作者: Evseenko, Denis ; Mayer, Erik N. ; Li, Liangliang ; Petrigliano, Frank A. ; Lin, Yucheng ; Limfat, Sean ; Weber, Alexander E. ; Van Der Horst, Robert ; Jalali, Omid ; Shkhyan, Ruzanna ; Liu, Nancy Q. ; Lee, Siyoung ; Wang, Liming ; Lieberman, Jay R.

ObjectiveInhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease‐modifying activity in OA.MethodsPrimary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3‐dimensional indentation tester (Mach‐1) was used to quantify the thickness and stiffness properties of the articular cartilage.ResultsInhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle‐treated controls). In JT09‐treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle‐treated controls).ConclusionThe results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

2019-10-01·Future Drug Discovery

Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain

Article

作者: Beck, Tyler C ; Dix, Thomas A

Drug addiction to prescription μ-opioid agonists used in the setting of pain is a major public health threat, affecting millions of Americans. κ-opioid agonists (KOAs) may serve as a possible solution. KOAs have demonstrated indistinguishable analgesic activity relative to μ-opioid agonists in models of acute and chronic pain; however, conventional KOAs suffer from central nervous system (CNS)-mediated psychoactive side-effects. In this review, we discuss our efforts, as well as other's efforts, in developing peripherally restricted KOAs with retained or improved efficacy in rodent models of pain. Results indicate that our lead compound, JT09, acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated side-effects. In this review, we discuss our former results and future directions.

2019-08-01·European Journal of Pharmacology3区 · 医学

Non-addictive orally-active kappa opioid agonists for the treatment of peripheral pain in rats

3区 · 医学

Article

作者: Reichel, Carmela M ; Helke, Kristi L ; Beck, Tyler C ; Bhadsavle, Sanat S ; Dix, Thomas A

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH₂, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (i.v.); however, they are inactive when administered orally. Application of our laboratory's proprietary non-natural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. Lead compound JT09 activates the kappa-opioid receptor with EC₅₀s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 is approximately as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, tolerance, addiction). Thus, we propose that JT09 has potential for development as a novel analgesic. PERSPECTIVE: This article presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current health care burden associated with prescription opioids.

项与 TP-2021 相关的新闻（医药）

2024-05-06

·BioSpace

Cara Therapeutics to Announce First Quarter 2024 Financial Results on May 13, 2024

STAMFORD, Conn., May 06, 2024 (GLOBE NEWSWIRE) -- Cara Therapeutics, Inc. (Nasdaq: CARA), a development-stage biopharmaceutical company leading a new treatment paradigm to improve the lives of patients suffering from pruritus, today announced the Company will report first quarter 2024 financial results on Monday, May 13, 2024, after the U.S. markets close. The press release will be available under “Press Releases” in the Investors section of the Company’s website at . About Cara Therapeutics Cara Therapeutics is a development-stage biopharmaceutical company leading a new treatment paradigm to improve the lives of patients suffering from pruritus. The Company is developing an oral formulation of difelikefalin, a selective, peripherally acting, non-scheduled kappa opioid receptor agonist, for the treatment of chronic pruritus associated with notalgia paresthetica (NP), a common, underdiagnosed neuropathy affecting the upper back for which there are no FDA-approved therapies. The Company is conducting a Phase 2/3 clinical program in NP with topline results of the dose-finding portion expected in the third quarter of 2024. Cara Therapeutics also developed an IV formulation of difelikefalin, which is approved in the United States, EU, and multiple other countries for the treatment of moderate-to-severe pruritus associated with advanced chronic kidney disease in adults undergoing hemodialysis. The IV formulation is out-licensed worldwide. For more information, visit and follow the company on X (Twitter), LinkedIn and Instagram. MEDIA CONTACT: Annie Spinetta 6 Degrees 973-768-2170 aspinetta@6degreespr.com INVESTOR CONTACT: Iris Francesconi, Ph.D. Cara Therapeutics 203-406-3700 investor@caratherapeutics.com

上市批准财报

2023-09-06

·BioSpace

Trevi Therapeutics to Participate in Upcoming September Events

NEW HAVEN, Conn., Sept. 6, 2023 /PRNewswire/ -- Trevi Therapeutics, Inc. (Nasdaq: TRVI), a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for difficult to treat patients with chronic cough in idiopathic pulmonary fibrosis (IPF), other chronic cough indications, and prurigo nodularis, today announced senior management will attend and participate in the following events in September. European Respiratory Society (ERS) International Congress 2023 September 9-13, Milan, Italy 2023 SVB Securities Biopharma Summit September 20-22, Montecito, CA 2023 Cantor Global Healthcare Conference September 26-28, New York, NY Corporate Presentation: Tuesday, September 26th, 4:55 PM ET Presenter: Jennifer Good, President and CEO About Trevi Therapeutics, Inc. Trevi Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for difficult to treat patients with chronic cough in idiopathic pulmonary fibrosis (IPF), other chronic cough indications, and prurigo nodularis. Haduvio is a dual ĸ-opioid receptor agonist and µ-opioid receptor antagonist that works both centrally as well as peripherally in the lungs and has the potential for a synergistic anti-tussive effect to treat chronic cough. The impact of chronic cough is significant and often leads to a decline in patients' social, physical, and psychological quality of life. There are no approved therapies for the treatment of chronic cough in IPF and current treatment options provide minimal relief to patients. In IPF, chronic cough may lead to worsening disease and may be associated with a higher risk of progression, death, or need for lung transplant. Parenteral nalbuphine is not scheduled by the US Drug Enforcement Agency. Trevi intends to propose Haduvio as the trade name for oral nalbuphine ER. Its safety and efficacy have not been evaluated by any regulatory authority. For more information, visit and follow Trevi on Twitter and LinkedIn. Investor Contact Katie McManus Trevi Therapeutics, Inc. 203-304-2499 k.mcmanus@trevitherapeutics.com Company Codes: NASDAQ-NMS:TRVI

2023-08-03

·PRNewswire

Trevi Therapeutics to Report Q2 2023 Financial Results and Provide a Corporate Update on August 10, 2023

Conference call and webcast to be held at 4:30 p.m. EDT NEW HAVEN, Conn., Aug. 3, 2023 /PRNewswire/ -- Trevi Therapeutics, Inc. (Nasdaq: TRVI), a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for difficult to treat patients with chronic cough in idiopathic pulmonary fibrosis (IPF), other chronic cough indications, and prurigo nodularis, today announced that senior management will host a conference call and live audio webcast on Thursday, August 10, 2023, at 4:30 p.m. ET, to provide a corporate update and review the Company's financial results for the second quarter ended June 30, 2023. To participate in the live conference call by phone, please dial (888) 317 6003 (domestic) or (412) 317 6061 (international) and provide access code 6064699. A live audio webcast will be accessible from the 'Investors & News' section on the Company's website at . An archived replay of the webcast will also be available for 30 days on the Company's website following the event. About Trevi Therapeutics, Inc. Trevi Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing the investigational therapy Haduvio™ (oral nalbuphine ER) for difficult to treat patients with chronic cough in idiopathic pulmonary fibrosis (IPF), other chronic cough indications, and prurigo nodularis. Haduvio is a dual ĸ-opioid receptor agonist and µ-opioid receptor antagonist that works both centrally as well as peripherally in the lungs and has the potential for a synergistic anti-tussive effect to treat chronic cough. The impact of chronic cough is significant and often leads to a decline in patients' social, physical, and psychological quality of life. There are no approved therapies for the treatment of chronic cough in IPF and current treatment options provide minimal relief to patients. In IPF, chronic cough may lead to worsening disease and may be associated with a higher risk of progression, death, or need for lung transplant. Parenteral nalbuphine is not scheduled by the US Drug Enforcement Agency. Trevi intends to propose Haduvio as the trade name for oral nalbuphine ER. Its safety and efficacy have not been evaluated by any regulatory authority. For more information, visit and follow Trevi on Twitter and LinkedIn. Investor Contact Katie McManus Trevi Therapeutics, Inc. 203-304-2499 [email protected] Media Contact Rosalia Scampoli 914-815-1465 [email protected] SOURCE Trevi Therapeutics, Inc.

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