electrical nerve stimulation of the jejunum and proximal colon were observed at day 14. Altogether, the present data give evidence for a modulation by kaolinite-controlled ingestion on satiety and anorexigenic signals as well as on intestinal and colonic motility