PainRelief.com: What are the main findings?
Response: One mechanism for ApAP-induced hepatotoxicity is via formation of the electrophilic reactive metabolite, NAPQI, which is detoxified through conjugation with reduced GSH, an important cellular antioxidant in the liver; GSH depletion appears to be a key event in ApAP-induced acute liver injury (6). Following toxic doses of ApAP, GSH is depleted and reactive oxygen and nitrogen species form, leading to mitochondrial permeability and hepatocyte death. 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 ApAP or SRP comppunds, only ApAP-, but not SRP-3D (DA)-treated mice generated the toxic metabolite NAPQI (Fig. 2). Another mechanism for ApAP hepatotoxicity is loss of hepatic tight junctions(7), and chicken wire’ hepatic tight junctions remain intact in SRP-treated animals while these junctions are lost in ApAP-treated animals. Further, immunostaining for nitrotyrosine, a marker of mitochondrial free radical formation and hepatocyte injury, correlates with the centrilobular necrosis and hepatic cell death observed in ApAP- but not SRP-3D (DA)-treated mice.
Lastly, increased levels of the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST, P <.0001) were present in the serum of CD1 mice treated oreally with toxic doses of ApAP (600 mg/kg) but not in the serum of mice treated with SRP-compounds-3D at 24 hour post-treatment. Notably, at this high dose, 60% of the ApAP-treated mice died within 48 hours, whereas all SRP-treated mice survived.
PainRelief.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 ApAP/NSAID compared to an opioid/ApAP analgesic combination(8). Another randomized trial of 547 patients with acute blunt musculoskeletal extremity trauma used ApAP alone at the maximum 4g/day and found it to be equally analgesic to an NSAID or an ApAP/NSAID combination(9). Finally, a Cochrane Collaboration review of acute post-operative dental pain found that ApAP/NSAIDs provide better analgesia than opioids(10).
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.
PainRelief.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.
PainRelief.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(2). 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.
As a Board-certified academic vascular surgeon and Program Director of the Vascular Surgery Fellowship at the Ochsner Clinic, my clinical expertise includes treatment of carotid artery disease and acute stroke, use of minimally invasive approaches for aortic aneurysms and peripheral arterial disease. In taking care of these patients, I have realized the clinical need for safer and more effective management of acute post-operative pain. Additionally, over the years, I have also realized the large societal need for safer and non-addictive pain relief in the acute/emergency room (ER) setting and in the post-operative period, particularly to avoid narcotic dependency and liver and kidney toxicity. South Rampart Pharma, LLC (https://southrampartpharma.com) was founded to address these major unmet needs by developing safer non-opioid therapies.
References:
1. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health (HHS Publication No. PEP19-5068, NSDUH Series H-54). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2019, https://www.samhsa.gov/data/.
2. Henschke N, Kamper SJ, Maher CG. The epidemiology and economic consequences of pain. Mayo Clin Proc. 2015;90(1):139-47. Epub 2015/01/13. doi: 10.1016/j.mayocp.2014.09.010. PubMed PMID: 25572198.
3. Mitchell RA, Rathi S, Dahiya M, Zhu J, Hussaini T, Yoshida EM. Public awareness of acetaminophen and risks of drug induced liver injury: Results of a large outpatient clinic survey. PloS one. 2020;15(3):e0229070. Epub 2020/03/05. doi: 10.1371/journal.pone.0229070. PubMed PMID: 32130228; PMCID: PMC7055817.
4. Bazan HA, Bhattacharjee S, Burgos C, Recio J, Abet V, R. PA, Jun B, Heap J, .J. LA, Gordon WC, Edwards S, Paul D, Alvarez-Builla J, Bazan NG. A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis. European Journal of Medicinal Chemistry. in press.
5. Bazan NG, Bazan HA, Alvirez-Builla Gomez J, Paul D, Burgos C, inventors. WO 2019/040122 A1, Compositions and methods for ameliorating pain. United States 28 February 2019.
6. Abdelmegeed MA, Moon KH, Chen C, Gonzalez FJ, Song BJ. Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity. Biochem Pharmacol. 2010;79(1):57-66. doi: 10.1016/j.bcp.2009.07.016. PubMed PMID: 19660437; PMCID: PMC2784150.
7. Gamal W, Treskes P, Samuel K, Sullivan GJ, Siller R, Srsen V, Morgan K, Bryans A, Kozlowska A, Koulovasilopoulos A, Underwood I, Smith S, Del-Pozo J, Moss S, Thompson AI, Henderson NC, Hayes PC, Plevris JN, Bagnaninchi PO, Nelson LJ. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver. Sci Rep. 2017;7:37541. doi: 10.1038/srep37541. PubMed PMID: 28134251; PMCID: PMC5278402.
8. Chang AK, Bijur PE, Esses D, Barnaby DP, Baer J. Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial. JAMA : the journal of the American Medical Association. 2017;318(17):1661-7. Epub 2017/11/09. doi: 10.1001/jama.2017.16190. PubMed PMID: 29114833; PMCID: PMC5818795.
9. Ridderikhof ML, Lirk P, Goddijn H, Vandewalle E, Schinkel E, Van Dieren S, Kemper EM, Hollmann MW, Goslings JC. Acetaminophen or Nonsteroidal Anti-Inflammatory Drugs in Acute Musculoskeletal Trauma: A Multicenter, Double-Blind, Randomized, Clinical Trial. Ann Emerg Med. 2018;71(3):357-68 e8. Epub 2017/10/17. doi: 10.1016/j.annemergmed.2017.08.041. PubMed PMID: 29033294.
10. Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice. J Am Dent Assoc. 2013;144(8):898-908. Epub 2013/08/02. doi: 10.14219/jada.archive.2013.0207. PubMed PMID: 23904576.
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Last Updated on July 24, 2020 by PainRelief.com