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Rimeporide as a fir...
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Previtali, Stefano C.IRCCS, Dept Neurol, San Raffaele Sci Inst, Milan, Italy.;IRCCS, INSPE, San Raffaele Sci Inst, Milan, Italy.
(author)
Rimeporide as a first- in-class NHE-1 inhibitor : Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
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Publisher, publication year, extent ...
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Elsevier BV,2020
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:kth-282285
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-282285URI
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https://doi.org/10.1016/j.phrs.2020.104999DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20201007
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Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.
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Gidaro, TeresaHop Trousseau, I Motion, Inst Myol, Paris, France.
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Diaz-Manera, JordiHosp Santa Creu i St Pau Barcelona Serv Neurol, Barcelona, Spain.;Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain.
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Zambon, AlbertoIRCCS, Dept Neurol, San Raffaele Sci Inst, Milan, Italy.;IRCCS, INSPE, San Raffaele Sci Inst, Milan, Italy.
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Carnesecchi, StephanieGeneva Univ UNIGE, Geneva, Switzerland.
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Roux-Lombard, PascaleGeneva Univ Hosp HUG, Immunol & Allergol Dept, Geneva, Switzerland.
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Spitali, PietroLeiden Univ, Med Ctr, Leiden, Netherlands.
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Signorelli, MirkoLeiden Univ, Med Ctr, Leiden, Netherlands.
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Al-Khalili Szigyarto, CristinaKTH,Systembiologi(Swepub:kth)u1c02mh9
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Johansson, CamillaKTH,Systembiologi(Swepub:kth)u1jemko2
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Gray, JulianEspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland.
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Labolle, DelphineEspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland.
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Thome, Florence PorteEspeRare, Campus Biotech,Innovat Pk,15 Ave Secheron, CH-1202 Geneva, Switzerland.
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Pitchforth, JacquelineUCL Great Ormond St Inst Child Hlth, London, England.;Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England.
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Domingos, JoanaUCL Great Ormond St Inst Child Hlth, London, England.;Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England.
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Muntoni, FrancescoUCL Great Ormond St Inst Child Hlth, London, England.;Great Ormond St Hosp Sick Children, Dubowitz Neuromuscular Ctr, London, England.;UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, Ormond St Inst Child Hlth,Great Ormond St Hosp Tr, London, England.
(author)
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IRCCS, Dept Neurol, San Raffaele Sci Inst, Milan, Italy.;IRCCS, INSPE, San Raffaele Sci Inst, Milan, Italy.Hop Trousseau, I Motion, Inst Myol, Paris, France.
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In:Pharmacological Research: Elsevier BV1591043-66181096-1186
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