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Neuropsychopharmacology : Official... Nov 2022Alzheimer's disease (AD) is the most common form of dementia with no effective treatment options. A complete elucidation of its underlying molecular mechanisms,...
Alzheimer's disease (AD) is the most common form of dementia with no effective treatment options. A complete elucidation of its underlying molecular mechanisms, including the transcription regulation of genes critically involved in AD, may shed light on new therapeutic development. RPS23RG1 is a newly identified AD-associated gene, whose expression is decreased in AD and restoration can attenuate AD-like phenotypes in animal models. However, the transcription regulation of RPS23RG1 remains unknown. In this study, we explored the promoter of RPS23RG1 and identified its transcription initiation site (TSS) at 1525 bp upstream of the ATG translation start codon. Progressive deletion analysis determined the presence of a negative regulatory region and a positive regulatory region within nucleotide positions +1127 to +1187 and +732 to +1127 relative to the TSS (+1), respectively. We conducted a reporter system to screen for compounds that increase RPS23RG1 expression through antagonizing its negative regulatory elements and identified phenazopyridine. Importantly, we demonstrated that phenazopyridine not only promoted RPS23RG1/Rps23rg1 expression, but also reduced AD-like pathologies and cognitive impairments in the APP/PS1 AD model mice. We also determined a critical negative regulatory domain of RPS23RG1 within nucleotide positions +1177 to +1187 and found that the transcription factor SMAD3 bound to this domain. Inhibition of SMAD3 promoted RPS23RG1 expression. Moreover, phenazopyridine reduced SMAD3 binding to the RPS23RG1 promoter without affecting SMAD3 phosphorylation and nuclear localization. Taken together, our results determine the transcription regulation mechanism of RPS23RG1 and show that phenazopyridine has potential for AD treatment through regulating RPS23RG1 transcription.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Codon, Initiator; Disease Models, Animal; Mice; Mice, Transgenic; Nucleotides; Phenazopyridine; Phenotype; Transcription Factors
PubMed: 35821069
DOI: 10.1038/s41386-022-01373-7 -
European Journal of Case Reports in... 2022Phenazopyridine is an over-the-counter urinary analgesic commonly used to alleviate the burning and urgency associated with lower urinary tract infections....
INTRODUCTION
Phenazopyridine is an over-the-counter urinary analgesic commonly used to alleviate the burning and urgency associated with lower urinary tract infections. Methaemoglobinaemia is an uncommon adverse effect of phenazopyridine use. We report a case of methaemoglobinaemia in a patient prescribed daily phenazopyridine to treat urethral and bladder irritation caused by a chronic indwelling Foley catheter.
CASE DESCRIPTION
A 55-year-old female resident of a long-term acute care facility with a chronic Foley, tracheostomy and ventilator-dependent respiratory failure was observed to have generalized dusky skin and hypoxia. Pulse oximetry was reading in the high 80s despite administration of 100% FiO2. ABG revealed paO2 of 451, oxyhaemoglobin level 75% and methaemoglobin level 22%. Medication review indicated that the patient was prescribed phenazopyridine 400 mg TID for the previous 2 months. This medication was discontinued. Considering she was chronically taking mirtazapine, she can increase risk of serotonin syndrome should she be administered first-line treatment with methylene blue. Vitamin C was thus instead administered as a second-line agent. Serial ABGs showed a rapid decline in methaemoglobin levels and an increase in oxyhaemoglobin within 2 days.
DISCUSSION
Acquired methaemoglobinaemia is a rare adverse effect of treatment with phenazopyridine. This risk increases when drug dosage and duration exceed manufacturer specifications. Treatment typically includes cessation of the offending drug and administration of methylene blue in severe cases. A thorough medication reconciliation should be performed prior to methylene blue initiation, as patients taking serotonergic medications (for example, MAOIs, SSRIs, SNRIs, TCAs) are at increased risk of serotonin toxicity with co-administration of methylene blue. In these instances, ascorbic acid/vitamin C can be chosen as an alternative treatment agent.
CONCLUSION
Work-up of refractory hypoxia should involve a thorough review of medications as even some over-the-counter drugs can cause the fatal side effect of methaemoglobinaemia. Treatment with vitamin C should be considered over methylene blue if serotonergic medications have been recently prescribed in order to avoid risk of serotonin syndrome.
LEARNING POINTS
Methaemoglobinaemia is an uncommon, life-threatening adverse effect of phenazopyridine use. Presentation depends on the severity of the disorder, ranging from headache, weakness, lightheadedness and dyspnoea, to arrhythmias, confusion, seizures and multiorgan failure.Workup of refractory hypoxia should involve a comprehensive medication review as even some over-the-counter drugs can cause methaemoglobinaemia.Management of methaemoglobinaemia involves cessation of the offending drug, administration of supplemental oxygen and treatment with methylene blue (1-2 mg/kg) if MetHb >30%, or for symptomatic patients with MetHb >20%. Vitamin C can be used as an alternative agent if there is a contraindication to methylene blue (for example, with patients simultaneously receiving serotonergic medications and/or those with G6PD deficiency).
PubMed: 35265556
DOI: 10.12890/2022_003191 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Environmental Exposure; Female; Humans; Liver Neoplasms
PubMed: 21863079
DOI: No ID Found -
Female Pelvic Medicine & Reconstructive... 2019The aims of this study were to determine the efficacy of phenazopyridine when used intraoperatively to assess ureteral patency and to investigate factors that may...
OBJECTIVES
The aims of this study were to determine the efficacy of phenazopyridine when used intraoperatively to assess ureteral patency and to investigate factors that may influence its efficacy.
METHODS
This is a retrospective chart review performed at the Olive View-UCLA Medical Center, a Los Angeles County teaching hospital, from January 2014 through July 2016. Patients undergoing cystoscopy at the time of gynecologic surgery were identified via department case logs. All women receiving preoperative oral phenazopyridine were included. If ureteral flow was unable to be visualized with phenazopyridine alone, the medication was deemed ineffective, and sodium fluorescein was given intraoperatively. Patients were divided into a phenazopyridine effective or phenazopyridine ineffective group. Patient demographics, renal function, intraoperative fluids and urine output, estimated blood loss, timing and dose of medication administration, and complications were gathered from the chart and compared between groups using Fisher exact test, 2-sample t test, Wilcoxon test, and logistic regression for multivariable analysis. P < 0.05 was determined to be significant.
RESULTS
Preoperative phenazopyridine was effective in 190 (91.8%) of 207 patients. It was ineffective in 17 patients who then required intraoperative sodium fluorescein. The group in which phenazopyridine was effective was more likely to have been given a 200-mg (vs 100-mg) dose (P = 0.02) and had lower intraoperative urine output (median, 450 vs 800 mL; P = 0.002).
CONCLUSIONS
Preoperative oral phenazopyridine is effective in more than 90% of cases to detect during gynecologic surgery. A higher phenazopyridine dose and lower intraoperative urine output were associated with increased efficacy.
Topics: Administration, Oral; Adult; Aged; Coloring Agents; Cystoscopy; Female; Fluorescein; Gynecologic Surgical Procedures; Humans; Intraoperative Complications; Intraoperative Period; Middle Aged; Phenazopyridine; Preoperative Period; Retrospective Studies; Surgical Wound; Ureter; Urine
PubMed: 29300258
DOI: 10.1097/SPV.0000000000000540 -
Journal of Pain and Symptom Management Apr 2021Dysphagia is a common concern, especially in the last several days of life. Medications are often crushed for ease of administration for individuals with swallowing...
CONTEXT
Dysphagia is a common concern, especially in the last several days of life. Medications are often crushed for ease of administration for individuals with swallowing difficulty.
OBJECTIVES
To assess palatability of commonly used crushed over-the-counter (OTC) medications. A secondary objective is to evaluate pharmacist knowledge and opinions of crushing medications.
METHODS
Pharmacist participants sampled crushed OTC medications and completed presampling and postsampling surveys about crushing medications. Participants were excluded for current smoking or tobacco use, pregnancy, allergy to any study medication or applesauce, or potential drug-drug interaction with study medications. Eight OTC medications were crushed and mixed in applesauce: naproxen, fexofenadine, phenazopyridine, multivitamin, loperamide, famotidine, sennosides, and sennosides-docusate. Participants were blinded to medication samples and control (plain applesauce). Samples were rated from one (least palatable) to five (most palatable). Investigators recorded participants' comments, behaviors, and facial expressions during sampling.
RESULTS
Nineteen volunteers completed the study. Most participants rated three samples as not palatable (score of two or less): fexofenadine, 16 (84%); loperamide, 13 (68%); and sennosides-docusate, 16 (84%). All participants rated famotidine and sennosides palatable. The percentage of participants who would consider palatability in recommendations for crushing medications increased from 47% prestudy to 79% poststudy.
CONCLUSION
Palatability should be considered when recommending crushed medications. Survey responses indicate that pharmacists' opinions of crushed medications changed after this palatability experiment. Clinicians should evaluate the appropriateness of all medications when dysphagia is a concern and deprescribe medications when appropriate to reduce burden for patients and caregivers.
Topics: Deglutition Disorders; Humans; Surveys and Questionnaires
PubMed: 32976943
DOI: 10.1016/j.jpainsymman.2020.09.020 -
Cureus Jan 2023Methemoglobinemia is a condition caused by increased methemoglobin, a reduced form of hemoglobin, in the blood. This causes the molecules to bind oxygen more tightly and...
Methemoglobinemia is a condition caused by increased methemoglobin, a reduced form of hemoglobin, in the blood. This causes the molecules to bind oxygen more tightly and decreases their ability to release that oxygen to tissue. Most cases of methemoglobinemia are acquired and occur either in pediatric populations or in individuals with predisposing conditions. This report illustrates a case of an otherwise healthy 31-year-old patient presenting to the emergency department with cyanosis of the hands and mouth and an O2 saturation of 78% after taking increased doses of the over-the-counter medication phenazopyridine. A "chocolate-brown" color of her arterial blood, and increased methemoglobin levels of 20.2%, confirmed the diagnosis of methemoglobinemia. She was treated with both methylene blue and ascorbic acid, and her oxygen saturation and serum chemistry returned to normal levels within a few hours. The case highlights the importance of discussing the dosage of all over-the-counter medications with patients and recognizing the signs and symptoms of methemoglobinemia.
PubMed: 36788851
DOI: 10.7759/cureus.33715 -
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