TRP Vanilloid 1 (TRPV1) channel, one of the major members of the TRP family was discovered to play a critical role in pain sensation, particularly inflammatory pain, and is associated with hyperalgesia, an enhanced sensitivity to pain. A new study by Fanet al."Structural basis of TRPV1 inhibition by SAF312 and cholesterol" sheds new light on the mechanistic structural basis of TRPV1 inhibition by SAF312 (Libvatrep), a TRPV1 antagonist, currently in phase II clinical trials. They discover that the binding site of SAF312 in TRPV1 is in close vicinity and partially overlaps with the binding site of cholesterol and that removal of cholesterol interferes with the ability of SAF312 to suppress TRPV1 current.

2024-11-01·European Journal of Pain

Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double‐blind, placebo‐controlled, crossover study

Article

作者: Rother, M. ; Schaffler, K. ; Segerdahl, M. ; Halldin, M. M. ; Popescu, T.

AbstractBackgroundThe TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1‐antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1‐antagonist (ACD440 Gel) in healthy subjects.MethodsThe study comprised two parts.In part 1, 24 healthy subjects were included in this randomized double‐blind, placebo‐controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB‐irradiated skin. Pain induced by thermo‐nociceptive CO2 laser impulses generated laser‐evoked potentials (LEPs), with readouts of peak‐to‐peak (PtP) amplitude in vertex‐EEG and pain assessments by VAS (0–100). Endpoints include effects at 1 hour post‐dose, AUC(Days 1–5) and AUC(0–24, Day 4). In UVB‐irradiated skin, also pain on pinprick and skin redness were assessed.Part 2 explored the plasma pharmacokinetics of ACD440.ResultsACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB‐irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug‐induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half‐life of ACD400.ConclusionsTopical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development.SignificanceThis study demonstrates that the topical administration of a TRPV1‐antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

2024-09-01·American Journal of Physiology-Renal Physiology

TRPV1 and mast cell involvement in repeated variate stress-induced urinary bladder dysfunction in adult female mice

Article

作者: Vizzard, Margaret A ; Campbell, Susan E. ; Vizzard, Margaret A. ; Sidwell, Amanda B. ; Sidwell, Amanda B ; Girard, Beatrice M. ; Campbell, Susan E ; Girard, Beatrice M

Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

项与 TRPV1 antagonist prodrug(JMackem) 相关的新闻（医药）

2024-06-13

·BioSpace

New Scientific Article Published on Positive Clinical Results with Painless ACD440 Against Neuropathic Pain

STOCKHOLM, SWEDEN / ACCESSWIRE / June 13, 2024 / AlzeCure Pharma (STO:ALZCUR)(FRA:AC6) AlzeCure Pharma AB (publ) (FN STO:ALZCUR), a pharmaceutical company that develops candidate drugs for diseases affecting the nervous system, focusing on Alzheimer's disease and pain, today announced that a scientific article has been published on the clinical phase Ib results that support the continued development of the lead drug candidate Painless ACD440. The article, titled Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study , has been published online in the European Journal of Pain and is written by Märta Segerdahl, MD, PhD and CMO at AlzeCure Pharma. Co-authors are Magnus Halldin, Matthias Rother, Traian Popescu and Klaus Schaffler. The article focuses on the clinical phase Ib study with ACD440. The results show that ACD440 had significant analgesic effects of laser-induced pain compared to placebo both when the individual was asked to rate their pain experience and when pain-related brain activity was measured. Furthermore, significant effects on mechanical pain sensitivity were also observed. The results also showed that the analgesic effects lasted for at least 9 hours and that the product was very well tolerated as a topical gel on the skin, which indicates good suitability for further clinical development, i.e. as a local treatment against nociceptive and neuropathic pain conditions. ACD440 is a first-in-class TRPV1 antagonist in clinical phase being developed as a new topical local treatment for peripheral neuropathic pain. The drug candidate, which was incorporated via a strategic in-licensing, originated in Big Pharma and is based on a strong scientific foundation, which in 2021 was awarded a Nobel Prize. The substance is developed as a gel for topical use, which keeps the systemic exposure very low while the concentration of the substance locally can be kept high to achieve a maximum analgesic effect, and over a long period of time. "The publication shows the proof-of mechanism for ACD440, i.e. that the substance has a high and significant pain-relieving effect. Combined with our Phase IIa clinical data in chronic patients with peripheral neuropathic pain, this strengthens the continued development opportunities for ACD440," said Märta Segerdahl, CMO at AlzeCure Pharma. "There is a great medical need for effective and safe non-opioid treatments for neuropathic pain. 7-8 out of 10 patients do not experience a satisfactory effect of existing treatment, and the area is the single largest in pain. Our project ACD440 has a very big potential," said Martin Jönsson, CEO of AlzeCure Pharma. The article is now available online via the following link: For more information, please contact Martin Jönsson, CEO Tel: +46 707 86 94 43 martin.jonsson@alzecurepharma.com About AlzeCure Pharma AB (publ) AlzeCure® is a Swedish pharmaceutical company that develops new innovative drug therapies for the treatment of severe diseases and conditions that affect the central nervous system, such as Alzheimer's disease and pain - indications for which currently available treatment is very limited. The company is listed on Nasdaq First North Premier Growth Market and is developing several parallel drug candidates based on three research platforms: NeuroRestore®, Alzstatin® and Painless. NeuroRestore consists of two symptomatic drug candidates where the unique mechanism of action allows for multiple indications, including Alzheimer's disease, as well as cognitive disorders associated with traumatic brain injury, sleep apnea and Parkinson's disease. The Alzstatin platform focuses on developing disease-modifying and preventive drug candidates for early treatment of Alzheimer's disease and comprises two drug candidates. Painless is the company's research platform in the field of pain and contains two projects: ACD440, which is a drug candidate in the clinical development phase for the treatment of neuropathic pain, and TrkA-NAM, which targets severe pain in conditions such as osteoarthritis. AlzeCure aims to pursue its own projects through preclinical research and development through an early clinical phase, and is continually working on business development to find suitable outlicensing solutions with other pharmaceutical companies. FNCA Sweden AB is the company's Certified Adviser. For more information, please visit . About neuropathic pain Neuropathic pain affects approximately 7-8 percent of the total global adult population, approximately 600 million individuals. Some patients, with indications such as diabetes and HIV, are affected to a greater extent, where approximately 25 and 35 percent respectively of the patients experience neuropathic pain. Peripheral neuropathic pain is the result of various types of damage to the nerve fibers, such as toxic, traumatic or nerve compression injuries as well a metabolic and infectious diseases. Common symptoms are painful tingling that can be described as "pins and needles", or choking or burning pain, as well as the feeling of getting an electric shock. Patients may also experience allodynia (pain caused by a stimulus that usually does not cause pain) or hyperalgesia (increased pain from a stimulus that normally provokes pain). The market for neuropathic pain is characterized by a major medical need in all indications and in all major markets, where about 70-80 percent of patients do not get effective pain relief with existing treatment. Due to the risk of abuse, overdose and secondary damage, people now try to avoid opiates as first-line treatment for pain conditions. Despite this treatment problem, these preparations are still used frequently, and therefore the need for new treatments that are not opiates is very great. The patient population will grow, among other things, due to an aging population and increased number of long-term cancer survivors and increasing prevalance of type-2 diabetes. The global market for neuropathic pain was valued at $11 billion in 2020 and is expected to grow to $25 billion by 2027. Image Attachments CEO Martin Jönsson CMO Märta Segerdahl 2023 Attachments New scientific article published on positive clinical results with Painless ACD440 against neuropathic pain SOURCE: AlzeCure Pharma View the original press release on accesswire.com

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100 项与 TRPV1 antagonist prodrug(JMackem) 相关的药物交易

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