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Duchne A.,Theranexus | Perier M.,French Institute of Health and Medical Research | Zhao Y.,French Institute of Health and Medical Research | Liu X.,The Interdisciplinary Center | And 12 more authors.
Sleep | Year: 2016

Study Objectives: Modafinil is a non-Amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors. Methods: Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices. Results: Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-Administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-Administration with flecainide. Conclusions: Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy.


PubMed | Montpellier University Hospital Center, Theranexus, Institute Of Recherche Biomedicale Des Armees, French Institute of Health and Medical Research and The Interdisciplinary Center
Type: Journal Article | Journal: Sleep | Year: 2016

Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors.Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices.Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-administration with flecainide.Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy.A commentary on this article appears in this issue on page 1175.


News Article | March 8, 2016
Site: news.yahoo.com

(Reuters) - Silicon Valley’s hoodie-wearing tech entrepreneurs are the poster kids of innovation. But the innovators who are really changing the world are more likely to wear labcoats and hold government-related jobs in Grenoble, Munich or Tokyo. That's the conclusion of Reuters’ Top 25 Global Innovators – Government, a list that identifies and ranks the publicly funded institutions doing the most to advance science and technology. Topping the list is France's Alternative Energies and Atomic Energy Commission (CEA), for its research into areas including renewable power, public health, and information security. Rounding out the top three: Germany’s Fraunhofer Society and Japan’s Science and Technology Agency. On a country-by-country basis, the United States leads the list, with six organizations ranked (France and Japan each have four, and Germany has three). The Department of Health & Human Services (HHS) is the top U.S. finisher, placing fourth. The rankings were compiled by the Intellectual Property & Science division of Thomson Reuters, which used proprietary data and analysis tools to examine patents and research papers from the past eight years to find the governmental organizations most likely to change the world. A separate ranking of similar data from universities was published last year. (Reuters.com/most-innovative-universities) It took a government agency to put a man on the moon, and even in the age of the Internet, governments are still moving science and technology forward. They do pure research that private companies often find it hard to justify and afford, and make discoveries that launch entire industries: publicly funded organizations split the atom, invented the Internet, and mapped the human genome. There are 16,000 technicians, engineers and researchers in 10 government-run centers throughout France working on the next great innovation. They’re all a part of CEA, a public research institution specializing in nuclear and renewable energies, defense and security, as well as information and health technologies. Established by General Charles de Gaulle at the end of World War II, the organization represents France in the nuclear sector, promoting safe and responsible use of nuclear energy for peaceful purposes. CEA ranks first among government research institutes in part because its researchers apply for and receive significantly more patents than most government organizations - an indication that their research has strong potential for commercial value. Those patents are also frequently cited by outside researchers, showing that CEA has a big impact on R&D efforts at other organizations. CEA receives the majority of its funding from the French government, and works closely with national agencies on projects ranging from building nuclear-powered naval vessels to improving the nation's cybersecurity. But it also has more than 500 industrial partners, and its research has led to the creation of 115 spinoff companies since 2000, including Paris-based biopharmaceutical company Theranexus, which is working on advanced treatments for psychiatric disorders. The second most innovative institution on the Top 25 Global Innovators – Government list also focuses on developing technology that can help fuel private industry. Germany’s Fraunhofer Society is Europe's largest applied research institution, with 24,000 staff members in 67 institutes and research units. Public sector funds account for only about a third of its annual budget; most of the Society's research is funded by contracts with industry. European institutions account for nine out of 25 ranked institutions, more than any other continent. Asia comes in second with eight institutions, including third-place finisher the Japan Science & Technology Agency, or JST. An independent administrative institution under the government's Ministry of Education, Culture, Sports, Science and Technology, it works primarily with academia, industry and other international research institutions. Three JST scientists won the Nobel Prize for Physics in 2014 for inventing efficient blue-light-emitting diodes, which have enabled bright, energy-saving white-light sources. HHS, the top-ranked government innovator in the U.S., is a cabinet-level department of the federal government tasked with protecting the health of American citizens. Although primarily known as a regulatory and service agency, the department's 11 operating divisions include some of the nation's most active centers of scientific research, including the National Institutes of Health, the Centers for Disease Control and Prevention, and the Food and Drug Administration. (Patents filed by these institutions list the name of their parent agency, so for the purposes of this list, Thomson Reuters ranked HHS instead of its subsidiaries.) Also on the list: The United States Navy and the United States Army. Like HHS, these military service organizations aren’t best known for science, but they perform a wide range of basic and applied research in pursuit of their mission. More than 60 researchers have won a Nobel Prize for work funded by the Office of Naval Research since it was established in 1946. The United States Army Laboratory, established in 1992, has developed products such as advanced coatings to shield vehicles from chemical warfare, which are now used to protect monuments, sculptures and artworks. To compile the ranking, the IP & Science division of Thomson Reuters began by identifying more than 500 global organizations - including universities, nonprofit charities, and government-funded institutions - that published the most articles in academic journals. Then they identified the total number of patents filed by each organization and evaluated each candidate on factors including how many patents it filed, how often those applications were granted, how many patents were filed to global patent offices in addition to local authorities and how often the patents were cited by other patents. Candidates were also evaluated in terms of the number of articles published by researchers in academic journals, how often those papers were cited by patents and how many articles featured a co-author from industry. Finally, they trimmed the list so that it only included government-run or funded organizations, and then ranked them based on their performance. (Full methodology: Reuters.com/global-innovators-government/methodology.)


News Article | November 9, 2016
Site: www.newsmaker.com.au

The report provides comprehensive information on the therapeutics under development for Narcolepsy ,complete with analysis by stage of development,drug target,mechanism of action (MoA),route of administration (RoA) and molecule type. The report also coversthe descriptive pharmacological action of the therapeutics,its complete research and development history and latest news and press releases. Additionally,the report provides an overview of key players involved in therapeutic development for Narcolepsy  and features dormant and discontinued projects. The report helps in identifying and tracking emerging players in the market and their portfolios,enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. Complete report on Narcolepsy  - Pipeline Review,H2 2016 addition with 29 market data tables and 12 figures, spread across 75 pages is available at http://www.rnrmarketresearch.com/narcolepsy-pipeline-review-h2-2016-market-report.html This report features investigational drugs from across globe covering over 20 therapy areas and nearly 3,000 indications. The report is built using data and information sourced from Global Markets Direct's proprietary databases,company/university websites,clinical trial registries,conferences,SEC filings,investor presentations and featured press releases from company/university sites and industry-specific third party sources. Drug profiles featured in the report undergoes periodic review following a stringent set of processes to ensure that all the profiles are updated with the latest set of information. Additionally,various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Bioprojet SCR,Evotec AG,Flamel Technologies S.A.,H.A.C. Pharma,Heptares Therapeutics Limited,Jazz Pharmaceuticals Plc,NLS Pharma Group,Ono Pharmaceutical Co., Ltd.,Sanofi,SK Biopharmaceuticals Co., Ltd.,Taisho Pharmaceutical Holdings Co., Ltd.,Theranexus SAS Inquire before buying http://www.rnrmarketresearch.com/contacts/inquire-before-buying?rname=748021(This is a premium report price at US$2000 for a single user PDF license).


M'Dahoma S.,French Institute of Health and Medical Research | M'Dahoma S.,University Pierre and Marie Curie | Barthelemy S.,French Institute of Health and Medical Research | Barthelemy S.,University Pierre and Marie Curie | And 15 more authors.
European Neuropsychopharmacology | Year: 2015

Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague-Dawley male rats were either injected intrathecally with BDNF (3.0 ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall-Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain. © 2015 Elsevier B.V. and ECNP.


Picoli C.,CEA Fontenay-aux-roses | Nouvel V.,CEA Fontenay-aux-roses | Aubry F.,Fondation Alliance BioSecure | Reboul M.,Fondation Alliance BioSecure | And 6 more authors.
Journal of Biomolecular Screening | Year: 2012

Connexins are transmembrane proteins involved in gap junction intercellular communication. They present cell- and tissue-specific expression, with own electric and metabolic coupling specificities. These proteins are involved in numerous physiological processes in the brain and among them neuronal synchronization and trafficking of glucose. Such proteins are also described as being misregulated in various pathologies in the central nervous system. Thus, connexin blockers have been proposed as pharmacological tools to dissect these implications. However, such approaches lack accurate characterization of known inhibitors toward gap junction isoform specificity. In addition, those compounds are limited to few chemical classes and exhibit other activities, for example, an anti-inflammatory effect. The aims of this study were to evaluate the selectivity of described inhibitors and to enrich this pharmacopeia by new chemical classes. In this study, we present the specificity of published inhibitors toward several connexin isoforms expressed in the brain. Furthermore, after a screening of compounds using cellular models, we identified seven new inhibitors, with high functional reversibility and different relative selectivity toward isoforms. They constitute new chemical classes of connexin modulators completing those previously described. These new inhibitors might also provide new insights in understanding numerous pathophysiological processes involving gap junctions. © 2012 Society for Laboratory Automation and Screening.


PubMed | Theranexus, CHU Clermont Ferrand, French Institute of Health and Medical Research and Collège de France
Type: | Journal: Scientific reports | Year: 2016

Antidepressants, prescribed as first line treatment of neuropathic pain, have a limited efficacy and poorly tolerated side effects. Because recent studies pointed out the implication of astroglial connexins (Cx) in both neuropathic pain and antidepressive treatment, we investigated whether their blockade by mefloquine could modulate the action of the tricyclic antidepressant amitriptyline. Using primary cultures, we found that both mefloquine and amitriptyline inhibited Cx43-containing gap junctions, and that the drug combination acted synergically. We then investigated whether mefloquine could enhance amitriptyline efficacy in a preclinical model of neuropathic pain. Sprague-Dawley rats that underwent chronic unilateral constriction injury (CCI) to the sciatic nerve (SN) were treated with either amitriptyline, mefloquine or the combination of both drugs. Whereas acute treatments were ineffective, chronic administration of amitriptyline reduced CCI-SN-induced hyperalgesia-like behavior, and this effect was markedly enhanced by co-administration of mefloquine, which was inactive on its own. No pharmacokinetic interactions between both drugs were observed and CCI-SN-induced neuroinflammatory and glial activation markers remained unaffected by these treatments in dorsal root ganglia and spinal cord. Mechanisms downstream of CCI-SN-induced neuroinflammation and glial activation might therefore be targeted. Connexin inhibition in astroglia could represent a promising approach towards improving neuropathic pain therapy by antidepressants.


Theranexus | Entity website

Paris, 19th October 2015 Biotechnology company Theranexusfounded by Franck Mouthon, CEO, and Mathieu Charveriat, Scientific Directoris pleased to announce the launch of the clinical efficacy phase of its lead program, THN102, in the treatment of sleep disorders. Based on the positive results obtained in phase I, which focused on the safety of THN102, Theranexus was granted authorisation to assess the efficacy of the product ...


LYON, France--(BUSINESS WIRE)--Theranexus: Inclusion of the first patient in the phase II clinical study that aims to test THN102 in patients affected by narcolepsy.


LYON, France--(BUSINESS WIRE)--Theranexus, une société biopharmaceutique au stade des essais cliniques, annonce aujourd’hui le recrutement du premier patient dans l’étude intitulée « tolérance et efficacité du THN102 sur la somnolence chez des patients narcoleptiques » (NCT02821715), un essai clinique de phase II évaluant l’efficacité et la tolérance du THN102 dans le traitement de la somnolence diurne excessive associée à la narcolepsie chez les patients adultes. Cet essai sera mené en double

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