28 Jul Promising New Analgesic Offers Pain Relief Without Liver Toxicity
MedicalResearch.com Interview with:
Hernan Bazan, MD DFSVS FACS
CEO & Co-founder, South Rampart Pharma, LLC and
Professor of Surgery, Section of Vascular/Endovascular Surgery
Program Director, Vascular Surgery Fellowship
Ochsner Clinic New Orleans, LA 70121
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The work in this paper is in large part due to several active and productive collaborations to address a simple problem: introduce a safer way to treat pain. That is, without the risk of opioids (abuse potential), acetaminophen/paracetamol (liver toxicity) and non-steroidal anti-inflammatory drugs (NSAIDs)/ibuprofen (kidney toxicity).
Acetaminophen hepatotoxicity remains the most common cause of acute liver failure in the U.S. with inadvertent hepatotoxicity the etiology in half of all case. Our aim was to overcome this toxicity by creating acetaminophen analogs and this paper describes the rationale for this synthesis, the library of compounds used to select the lead compounds to develop, the consistent lack of hepatotoxicity cell lines and small animals, and its ability to reduce pain and fever in small animal studies. Moreover, we explain the mechanisms of action for the lack of hepatotoxicity.
One mechanism for acetaminophen-induced hepatotoxicity is via formation of the electrophilic reactive metabolite, NAPQI. Using ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS) to detect NAPQI, we observed that after CD1 mice were exposed to high doses (600 mg/kg) of either acetaminophen or SRP compounds, only acetaminophen-, but not SRP-compound-treated mice, generated the toxic metabolite NAPQI. Another mechanism for acetaminophen hepatotoxicity is loss of hepatic tight junctions and chicken wire’ hepatic tight junctions remain intact in SRP-treated animals while these junctions are lost in acetaminophen-treated animals.
MedicalResearch.com: What should readers take away from your report?
Response: A recent trial of 416 randomized patients with moderate/severe acute extremity pain found no difference in pain reduction 2 hours following a single-dose acetaminophen/NSAID compared to an opioid/acetaminophen analgesic combination. Another randomized trial of 547 patients with acute blunt musculoskeletal extremity trauma used acetaminophen alone at the maximum 4g/day and found it to be equally analgesic to an NSAID or an acetaminophen/NSAID combination. Finally, a Cochrane Collaboration review of acute post-operative dental pain found that acetaminophen/NSAIDs provide better analgesia than opioids. Therefore, the evidence is there that acute pain can indeed be treated effectively with non-opioids. We are close to beginning clinical trials to assess the safety and efficacy of this new drug that we are developing to address this.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our goal is to advance acute pain treatment by developing an intravenous (IV) formulation of our lead molecule, SRP-3D (DA), a new non-narcotic and non-hepatotoxic small molecule. We are actively doing this thru the pre-clinical drug development and – soon to be – Phase 1 clinical trials. We foresee clinical application of SRP-3D (DA) instead of narcotics in the acute in-patient hospital setting, such as the post-operative period, and in ambulatory patients, including for acute pain in the ER and after out-patient procedures.
MedicalResearch.com: Is there anything else you would like to add?
Response: Worldwide, 20% of adults are estimated to suffer from pain a leading cause of disability, productivity loss, and a major contributor to health care costs. Compared to other high-income comparable economies, the U.S, spends twice as much on healthcare, and pharmaceutical spending is a large portion of healthcare costs. Given the high prevalence of pain and costs associated with treating such a large population, development of expensive therapies, such as biologics, for an omnipresent disease state like pain would add additional financial stress on the U.S. economy. In contrast, successful development of SRP-3D (DA), a small molecule, will result in a low-cost product that would be accessible to many patients.
Hernan A. Bazan, Surjyadipta Bhattacharjee, Carolina Burgos, Javier Recio, Valentina Abet, Amanda R. Pahng, Bokkyoo Jun, Jessica Heap, Alexander J. Ledet, William C. Gordon, Scott Edwards, Dennis Paul, Julio Alvarez-Builla, Nicolas G. Bazan. A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis. European Journal of Medicinal Chemistry, 2020; 202: 112600 DOI: 10.1016/j.ejmech.2020.112600
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