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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 -
Female Pelvic Medicine & Reconstructive... Feb 2021The objective of our study was to determine if phenazopyridine reduces void trial (VT) failure rates after prolapse surgery. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The objective of our study was to determine if phenazopyridine reduces void trial (VT) failure rates after prolapse surgery.
METHODS
A single-institution randomized controlled trial was conducted comparing a second dose of phenazopyridine 200 mg on postoperative day 1 versus no additional phenazopyridine in women undergoing prolapse surgery. All subjects (including controls) received 200 mg of phenazopyridine preoperatively for ureteral patency verification. The intervention group received a second dose of phenazopyridine 200 mg the morning of postoperative day 1. The primary outcome was assessed using a standardized VT. Secondary outcomes included pain, opioid usage, urinary tract infections, and prolonged or recurrent urinary retention. An intent-to-treat analysis was performed with a χ2 test to compare failure rates between the intervention and control groups.
RESULTS
We enrolled 152 women, and 76 were randomized to each group. There was no difference in VT failures between the 2 groups-34% failed without phenazopyridine on postoperative day 1, and 42% failed with phenazopyridine on postoperative day 1 (P = 0.326). Subject characteristics were similar across both groups. Pain scores immediately before the VT were 3 out of 10 in both groups (P = 0.206), with no difference in opioid consumption (P = 0.750). There were no differences in the rate of urinary tract infections or prolonged or recurrent urinary retention between the groups (P = 0.304 and P = 0.745).
CONCLUSIONS
While previous studies suggested an improvement in immediate postoperative voiding with phenazopyridine, our randomized controlled trial does not support this.
Topics: Anesthetics; Female; Humans; Middle Aged; Pelvic Organ Prolapse; Phenazopyridine; Postoperative Care; Postoperative Complications; Premedication; Urinary Retention
PubMed: 31033527
DOI: 10.1097/SPV.0000000000000737 -
Journal of Oncology Pharmacy Practice :... Mar 2020Phenazopyridine is a urinary tract analgesic indicated for short-term treatment of irritation in the lower urinary tract. Despite the lack of evidence for extended use,...
BACKGROUND
Phenazopyridine is a urinary tract analgesic indicated for short-term treatment of irritation in the lower urinary tract. Despite the lack of evidence for extended use, it is often used in varying durations for supportive care for cancer patients with radiation-induced cystitis. The objective of this study was to compare the incidence of adverse drug reactions in patients with radiation cystitis receiving long-term phenazopyridine (>14-day supply) compared to a matched comparator group.
METHODS
This retrospective cohort study compared adverse events among cancer patients with and without phenazopyridine exposure. Included patients received radiation and at least one chronic medication between 1 July 2008 and 30 June 2017. The phenazopyridine group also received >14-day supply of phenazopyridine during the study period. Patients were matched based on gender, age (±5 years), cancer diagnosis, and palliative or curative treatment intent. Data collection occurred at baseline, during the time of presumed exposure, and through the end of the study period for surveillance purposes.
RESULTS
A total of 272 patients received phenazopyridine for >14-day supply during the study period. Of these, 90 patients were included and matched to an equal number of patients in the comparator group. The included patients were similar between groups and were largely male with a diagnosis of prostate cancer. Most patients received between a 30- and 60-day supply of phenazopyridine. There were a total of 13 adverse drug reactions in the phenazopyridine group and 18 in the comparator group ( = 0.32). No differences were identified between the phenazopyridine and comparator groups for the incidence of individual adverse drug reactions, emergency department visits, hospitalizations, or new diagnoses of hepatocellular or colorectal cancer.
CONCLUSION
There was no difference in adverse drug reactions among patients receiving phenazopyridine for >14 days compared to a matched comparator group. The overall incidence of adverse events in both groups was low.
Topics: Aged; Cohort Studies; Cystitis; Drug Administration Schedule; Humans; Male; Middle Aged; Phenazopyridine; Radiation Injuries; Retrospective Studies
PubMed: 31006341
DOI: 10.1177/1078155219842646 -
Urology Aug 2019Phenazopyridine is a common, well-tolerated medication with minimal side effects. Severe side effects are rare and include methemoglobinemia in setting of overdose,...
Phenazopyridine is a common, well-tolerated medication with minimal side effects. Severe side effects are rare and include methemoglobinemia in setting of overdose, elderly patients, renal insufficiency, and chronic use. Here, we report a case of methemoglobinemia-induced perioperative hypoxia in an adolescent patient without renal insufficiency or overdose which has not been reported previously. This case underscores the importance of judicious use of this medication in all patients but notably in pediatric patients and those with chronic lung disease.
Topics: Adolescent; Humans; Hypoxia; Male; Methemoglobinemia; Phenazopyridine; Postoperative Complications
PubMed: 30917912
DOI: 10.1016/j.urology.2019.03.017 -
Female Pelvic Medicine & Reconstructive... Nov 2020The aim of this study was to determine the safety and efficacy of methods for intraoperative evaluation of urinary tract injury during pelvic surgery.
OBJECTIVE
The aim of this study was to determine the safety and efficacy of methods for intraoperative evaluation of urinary tract injury during pelvic surgery.
METHODS
PubMed, EMBASE, CINAHL, Web of Science, Scopus, ProQuest, the Cochrane Library, and Clinicaltrials.gov were searched from 1947 to February 2018. Articles or abstracts describing the routine evaluation of urinary tract injuries during pelvic surgery in adults were included, surgical indications of urinary tract anomaly, stones, or malignancy were excluded. There were no restrictions on study design or language. Outcomes included injuries diagnosed intraoperatively, delayed diagnoses, adverse effects, subjective assessments, time to use, and cost. Data were extracted in duplicate at an individual-participant level. Prevalence of injuries, sensitivity, specificity, and predictive values of each diagnostic method were calculated. A combination of generalized linear models and a Bayesian approach were used to separately pool diagnostic accuracy measures.
RESULTS
There were 5303 titles, 527 abstracts, and 164 full-text articles assessed for eligibility; 69 articles were analyzed. Diagnostic methods retrieved were cystoscopy using saline, dextrose or unspecified distention media, oral phenazopyridine and vitamin B, intravenous (IV) methylene blue, IV sodium fluorescein, IV indigo carmine, prophylactic retrograde ureteral stents, and transabdominal Doppler ultrasound. Prevalence of urinary tract injury ranged from 0.3% to 2.8%. Sensitivity ranged 63% to 91%, and specificity, 99.7% to 100%, with no significant differences suggested between methods.
CONCLUSIONS
All evaluable methods of intraoperative urinary tract assessment during pelvic surgery are safe and effective with specificity of greater than 99% and low rates of complications. Larger, more rigorous studies are required to evaluate the diagnostic accuracy of some newer methods.
Topics: Cystoscopy; Humans; Iatrogenic Disease; Intraoperative Complications; Lower Urinary Tract Symptoms; Urinary Tract; Urologic Diseases
PubMed: 30570501
DOI: 10.1097/SPV.0000000000000679 -
Environmental Technology Sep 2019Photocatalytic degradation of waste pharmaceutics, with solar radiation, is described here as a feasible method to purify pre-contaminated soils. Phenazopyridine has...
Photocatalytic degradation of waste pharmaceutics, with solar radiation, is described here as a feasible method to purify pre-contaminated soils. Phenazopyridine has been used as a model soil contaminant. Two different nano-size powders have been first examined as catalysts, namely commercial TiO (anatase) and commercial ZnO. As the ZnO showed higher catalytic efficiency, the study was then focused on it. The commercial ZnO powder was then compared with lab-prepared ZnO powder, and the latter shows relatively higher efficiency. The ZnO was used in two different ways. In one way, dry ZnO catalyst powder was spread onto the soil, while in the other way the ZnO was sprayed onto the soil surface by a wet spray method. The spray technique shows slightly higher efficiency, in addition to being easier to apply at future large scale. Depending on conditions and type of photocatalyst used, up to 90% contaminant removal can be achieved in 30 min. In case of photocatalysis experiments, the reacted contaminant molecules undergo complete degradation with no detectable side reaction organic products. Possible evaporation or escape of organic contaminant, or other possibly resulting organics, is ruled out by a series of control experiments. Photodegradation process takes place only at the catalytic sites on the soil surface, where contaminant molecules that diffuse from the soil bulk are completely degraded. Other useful organisms inside the soil are not affected as they are kept away from catalyst sites. A plausible mechanism is proposed for the degradation process.
Topics: Catalysis; Phenazopyridine; Photolysis; Soil; Sunlight; Zinc Oxide
PubMed: 29600741
DOI: 10.1080/09593330.2018.1459873