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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 -
Journal of Family Medicine and Primary... Jun 2019We present here a case of severe dyspnea after a percutaneous nephrostolithotomy, which resulted from an urinothorax, an uncommon complication of posturological...
We present here a case of severe dyspnea after a percutaneous nephrostolithotomy, which resulted from an urinothorax, an uncommon complication of posturological procedures. Chest X-ray indicated a significant left pleural effusion, and a diagnosis was confirmed by the pleural fluid analysis. Chest tube placement did not improve the patient's clinical status; retrograde pyelogram was performed, and a stent was placed in the left ureter orifice where a narrowing was discovered. Correcting the cause of the urinothorax is the key in such cases of severe pleural effusions as seen in our case.
PubMed: 31334200
DOI: 10.4103/jfmpc.jfmpc_28_17 -
International Journal of Emergency... Nov 2018Phenazopyridine-induced methemoglobinemia is relatively rare with fewer than ten cases reported over the past 35 years. We describe a case of phenazopyridine-induced...
BACKGROUND
Phenazopyridine-induced methemoglobinemia is relatively rare with fewer than ten cases reported over the past 35 years. We describe a case of phenazopyridine-induced methemoglobinemia that is unique in the way the patient presented and how initial workup was completed.
CASE PRESENTATION
The patient presented with lethargy, diarrhea, light-headedness, and headaches, with past medical history of breast cancer, seizures, and recent dysuria for which she had been taking phenazopyridine. She was noted to have a persistent hypoxemia despite supplemental oxygen delivery and a shunting process was considered, with pulmonary embolus and methemoglobinemia due to phenazopyridine use being of chief concern. She was stabilized, and confirmation of original diagnosis was made at the main ED and treatment successfully rendered with good effect.
CONCLUSIONS
Methemoglobinemia, while rare, can be associated with use of over-the-counter medicines and should be considered as part of a broad differential. This case serves to emphasize the importance of a thorough history and physical-tools especially helpful when at a satellite facility with relatively limited resources.
PubMed: 31179913
DOI: 10.1186/s12245-018-0208-5 -
Urologiia (Moscow, Russia : 1999) Jun 2019Dysuria is the one of the most common conditions in urology. Although dysuria is not an independent disease, it accompanies a wide range of urological diseases of both... (Review)
Review
Dysuria is the one of the most common conditions in urology. Although dysuria is not an independent disease, it accompanies a wide range of urological diseases of both infectious and non-infectious origin. Dysuria is traditionally understood as a feeling of discomfort, a burning sensation, or a sensation of pain during urination. Despite a significant reduction in the quality of life of this category of patients, pathogenetic treatment of the underlying cause is often performed in routine clinical practice, while the dysuria itself can remain without proper attention. The current possibilities of symptomatic relief of dysuria are reviewed in this article.
Topics: Dysuria; Humans; Quality of Life; Urination Disorders; Urologic Diseases
PubMed: 31162909
DOI: No ID Found -
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 -
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 -
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 -
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 -
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