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Frontiers in Pharmacology 2021Phenazopyridine is a widely used drug against urinary tract pain. The compound has also been shown to enhance neural differentiation of pluripotent stem cells. However,...
Phenazopyridine is a widely used drug against urinary tract pain. The compound has also been shown to enhance neural differentiation of pluripotent stem cells. However, its mechanism of action is not understood. Based on its chemical structure, we hypothesized that phenazopyridine could be a kinase inhibitor. Phenazopyridine was investigated in the following experimental systems: 1) activity of kinases in pluripotent stem cells; 2) binding to recombinant kinases, and 3) functional impact on pluripotent stem cells. Upon addition to pluripotent stem cells, phenazopyridine induced changes in kinase activities, particularly involving Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinases, and AKT pathway kinases. To identify the primary targets of phenazopyridine, we screened its interactions with 401 human kinases. Dose-inhibition curves showed that three of these kinases interacted with phenazopyridine with sub-micromolar binding affinities: cyclin-G-associated kinase, and the two phosphatidylinositol kinases PI4KB and PIP4K2C, the latter being known for participating in pain induction. Docking revealed that phenazopyridine forms strong H-bonds with the hinge region of the ATP-binding pocket of these kinases. As previous studies suggested increased autophagy upon inhibition of the phosphatidyl-inositol/AKT pathway, we also investigated the impact of phenazopyridine on this pathway and found an upregulation. In conclusion, our study demonstrates for the first time that phenazopyridine is a kinase inhibitor, impacting notably phosphatidylinositol kinases involved in nociception.
PubMed: 34421588
DOI: 10.3389/fphar.2021.664608 -
European Journal of Pharmacology Mar 2023and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain...
BACKGROUND
and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall.
EXPERIMENTAL APPROACH
The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice.
KEY RESULTS
PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3.
CONCLUSION AND IMPLICATIONS
PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP.
Topics: Animals; Cricetinae; Humans; Mice; Calcium; Cricetulus; Fura-2; Ganglia, Spinal; HEK293 Cells; Menthol; Pain; Phenazopyridine; Sensory Receptor Cells; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; Urinary Bladder
PubMed: 36657655
DOI: 10.1016/j.ejphar.2023.175512 -
Clinical Practice and Cases in... May 2022As ketamine gains traction as an alternative to opiates in the treatment of chronic pain, ketamine-induced ulcerative cystitis is now being recognized as a complication...
INTRODUCTION
As ketamine gains traction as an alternative to opiates in the treatment of chronic pain, ketamine-induced ulcerative cystitis is now being recognized as a complication of its use. The first-line treatment is phenazopyridine, an over-the-counter medication for dysuria that historically has been known to cause methemoglobinemia. This report details the case of a patient presenting to the emergency department (ED) with methemoglobinemia.
CASE REPORT
A 66-year-old woman with a complicated medical history presented to the ED with anemia and hypoxia after extended use of phenazopyridine for treatment of ketamine-induced ulcerative cystitis. She was found to have methemoglobinemia secondary to phenazopyridine used to treat her ketamine-induced ulcerative cystitis, a previously undocumented sequelae of chronic ketamine use. She was admitted to the hospital for three days and made a full recovery.
CONCLUSION
This case highlights the need to suspect ketamine-induced ulcerative cystitis in patients who use ketamine chronically and be judicious in the use of phenazopyridine for symptom management to prevent life-threatening complications.
PubMed: 35701344
DOI: 10.5811/cpcem.2022.1.55277 -
The Canadian Veterinary Journal = La... Jul 2021The objective of this study was to describe the clinical findings, medical management, and outcomes of horses with sabulous cystitis, and to describe a high flow bladder...
The objective of this study was to describe the clinical findings, medical management, and outcomes of horses with sabulous cystitis, and to describe a high flow bladder lavage procedure in horses that are standing or under general anesthesia. The medical records of 13 horses diagnosed with sabulous cystitis cystoscopy between 2013 and 2020 were reviewed. Geldings (92%) and Warmbloods (46%) were overrepresented. The most common presenting complaint was urinary incontinence (69%). Complete blood cell count, serum biochemistry profile and urine cytology results were non-specific. Six (46%) horses had various degrees of erosion, ulceration, and hemorrhage of the bladder mucosa. All horses were treated with bladder lavage either with standing sedation ( = 12) or general anesthesia ( = 2), as well as antimicrobials (54%), anti-inflammatory drugs (62%), bethanechol (15%), and phenazopyridine (15%). Most horses (85%) were discharged from the hospital, but only a small percentage (23%) was reported as having no urinary abnormalities on follow-up communication. Key clinical message: Copious bladder lavage with a high flow rate system could mitigate the acute clinical signs and improve the quality of life of horses with sabulous cystitis, but the prognosis for return to previous level of athletic performance and long-term survival is guarded.
Topics: Animals; Cystitis; Horse Diseases; Horses; Male; Quality of Life; Urinary Incontinence
PubMed: 34219784
DOI: No ID Found -
Cureus Jun 2023Sulfhemoglobin is formed by the irreversible bonding of sulfur atoms to the heme molecule. Oxygen is then unable to bind the heme molecule, rendering the hemoglobin...
Sulfhemoglobin is formed by the irreversible bonding of sulfur atoms to the heme molecule. Oxygen is then unable to bind the heme molecule, rendering the hemoglobin molecule unable to carry oxygen. The most common etiology of sulfhemoglobinemia is the use/misuse of sulfur-containing medications such as AZO. Unlike methemoglobin, sulfhemoglobin, due to its irreversible binding, has no antidote, and the treatment is ultimately supportive. We present a case of a 53-year-old female who presented to the emergency room endorsing dysuria and was noted to have abnormally low oxygen saturation (SpO2) despite having high arterial oxygen pressure (PaO2) on blood gas. History was significant for dysuria developed while traveling and the use of over-the-counter AZO four times daily for the past 10 days. She was diagnosed with a presumed dyshemoglobinemia and, upon return of send-out labs, was confirmed to have sulfhemoglobinemia attributed to phenazopyridine. This case highlights the importance of the recognition of potential dyshemoglobinemias and consideration of sulfhemoglobinemia as a potential causative etiology, especially in patients taking sulfur-containing medications.
PubMed: 37496545
DOI: 10.7759/cureus.40944 -
Urology Journal Sep 2020Intravesical BCG (Bacillus Calmette-Guérin) therapy is indicated as an effective treatment for patients with non-muscle-invasive bladder cancer, despite associate with... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of the Efficacy of Oxybutynin, Phenazopyridine, Celecoxib, and Placebo in the Treatment of Urinary Tract Symptoms after BCG Therapy in Patients with Bladder Tumors.
PURPOSE
Intravesical BCG (Bacillus Calmette-Guérin) therapy is indicated as an effective treatment for patients with non-muscle-invasive bladder cancer, despite associate with the side effects. In this study, the incidence of BCG therapy adverse effects was compared among three groups of patients who received celecoxib, phenazopyridine, and oxybutynin with placebo.
MATERIALS AND METHODS
The randomized controlled clinical trial was conducted on four groups using the parallel group method. A checklist is used for weekly assessment of urinary symptoms, systemic symptoms of BCG therapy, and adverse drug reactions.
RESULTS
The study included 120 patients, 10 female and 110 male. The mean age 59.65 ± 6.2 years. The results of multivariate analysis show that there is a significant decrease in urinary frequency for patients who received phenazopyridine (95% CI: 0.09, 0.31, OR = 0.17, P <.001) and also celecoxib group (95% CI: 0.10, 0.43, OR = 0.21, P <.001) compared to those in placebo group. Patients in celecoxib group (95% CI: 0.02, 0.07 ,OR = 0.04, P <.001), phenazopyridine (95% CI : 0.07, 0.37,OR=0.16, P <.001) and oxybutynin (95% CI: 0.02, 0.12,OR = 0.05, P <.001) were less likely to have urgency than those in placebo. Moreover, significant decrease was found for dysuria in the three treatment groups in comparison with placebo group.
CONCLUSION
According to the results, celecoxib, phenazopyridine and oxybutynin can effectively decrease the side effects of BCG immunotherapy compared to placebo. Among these three treatments, the most effective and safest treatment option is celecoxib.
Topics: Adjuvants, Immunologic; Administration, Intravesical; Aged; BCG Vaccine; Celecoxib; Female; Humans; Male; Mandelic Acids; Middle Aged; Phenazopyridine; Urinary Bladder Neoplasms; Urinary Tract
PubMed: 32981029
DOI: 10.22037/uj.v16i7.5947 -
Journal of Virology Jun 2019Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public...
Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs We screened 56 hits from the HTS data and validated 36 compounds using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection. Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.
Topics: Amaryllidaceae Alkaloids; Animals; Antiviral Agents; Cell Line; Coronavirus; Coronavirus OC43, Human; Drug Evaluation, Preclinical; Emetine; High-Throughput Screening Assays; Humans; Mice; Mice, Inbred BALB C; Middle East Respiratory Syndrome Coronavirus; Phenanthridines; Severe acute respiratory syndrome-related coronavirus
PubMed: 30918074
DOI: 10.1128/JVI.00023-19 -
BMJ Case Reports Feb 2019
Topics: Eating; Female; Humans; Hypoxia; Methemoglobinemia; Middle Aged; Patient Education as Topic; Phenazopyridine; Urinary Incontinence, Urge
PubMed: 30772834
DOI: 10.1136/bcr-2018-227538 -
European Review For Medical and... Sep 2016Overactive bladder is a syndrome of urinary frequency and urgency, with or without urge incontinence, in the absence of local pathological factors. Since multiple causes... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Overactive bladder is a syndrome of urinary frequency and urgency, with or without urge incontinence, in the absence of local pathological factors. Since multiple causes are responsible for OAB, it requires proper diagnosis and comprehensive management. For decades, flavoxate is a globally used and accepted molecule by the urologists and the general physicians for the symptomatic treatment of OAB. In spite of its extensive use in OAB, a meta-analysis of the available publications for efficacy, safety and tolerability of flavoxate has not been conducted. This paper evaluates the strength of evidence of clinical effectiveness of safety and tolerability of flavoxate in the symptomatic treatment of OAB.
METHODS
Review articles, original studies and case reports on MEDLINE, the Cochrane Library, Google Scholar, Scirus, internal repository, etc. were searched using the keyword "flavoxate". For the primary outcome, the comparative data of flavoxate versus comparator was extracted for following parameters - overall efficacy and its side effect profile. Similarly as for secondary outcome, data were extracted for flavoxate per se for overall efficacy, frequency, urinary incontinence, mixed incontinence, nocturia, unpleasant urination, stranguria and its side effect profile and were analyzed using Comprehensive Meta-Analysis (CMA) software version 2.0.
RESULTS
In the current meta-analysis, 43 relevant published studies were considered which clearly demonstrated that flavoxate had improved clinical efficacy than placebo, emepronium, propantheline, and phenazopyridine.
CONCLUSIONS
Amongst all the interventions studied, flavoxate was effective and well-tolerated, with almost negligible side effects, making it worthy of consideration for the treatment of OAB.
Topics: Dysuria; Flavoxate; Humans; Treatment Outcome; Urinary Bladder, Overactive; Urination; Urological Agents
PubMed: 27649675
DOI: No ID Found -
ChemMedChem Apr 2021Rev1 is a protein scaffold of the translesion synthesis (TLS) pathway, which employs low-fidelity DNA polymerases for replication of damaged DNA. The TLS pathway helps...
Rev1 is a protein scaffold of the translesion synthesis (TLS) pathway, which employs low-fidelity DNA polymerases for replication of damaged DNA. The TLS pathway helps cancers tolerate DNA damage induced by genotoxic chemotherapy, and increases mutagenesis in tumors, thus accelerating the onset of chemoresistance. TLS inhibitors have emerged as potential adjuvant drugs to enhance the efficacy of first-line chemotherapy, with the majority of reported inhibitors targeting protein-protein interactions (PPIs) of the Rev1 C-terminal domain (Rev1-CT). We previously identified phenazopyridine (PAP) as a scaffold to disrupt Rev1-CT PPIs with Rev1-interacting regions (RIRs) of TLS polymerases. To explore the structure-activity relationships for this scaffold, we developed a protocol for co-crystallization of compounds that target the RIR binding site on Rev1-CT with a triple Rev1-CT/Rev7 /Rev3-RBM1 complex, and solved an X-ray crystal structure of Rev1-CT bound to the most potent PAP analogue. The structure revealed an unexpected binding pose of the compound and informed changes to the scaffold to improve its affinity for Rev1-CT. We synthesized eight additional PAP derivatives, with modifications to the scaffold driven by the structure, and evaluated their binding to Rev1-CT by microscale thermophoresis (MST). Several second-generation PAP derivatives showed an affinity for Rev1-CT that was improved by over an order of magnitude, thereby validating the structure-based assumptions that went into the compound design.
Topics: Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Humans; Molecular Structure; Nucleotidyltransferases; Phenazopyridine; Structure-Activity Relationship
PubMed: 33314657
DOI: 10.1002/cmdc.202000893