A 4 week phase 2a, multicentre, randomised, double-blind, placebo-controlled add-on study into safety, tolerability and efficacy of 200 mg t.i.d. of PL37 in patients with peripheral neuropathic pain of diabetic origin treated with pregabalin or gabapentin.

开始日期2014-03-31

申办/合作机构

Pharmaleads SA

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2024-03-01·Headache: The Journal of Head and Face Pain

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine

Article

作者: Rossignol, Jeanne ; Poras, Hervé ; Luccarini, Philippe ; Ouimet, Tanja ; Dallel, Radhouane

AbstractObjectiveThe aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect.BackgroundCombination treatment is frequently used to improve the therapeutic efficacy of drugs. The co‐administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co‐administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5‐HT1B/1D receptor agonist.MethodsWe investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37.ResultsSumatriptan as well as PL37 each produced a dose‐dependent inhibition of ISDN‐induced cephalic MH. Median effective dose (ED50) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04.ConclusionThese results suggest that PL37 acts synergistically with sumatriptan to produce an anti‐allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine.Plain Language SummaryThere have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.

2023-05-01·Headache

Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors.

Article

作者: Dussor, Gregory ; Ouimet, Tanja ; Hu, Ya-Yu ; Kapadia, Soneet ; Poras, Hervé ; Mei, Hao-Ruei

OBJECTIVEThe aim of this study was to evaluate whether elevating levels of enkephalin by inhibiting their degradation can attenuate stress-induced migraine-like behaviors in mice.BACKGROUNDPrevious studies in animals have suggested the delta opioid receptor (DOR) as a novel migraine target. The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects.METHODSThis study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37.RESULTSOn day two post-stress, PL37 given to mice via either intravenous injection (10 mg/kg) or oral gavage (20 mg/kg) significantly attenuated stress-induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10 mg/kg) and oral gavage (20 mg/kg) of PL37 prior to SNP (0.1 mg/kg) administration on day 14 post-stress significantly reduced SNP-induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1 mg/kg) but not the mu-opioid receptor antagonist CTAP (1 mg/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5 mg/kg) blocked the effects of PL37.CONCLUSIONSThese data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress-induced migraine-like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.

2023-04-01·Theoretical and Applied Genetics

Introgression and targeting of the Pl37 and Pl38 genes for downy mildew resistance from wild Helianthus annuus and H. praecox into cultivated sunflower (Helianthus annuus L.)

Article

作者: Ma, G J ; Talukder, Z I ; Seiler, G J ; Qi, L L

KEY MESSAGETwo new downy mildew resistance genes, Pl₃₇ and Pl₃₈, were introgressed from wild sunflower species into cultivated sunflower and mapped to sunflower chromosomes 4 and 2, respectively Downy mildew (DM), caused by the oomycete pathogen Plasmopara halstedii (Farl.) Berl. & de Toni, is known as the most prevalent disease occurring in global sunflower production areas, especially in North America and Europe. In this study, we report the introgression and molecular mapping of two new DM resistance genes from wild sunflower species, Helianthus annuus and H. praecox, into cultivated sunflower. Two mapping populations were developed from the crosses of HA 89/H. annuus PI 435417 (Pop1) and CMS HA 89/H. praecox PRA-417 (Pop2). The phenotypic evaluation of DM resistance/susceptibility was conducted in the BC₁F₂-derived BC₁F₃ populations using P. halstedii race 734. The BC₁F₂ segregating Pop1 was genotyped using an Optimal GBS AgriSeq™ Panel consisting of 768 mapped SNP markers, while the BC₁F₂ segregating Pop2 was genotyped using a genotyping-by-sequencing approach. Linkage analysis and subsequent saturation mapping placed the DM resistance gene, designated Pl₃₇, derived from H. annuus PI 435417 in a 1.6 cM genetic interval on sunflower chromosome 4. Pl₃₇ co-segregated with SNP markers SPB0003 and C4_5738736. Similarly, linkage analysis and subsequent saturation mapping placed the DM resistance gene, designated Pl₃₈, derived from H. praecox PRA-417 in a 0.8 cM genetic interval on sunflower chromosome 2. Pl₃₈ co-segregated with seven SNP markers. Multi-pathotype tests revealed that lines with Pl₃₇ or Pl₃₈ are immune to the most prevalent and virulent P. halstedii races tested. Two germplasm lines, HA-DM15 with Pl₃₇ and HA-DM16 with Pl₃₈, were developed for use in sunflower DM-resistance breeding.

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2022-06-29

·BioSpace

IACTA Pharmaceuticals Announces Expansion of Scientific Advisory Board with Two World-Renowned Key Opinion Leaders

June 29, 2022 12:00 UTC GUAYNABO, Puerto Rico--(BUSINESS WIRE)-- IACTA Pharmaceuticals Inc. ("IACTA"), an innovation leader in ophthalmic therapeutics, today announced the expansion of its Scientific Advisory Board (SAB) with the appointments of Dr. Richard L. Abbott and Dr. Lixin Xie. Dr. Abbott and Professor Xie join an established group of global advisors who will provide strategic insight and guidance to complement the company's expertise in ophthalmology. "As we progress our pipeline of ophthalmic therapeutics, we are excited to strengthen our SAB with two key members to support our evolution into a clinical-stage and global development accelerator company," said Damon Burrows, Chief Executive Officer of IACTA. "Both Dr. Abbott and Professor Xie bring unique perspectives and will provide valuable insights to support the advancement of our novel treatments for patients suffering from dry eye disease and ocular pain, as well as other potential programs across the ophthalmic space." "IACTA's approach to developing effective eye care treatments represents a promising path to treating patients with ocular pain who want to avoid opioids and their side effects," said Dr. Richard L. Abbott. "I look forward to collaborating with the team on the edge of innovative discoveries in the ocular market for patients with unmet needs." "I am pleased to join the Scientific Advisory Board at IACTA, a company committed to pioneering research in ocular diseases," said Professor Xie. "I look forward to supporting the advancement of IACTA's clinical pipeline during this transformative period for the company." Dr. Richard L. Abbott serves as the Secretary for Global Alliances for the American Academy of Ophthalmology (AAO). He also serves as the Secretary-General of Academia Ophthalmologica Internationalis, an international body committed to global vision research, education, and service. Previously, Dr. Abbott was President of the AAO, as well as the President of both the Pan American Association of Ophthalmology and the Pan American Ophthalmological Foundation. He has received numerous honors and awards, including the U.S. President's 25-year Volunteer Service Award, the Sir Stuart Duke Elder International Gold Medal, the International Golden Service Award from the Chinese Academy of Ophthalmology, the AE Maumenee Pan American Medal for Distinguished Service to Latin America from the Pan American Association of Ophthalmology, the Asia Pacific Cornea Foundation Medal from the Asia Pacific Cornea Society, the Mark Tso Golden Apple International Teaching Award from the International Council of Ophthalmology and the American Academy of Ophthalmology's Lifetime Achievement Award. In addition, he has authored or co-authored 90 scientific publications and 32 book chapters and has delivered over 800 invited lectures and 36 named lectures. Dr. Lixin Xie is an academic at the Chinese Academy of Engineering, where he serves as professor, researcher, and doctoral supervisor. He is also the honorary Chairman of Asia Corneal Society and Chinese Ophthalmological Society, the Professor of the Shandong First Medical University and Shandong Eye Institute, and the Director of Qingdao Eye Hospital. Dr. Xie performs clinical diagnoses of corneal and cataract disease while pioneering research on corneal endothelial cells, infective corneal disease and slow-release drug injection into the eyes. He is the first individual who has won 15 scientific progress prizes at the national and provincial levels and four national invention patents. Dr. Xie has publicized works on Corneal Transplantation Science and Corneal Disease in addition to publishing 356 academic papers in both domestic and abroad journals of ophthalmology. About IACTA Pharmaceuticals, Inc. IACTA is an innovation leader in ophthalmic therapeutics, led by former top executives from one of the leading eye care companies in the world. The company currently has four products in development for major market opportunities. IC 800 is a novel, non-opioid, dual enkephalinase inhibitor (DENKI), being studied for the treatment of acute ocular pain. In addition, IACTA's IC 265, is a SYK kinase inhibitor being developed as a potential novel treatment for dry eye disease. Solidified by management's world-class, proven R&D experience and supported by the company's IPAC subsidiary in Asia, IACTA is equipped to identify high-quality pharmaceutical technologies, create novel formulations, develop clinic-ready assets, and manage regulatory and intellectual property challenges to accelerate the development and commercialization of innovative NCEs. For more information, please visit . Forward-Looking Statements Any statements in this press release that are not historical facts are forward-looking statements made under the provisions of the Private Securities Litigation Reform Act of 1995. Any forward-looking statements involve risks and uncertainties that could cause actual results to be materially different from historical results or any future results expressed or implied by such forward-looking statements. Such statements include the potential for IC 800 and IC 265. Any forward-looking statements in this press release represent the Company’s views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. The Company specifically disclaims any obligation to update this information as a result of future events or otherwise, except as required by applicable law. IACTA is a registered trademark of Iacta Pharmaceuticals, Inc., and DENKI is a trademark licensed to Iacta Pharmaceuticals, Inc. All other trademarks are owned by their respective owners.

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