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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 -
Clinics and Practice Oct 2022Methemoglobinemia is a rare blood disorder characterized by the oxidation of heme iron from ferrous (Fe) to ferric (Fe) state, which increases oxygen affinity and...
Methemoglobinemia is a rare blood disorder characterized by the oxidation of heme iron from ferrous (Fe) to ferric (Fe) state, which increases oxygen affinity and impairs oxygen release to the tissue causing hypoxia. It can be congenital or acquired; however, most cases are acquired and caused by exogenous substances such as medications, chemicals, and environmental substances. Phenazopyridine is an over-the-counter urinary analgesic medication commonly used for symptomatic relief of dysuria and has been reported to cause methemoglobinemia. However, only a handful of cases of phenazopyridine-induced methemoglobinemia have been reported. We present a case of an 89-year-old female who presented with severe hypoxia, shortness of breath, headache, nausea, and dizziness caused by phenazopyridine-induced methemoglobinemia. She was found to have a methemoglobin level of 21.5% and was treated with methylene blue, leading to a rapid improvement of her symptoms. She was taking one over-the-counter phenazopyridine 200 mg tablet three times daily for two weeks for her chronic dysuria. This case highlights the need to have a high index of suspicion of phenazopyridine-induced methemoglobinemia in a patient presenting with unexplained shortness of breath with a history of phenazopyridine use as it could lead to severe methemoglobinemia with hypoxia that could potentially be fatal if not promptly diagnosed.
PubMed: 36412668
DOI: 10.3390/clinpract12060089 -
Asia Pacific Allergy Jan 2022Delayed hypersensitivity reaction of penicillin is commonly seen, but never reported in pyridium. This case illustrates a patient with delayed hypersensitivity reaction...
Delayed hypersensitivity reaction of penicillin is commonly seen, but never reported in pyridium. This case illustrates a patient with delayed hypersensitivity reaction after the use of augmentin and pyridium. Skin patch test, surprisingly, confirmed pyridium delayed hypersensitivity.
PubMed: 35174061
DOI: 10.5415/apallergy.2022.12.e10 -
International Urogynecology Journal Dec 2023Dysuria is a common symptom present in several urological and gynecological conditions. Management relies on the underlying disease but may require additional... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION AND HYPOTHESIS
Dysuria is a common symptom present in several urological and gynecological conditions. Management relies on the underlying disease but may require additional symptomatic treatment. This study evaluated the combination of methenamine 250 mg and methylthioninium chloride 20 mg in the treatment of dysuria versus phenazopyridine.
METHODS
This was a multicenter, single-blind, randomized, superiority clinical trial, including individuals over 18 with dysuria and a score ≥ 5 points on the pre-treatment categorical scale for pain. The primary outcome was the proportion of participants presenting excellent clinical response within 24 h after treatment. Improvement up to 72 h, time to reach improvement, sustained healing, investigators' opinion, and safety were also evaluated.
RESULTS
Three hundred and fifteen participants were evaluated. Demographic characteristics and symptoms of dysuria were comparable between groups at baseline. The difference in the excellent response rate between treatments within 24 h was 12.7% (95% CI 6.16, 19.21) for pain, 9.4% (95% CI 3.32, 15.39) for burning, and 12.7% (95% CI 6.37, 18.99) for burning on urination, all in favor of the test drug, which was also superior from 36 to 48 h. Treatments were similar concerning time to reach the absence of symptoms and in the percentage of participants with sustained healing after 72 h.
CONCLUSIONS
The association of methenamine with methylthioninium is superior to phenazopyridine in the treatment of dysuria.
Topics: Humans; Dysuria; Methenamine; Methylene Blue; Pain; Phenazopyridine; Single-Blind Method; Adult
PubMed: 37851092
DOI: 10.1007/s00192-023-05669-0 -
BMJ Case Reports Sep 2012Methaemoglobin is an altered state of haemoglobin in which the ferrous ions of haeme are oxidised to the ferric state. This results in increased affinity to the bound...
Methaemoglobin is an altered state of haemoglobin in which the ferrous ions of haeme are oxidised to the ferric state. This results in increased affinity to the bound oxygen and decreasing its availability to tissues. Most cases of methaemoglobinaemia are acquired, resulting from an increased methaemoglobin formation by various exogenous agents. The authors report an elderly patient presenting to the emergency department with a 1-month history of shortness of breath. Around the same time she had started using over-the-counter (OTC) phenazopyridine tablets for urinary symptoms. The patient was hypoxic and cyanotic; however, lacked evidence of hypoxaemia on the arterial blood gas. The presence of abnormal haemoglobin was suspected and confirmed by elevated levels of methaemoglobin. Phenazopyridine was proposed to be the likely aetiology of the methaemoglobinaemia, which the patient was not aware of. This case highlights the importance of always inquiring the OTC drug use especially in geriatric population.
Topics: Aged; Anesthetics, Local; Female; Humans; Methemoglobin; Methemoglobinemia; Phenazopyridine; Renal Insufficiency
PubMed: 22987905
DOI: 10.1136/bcr-2012-006756 -
Clinical Case Reports Jun 2018Hydroxocobalamin causes reddish discoloration of the urine, mimicking hematuria. Clinicians should be aware of this common side effect of the rarely used drug to prevent...
Hydroxocobalamin causes reddish discoloration of the urine, mimicking hematuria. Clinicians should be aware of this common side effect of the rarely used drug to prevent unnecessary consultations and work-up. Additional benign causes of red urine include foods such as beets, rhubarb, and medications such as rifampin, phenazopyridine.
PubMed: 29881591
DOI: 10.1002/ccr3.1514 -
International Journal of Women's Health 2022To assess patient reliance on various over-the-counter (OTC) modalities used for prevention of recurrent urinary tract infection (RUTI) after electrofulguration (EF).
PURPOSE
To assess patient reliance on various over-the-counter (OTC) modalities used for prevention of recurrent urinary tract infection (RUTI) after electrofulguration (EF).
PATIENTS AND METHODS
Following IRB approval, qualifying women were offered a short survey over the phone by a medical researcher to collect information about their use of various OTC modalities for prophylaxis of RUTI. Data was compared between two cohorts, ≥70 years old and <70 years old, using chi-squared and Student's -tests.
RESULTS
From a database of 324 patients, 163 accepted the interview. 17% (28/163) reported current use of cranberry supplements, 10% (16/163) D-mannose supplements, and 42% (69/163) another non-prescription modality for RUTI prophylaxis. The non-geriatric (<70 years old) cohort spent, on average, $80 less annually on cranberry/D-mannose supplements (=0.043) than the geriatric cohort and were more likely to use non-prescription modalities for the prevention of UTI (52% vs 30%; =0.0061). Individuals using D-mannose were also much more likely to purchase their product online compared to those using cranberry supplements (85% vs 56%). Across all modalities, the perceived benefit difference in reducing UTI/year ranged from a median of 0 for Pyridium® (phenazopyridine hydrochloride) to four for probiotics, with D-mannose and cranberry at two/year, and those increasing daily fluid consumption at 2.5 fewer UTI/year.
CONCLUSION
Continued use of non-prescription modalities for RUTI prophylaxis were common among women with an EF history, but varied based on age groups. Across both age cohorts, annual expenditure and perceived benefit also varied among different OTC prophylactic modalities. Awareness of type and method of OTC modality implementation by patients with RUTI is essential to aligning use with current field recommendations.
PubMed: 35535150
DOI: 10.2147/IJWH.S355469 -
ChemMedChem Sep 2019Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first-line genotoxic chemotherapies by...
Translesion synthesis (TLS) has emerged as a mechanism through which several forms of cancer develop acquired resistance to first-line genotoxic chemotherapies by allowing replication to continue in the presence of damaged DNA. Small molecules that inhibit TLS hold promise as a novel class of anticancer agents that can serve to enhance the efficacy of these front-line therapies. We previously used a structure-based rational design approach to identify the phenazopyridine scaffold as an inhibitor of TLS that functions by disrupting the protein-protein interaction (PPI) between the C-terminal domain of the TLS DNA polymerase Rev1 (Rev1-CT) and the Rev1 interacting regions (RIR) of other TLS DNA polymerases. To continue the identification of small molecules that disrupt the Rev1-CT/RIR PPI, we generated a pharmacophore model based on the phenazopyridine scaffold and used it in a structure-based virtual screen. In vitro analysis of promising hits identified several new chemotypes with the ability to disrupt this key TLS PPI. In addition, several of these compounds were found to enhance the efficacy of cisplatin in cultured cells, highlighting their anti-TLS potential.
Topics: Animals; Azo Compounds; DNA-Directed DNA Polymerase; Drug Evaluation, Preclinical; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Nucleotidyltransferases; Protein Binding; Protein Domains; Pyridines
PubMed: 31361935
DOI: 10.1002/cmdc.201900307 -
Cureus Feb 2024Urinary tract infections (UTIs) pose a significant challenge in the care of renal transplant recipients. This comprehensive review explores this population's... (Review)
Review
Urinary tract infections (UTIs) pose a significant challenge in the care of renal transplant recipients. This comprehensive review explores this population's multifaceted landscape of UTIs, emphasizing the importance of early diagnosis and tailored management strategies. Renal transplant recipients face an elevated risk of UTIs due to immunosuppression, altered urinary tract anatomy, and complex comorbidities. Complications of UTIs can lead to graft dysfunction and systemic illness, underscoring the need for effective management. The emergence of multidrug-resistant uropathogens adds complexity to treatment, highlighting the importance of targeted antibiotic therapy. Antibiotics are the most commonly prescribed drugs for UTIs, with nitrofurantoin, fosfomycin, amoxicillin, and amoxicillin-clavulanate potassium being some of the commonly used antibiotics. However, the emergence of multidrug-resistant uropathogens has led to the exploration of alternative treatments, such as bacteriophage therapy, as a potential alternative against multidrug-resistant uropathogenic bacteria. Analgesics such as phenazopyridine can be prescribed to relieve discomfort associated with UTIs. Estrogen therapy has also been suggested as a potential treatment option for UTIs, particularly in postmenopausal women. Trimethoprim-sulfamethoxazole or trimethoprim is recommended as first-line therapy for uncomplicated UTIs. The choice of drug and therapy for UTIs depends on the severity of the infection, the causative organism, and the presence of antibiotic resistance. Preventive measures encompass pre-transplant evaluation, perioperative strategies, post-transplant follow-up, and vaccination. A multidisciplinary approach involving transplant specialists, infectious disease experts, pharmacists, and patient engagement is vital for successful care. The future of UTI management lies in ongoing research, exploring personalized medicine, novel therapies, and innovative prevention strategies. By implementing these strategies and advancing research, healthcare providers can improve graft and patient survival, enhancing the quality of care for renal transplant recipients.
PubMed: 38465031
DOI: 10.7759/cureus.53882 -
Fertility and Sterility May 2007The embryo transfer is a critical part of in vitro fertilization. When performed under abdominal ultrasound guidance, the embryo transfer procedure requires a full... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
The embryo transfer is a critical part of in vitro fertilization. When performed under abdominal ultrasound guidance, the embryo transfer procedure requires a full bladder. Patients often state that the discomfort of the distended bladder causes more pain than the actual transfer procedure. Phenazopyridine HCl is a bladder analgesic. The objective of this study was to determine if a single dose of phenazopyridine prior to embryo transfer reduces patient discomfort during that procedure.
DESIGN
Prospective randomized double-blinded clinical trial.
SETTING
University-based Reproductive Medicine practice.
PATIENT(S)
Eighty-five reproductive age infertile women undergoing in vitro fertilization.
INTERVENTION(S)
Phenazopyridine (200 mg) or placebo taken 1 hour prior to embryo transfer utilizing transabdominal sonography.
MAIN OUTCOME MEASURE(S)
Pain as assessed by visual analogue pain scale and physician and nurse assessment of patient discomfort.
RESULT(S)
Study groups were similar in their demographic background. Mean pain score as assessed by a visual analogue pain scale during the procedure was 2.95 +/- 2.4 in the placebo group, and 3.03 +/- 2.6 in the active medication group (NS). There were also no significant differences in the observations of pain assessments.
CONCLUSION(S)
Phenazopyridine used in a single dose prior to embryo transfer does not alleviate patient discomfort.
Topics: Adult; Double-Blind Method; Embryo Transfer; Female; Humans; Pain; Pain Measurement; Phenazopyridine; Prospective Studies
PubMed: 17239870
DOI: 10.1016/j.fertnstert.2006.08.097