MP03-01 THE EVOLVING STORY OF PHENAZOPYRIDINE: EXPLORING THE PHARMACOLOGICAL EFFECTS IN ANIMAL MODELS OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP03-01 THE EVOLVING STORY OF PHENAZOPYRIDINE: EXPLORING THE PHARMACOLOGICAL EFFECTS IN ANIMAL MODELS OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME Parva Purohit, Heta Pandya, Kavya Jash, Vishal Unadkat, Ketan Variya, and Ganesh Sangle Parva PurohitParva Purohit More articles by this author , Heta PandyaHeta Pandya More articles by this author , Kavya JashKavya Jash More articles by this author , Vishal UnadkatVishal Unadkat More articles by this author , Ketan VariyaKetan Variya More articles by this author , and Ganesh SangleGanesh Sangle More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003214.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Phenazopyridine (PhP) is a DESI drug widely prescribed for the symptomatic relief of pain, burning, urgency, and frequency related to lower urinary tract infections. PhP is believed to exert its analgesic effect on the urinary tract mucosa, however, the exact active metabolite contributing to efficacy remains unclear. PhP metabolism is highly variable across the species with most studies focusing on acetaminophen (APAP) as an active metabolite. In addition to APAP, there are five other metabolites reported with no systematic study to envisage their role in efficacy against bladder pain. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition characterized by recurrent pain, discomfort, or tenderness in the urinary bladder and pelvic region. The overall prevalence of IC/BPS in the US as per the National Institute of Diabetes and Digestive and Kidney Diseases is approximately 4-12 million patients. The objective of current study is to evaluate the pharmacological effects of PhP metabolites in animal models of IC/BPS. METHODS: Phenazopyridine metabolites (KSHN002001, KSHN002002, KSHN002003, KSHN002004, and KSHN002005) were synthesized and characterized. The Cyclophosphamide (CYP) induced cystitis model was selected as it is well-validated and represents substantial features of human IC/BPS. Intraperitoneal (i.p.) injection of CYP causes pain-related behavior and bladder overactivity. Cystitis was induced in Female Sprague-Dawley rats by 150 mg/kg CYP i.p. injection (acute model), 50 mg/kg CYP i.p. injection on days 0, 3 and 6 (chronic model) and normal control group administered saline. For the acute model, PhP metabolites were administered orally at a single dose of 20 mg/kg before CYP administration, whereas once daily and twice daily doses of 20 mg/kg were administered on days 8, 9 and 10 in the chronic model. The pain was assessed at 0 hr and 4 hr (acute model), whereas on days 0 and 10 (chronic model) using Von Frey filaments. Pain was reported as the area under the curve (AUC) which was calculated by plotting individual nociceptive scores against Von Frey forces. Other efficacy parameters like bladder pressure, bladder weight, hemorrhage scores and vascular permeability were also measured. RESULTS: In CYP treated group, increased pain response AUCs were observed in both acute and chronic models. In the acute model, mild pain reduction was observed with APAP, PhP and KSHN002002, whereas KSHN002004 showed a significant reduction in pain score (p<0.01) compared to other metabolites. Furthermore, KSHN002004 metabolite also showed a significant reduction in pain score with once-daily as well as twice-daily administration in the chronic model. The data indicates that KSHN002004 metabolite showed consistent efficacy in an acute and chronic model of IC/BPS confirming its role as the major source of efficacy. Additionally, KSHN002004 showed a significant reduction in bladder inflammation as well as vascular permeability. CONCLUSIONS: KSHN002004 is identified as an active metabolite of PhP contributing to analgesic efficacy, whereas APAP demonstrated minimal efficacy in the IC/BPS animal model. Source of Funding: Kashiv BioSciences Pvt. Ltd © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e21 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Parva Purohit More articles by this author Heta Pandya More articles by this author Kavya Jash More articles by this author Vishal Unadkat More articles by this author Ketan Variya More articles by this author Ganesh Sangle More articles by this author Expand All Advertisement PDF downloadLoading ...