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Blaess Julien - One of the best experts on this subject based on the ideXlab platform.
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Traitements de fond de la polyarthrite rhumatoïde : revue systématique des essais cliniques à partir des 17 bases de données recensées par l’OMS
'Medecine et Hygiene', 2020Co-Authors: Blaess JulienAbstract:Médecine. RhumatologieIntroduction : l’arsenal thérapeutique dans la polyarthrite rhumatoïde s’est considérablement développé ces dernières années avec l’arrivée sur le marché dans un premier temps des DMARDs (disease-modifying anti-rheumatic drugs) dits conventionnels (csDMARDs) avec comme chef de file le méthotrexate puis des biothérapies (bDMARDS) fabriquées à partir d’organismes vivants et enfin plus récemment les thérapies ciblées synthétiques (tsDMARDs). Malgré ces récents progrès seuls environs 20% des patients non répondeurs au méthotrexate atteignent une réponse ACR70. Pour ces patients n’atteignant pas la rémission et qui continuent à s’aggraver, une meilleure compréhension de la maladie et la recherche de nouvelles approches thérapeutiques est un enjeu majeur. L’objectif de notre étude était d’analyser l’ensemble des essais cliniques évaluant des traitements de fond (cs-, b- et tsDMARDs) de la polyarthrite rhumatoïde et d’en décrire leur mécanisme d’action ainsi que leur phase de développement clinique. Méthode : nous avons effectué une revue systématique de l’ensemble des molécules faisant l’objet d’un essai clinique dans la polyarthrite rhumatoïde à partir des 17 bases de données internationales référencées par l’OMS. Nous avons exclu les essais ne faisant pas l’objet d’une thérapeutique médicamenteuse, les thérapies cellulaires, les anti inflammatoires non stéroïdiens, les glucocorticoïdes et leurs dérivés, les molécules n’ayant pas d’effet immunomodulateur. Résultats : notre recherche a abouti à 4652 essais cliniques à partir desquels nous avons identifié 243 molécules. Ces molécules sont des csDMARDs (n=22), bDMARDs (n=118) et tsDMARDs (n=103). Parmi elles, 24 sont actuellement commercialisées dans au moins un pays. Les molécules en développement sont principalement des bDMARDs (n=34) et tsDMARDs (n=33). Sept molécules (en dehors de celles déjà commercialisées) ont atteint au moins un essai clinique de phase III. Parmi elles, nous retrouvons un nouvel anti TNF-alpha (ozoralizumab), un inhibiteur direct de l’IL-6 (olokizumab), un inhibiteur de l’IL-17 (sécukinumab) et un inhibiteur de RANKL (dénosumab). Les trois autres molécules évaluées en phase III ciblent des voies physiopathologiques novatrices, l’otilimab, un inhibiteur de GM-CSF évalué actuellement dans deux essais de phase III. Le télitacicept, un inhibiteur de la protéine de fusion TACI qui est un récepteur exprimé par les lymphocytes B. Le Piclidenoson un agoniste du récepteur A3 de l’adénosine induisant des effets anti-inflammatoires via l’inhibition de la voie NF-KB. Notre étude a également permis de relever un nombre important de molécules abandonnées (n=150). Parmi les causes d’abandons de molécules, la première est le manque d’efficacité (pour 66 molécules sur 150). Conclusion : la poursuite de la recherche est toujours active avec 243 molécules faisant l’objet d’essais cliniques. L’objectif étant d’explorer de nouvelles voies thérapeutiques et développer de nouveaux médicaments que l’on souhaiterait idéalement : plus efficaces, mieux tolérés et à l’administration moins contraignante afin de favoriser une meilleure observance thérapeutique.Objectives: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development. Methods: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials. Results: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs (n=22), bDMARDs (n=118), tsDMARDs (n=103). Twenty-four molecules are already marketed in RA in at least one country: 8 csDMARDs, 10 bDMARDs and 6 tsDMARDs. Molecules under current development are mainly bDMARDs (n=34) and tsDMARDs (n=33). Seven of those have reached phase III. A large number of molecules (150 /243, 61.7%) have been withdrawn. Conclusion: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With 7 molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come
Pnina Fishman - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson
Hindawi Limited, 2018Co-Authors: Shira Cohen, Faina Barer, Inbal Itzhak, Michael H. Silverman, Pnina FishmanAbstract:Interleukin-17 and interleukin-23 play major roles in the inflammatory process in psoriasis. The Gi protein-associated A3 adenosine receptor (A3AR) is known to be overexpressed in inflammatory cells and in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory conditions. Piclidenoson, a selective agonist at the A3AR, induces robust anti-inflammatory effect in psoriasis patients. In this study, we aimed to explore A3AR expression levels in psoriasis patients and its role in mediating the anti-inflammatory effect of Piclidenoson in human keratinocyte cells. A3AR expression levels were evaluated in skin tissue and PBMCs derived from psoriasis patients and healthy subjects. Proliferation assay and the expression of signaling proteins were used to evaluate Piclidenoson effect on human keratinocytes (HaCat). High A3AR expression levels were found in a skin biopsy and in PBMCs from psoriasis patients in comparison to healthy subjects. Piclidenoson inhibited the proliferation of HaCat cells through deregulation of the NF-κB signaling pathway, leading to a decrease in interleukin-17 and interleukin-23 expression levels. This effect was counteracted by the specific antagonist MRS 1523. A3AR overexpression in skin and PBMCs of psoriasis patients may be used as a target to inhibit pathological cell proliferation and the production of interleukin-17 and interleukin-23
Shira Cohen - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson
Hindawi Limited, 2018Co-Authors: Shira Cohen, Faina Barer, Inbal Itzhak, Michael H. Silverman, Pnina FishmanAbstract:Interleukin-17 and interleukin-23 play major roles in the inflammatory process in psoriasis. The Gi protein-associated A3 adenosine receptor (A3AR) is known to be overexpressed in inflammatory cells and in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory conditions. Piclidenoson, a selective agonist at the A3AR, induces robust anti-inflammatory effect in psoriasis patients. In this study, we aimed to explore A3AR expression levels in psoriasis patients and its role in mediating the anti-inflammatory effect of Piclidenoson in human keratinocyte cells. A3AR expression levels were evaluated in skin tissue and PBMCs derived from psoriasis patients and healthy subjects. Proliferation assay and the expression of signaling proteins were used to evaluate Piclidenoson effect on human keratinocytes (HaCat). High A3AR expression levels were found in a skin biopsy and in PBMCs from psoriasis patients in comparison to healthy subjects. Piclidenoson inhibited the proliferation of HaCat cells through deregulation of the NF-κB signaling pathway, leading to a decrease in interleukin-17 and interleukin-23 expression levels. This effect was counteracted by the specific antagonist MRS 1523. A3AR overexpression in skin and PBMCs of psoriasis patients may be used as a target to inhibit pathological cell proliferation and the production of interleukin-17 and interleukin-23
Fishman P - One of the best experts on this subject based on the ideXlab platform.
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Targeting the A3 adenosine receptor to treat cytokine release syndrome in cancer immunotherapy
Dove Medical Press, 2019Co-Authors: Cohen S, Fishman PAbstract:Shira Cohen, Pnina FishmanCan-Fite BioPharma Ltd., Kiryat-Matalon, Petah-Tikva 49170, IsraelAbstract: Cancer patients undergoing immunotherapy may develop cytokine release syndrome (CRS), an inflammatory cytokine storm condition, followed by neurotoxic manifestations and may be life-threatening. The current treatments for CRS successfully reduce the inflammatory response but may limit the anticancer effect of the given immunotherapy and fail to overcome the neurotoxic adverse events. Adenosine, a ubiquitous purine nucleoside, induces a plethora of effects in the body via its binding to four adenosine receptors A1, A2a, A2b, and the A3. Highly selective agonists to the A3 adenosine receptor act as inhibitors of proinflammatory cytokines, possess robust anti-inflammatory and anticancer activity, and concomitantly, induce neuroprotective effects. Piclidenoson and namodenoson belong to this group of compounds, are effective upon oral administration, show an excellent safety profile in human clinical studies, and therefore, may be considered as drug candidates to treat CRS. In this article, the detailed anti-inflammatory characteristics of these compounds and the rationale to use them as drugs to combat CRS are described. Keywords: A3, adenosine receptor, cytokine release syndrome, treatment, immunotherap
Faina Barer - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson
Hindawi Limited, 2018Co-Authors: Shira Cohen, Faina Barer, Inbal Itzhak, Michael H. Silverman, Pnina FishmanAbstract:Interleukin-17 and interleukin-23 play major roles in the inflammatory process in psoriasis. The Gi protein-associated A3 adenosine receptor (A3AR) is known to be overexpressed in inflammatory cells and in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory conditions. Piclidenoson, a selective agonist at the A3AR, induces robust anti-inflammatory effect in psoriasis patients. In this study, we aimed to explore A3AR expression levels in psoriasis patients and its role in mediating the anti-inflammatory effect of Piclidenoson in human keratinocyte cells. A3AR expression levels were evaluated in skin tissue and PBMCs derived from psoriasis patients and healthy subjects. Proliferation assay and the expression of signaling proteins were used to evaluate Piclidenoson effect on human keratinocytes (HaCat). High A3AR expression levels were found in a skin biopsy and in PBMCs from psoriasis patients in comparison to healthy subjects. Piclidenoson inhibited the proliferation of HaCat cells through deregulation of the NF-κB signaling pathway, leading to a decrease in interleukin-17 and interleukin-23 expression levels. This effect was counteracted by the specific antagonist MRS 1523. A3AR overexpression in skin and PBMCs of psoriasis patients may be used as a target to inhibit pathological cell proliferation and the production of interleukin-17 and interleukin-23