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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 -
Mini Reviews in Medicinal Chemistry 2021Azo molecules possess the characteristic azo bond (-N=N-) and are considered fascinating motifs in organic chemistry. Since the last century, these brightly colored... (Review)
Review
Azo molecules possess the characteristic azo bond (-N=N-) and are considered fascinating motifs in organic chemistry. Since the last century, these brightly colored compounds have been widely employed as dyes across several industries in applications for printing, food, paper, cosmetics, lasers, electronics, optics, material sciences, etc. The discovery of Prontosil, an antibacterial drug, propelled azo compounds into the limelight in the field of medicinal chemistry. Subsequent discoveries including Phenazopyridine, Basalazide, and Sulfasalazine enabled azo compounds to occupy a significant role in the drug market. Furthermore, azo compounds have been employed as antibacterial, antimalarial, antifungal, antioxidant, as well as antiviral agents. The metabolic degradation of many azo dyes can induce liver problems if ingested, posing a safety concern and limiting their application as azo dyes in medicinal chemistry. However, azo dyes remain particularly significant for applications in cancer chemotherapy. Recently, a paradigm shift has been observed in the use of azo dyes: from medicinal chemistry to biomedical sciences. The latter benefits from azo dye application are related to imaging, drug delivery, photo-pharmacology and photo switching. Herein, we have compiled and discussed recent works on azo dye compounds obtained so far, focusing on their medicinal importance and future prospects.
Topics: Azo Compounds; Biomedical Research; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Molecular Structure
PubMed: 33231147
DOI: 10.2174/1389557520999201123210025 -
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 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 -
Urologiia (Moscow, Russia : 1999) Sep 2020Cystoscopy is one of the most common procedures in urology. There is no single approach to pain relief. In the literature, there are conflicting data on the efficiency... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Cystoscopy is one of the most common procedures in urology. There is no single approach to pain relief. In the literature, there are conflicting data on the efficiency of intra-urethral gels. The use of non-steroidal anti-inflammatory drugs, intravenous sedation, and nitric oxide analgesia has been described. Phenazopyridine has been known for a long time. Acting on the bladder mucosa, it has a local analgesic effect. AN evaluation of phenazopyridine intake prior to cystoscopy in order to decrease pain during procedure and facilitate subsequent urination was performed.
MATERIALS AND METHODS
A total of 97 patients were included in the study. Indications for cystoscopy were as following: hematuria, lower urinary tract symptoms/pain, a need to remove ureteral stent. The patients were randomized into two groups. In the main group (n=50), phenazopyridine 200 mg was administered 20 minutes before cystoscopy and then at a dose of 200 mg every 8 hours (in total three doses) in combination with lidocaine gel. In the control group (n=47), only lidocaine gel was used. Heart rate was measured before and after the procedure. All patients were asked to complete a visual analogue scale (VAS) 3, 8 and 24 hours after cystoscopy with the assessment of the first urination.
RESULTS
After cystoscopy, the difference between groups in VAS score was 27.7% in favor of the main group (p<0.001). After 3 hours, the average score in the main group was two times less than in the Control (p=0.012), while 3 and 8 hours after cystoscopy, the proportion of "zero" results was 10% and 0%, 28% and 4%, respectively, p<0.005. The heart rate after the procedure in the main group was 75.1 beats/min, compared to 77.9 beats/min in the control group (p=0.016).
CONCLUSION
The intake of phenazopyridine allows to reduce pain intensity during and after cystoscopy and alleviate pain during first urination.
Topics: Cystoscopy; Humans; Pain; Phenazopyridine; Ureter
PubMed: 32897014
DOI: No ID Found -
Urologiia (Moscow, Russia : 1999) Jun 2020to evaluate the efficiency and safety of phenazopyridine for the treatment of patients with uncomplicated lower urinary tract infection, accompanied by pain. (Randomized Controlled Trial)
Randomized Controlled Trial
[Efficiency and safety of phenazopyridine for treatment of uncomplicated urinary tract infection: results of multi-center, randomized, placebo-controlled, clinical study].
AIM
to evaluate the efficiency and safety of phenazopyridine for the treatment of patients with uncomplicated lower urinary tract infection, accompanied by pain.
MATERIALS AND METHODS
A multicenter double-blind, randomized, placebo-controlled study with parallel groups to evaluate the efficacy and safety of phenazopyridine in patients with acute uncomplicated cystitis was performed. A total of 60 women were divided into two groups of 30 patients. In the main group (average age 32.6+/-7.4 years) phenazopyridine was prescribed (2 tablets of 100 mg p.o., with a total dose of 200 mg, once). In the control group, patients (mean age 35.53+/-8.79 years) received a placebo according to the same scheme. To evaluate the efficiency of treatment, the severity of the main symptoms 6 hours after taking the drug was analyzed. After that, patients started antibiotic therapy. They were followed-up for the next three days. The tolerance of therapy was evaluated by the presence of adverse events.
RESULTS
All 30 patients taking phenazopyridine had an improvement after 6 hours, and the most frequent response was "significant improvement" (43.3%). The responses of patients in the main group significantly (p<0.05) differed from responses of patients in the control group. Six hours after taking phenazopyridine/placebo, the severity of all values according to VAS score, including the degree of general discomfort, pain during urination and increased frequency of urination improved significantly in the main group compared to the control group. The average assessment of general discomfort in the main group decreased by 53.4% in comparison with 28.8% in the control group, while the severity of pain during urination and urination frequency decreased by 57.4 vs. 35.9% and 39.6 vs. 27.6%, respectively. An analysis of the time before the complete absence of the general discomfort was performed. In the main group this period of time was significantly less than in the control group (p<0.05). There were no serious adverse events while taking phenazopyridine. Rate of adverse events was comparable between two groups.
CONCLUSION
The results of the study showed that phenazopyridine is an effective and well-tolerated drug for symptomatic therapy in patients with acute uncomplicated cystitis and can be recommended in addition to etiological therapy.
Topics: Adult; Anti-Bacterial Agents; Cystitis; Double-Blind Method; Female; Humans; Phenazopyridine; Treatment Outcome; Urinary Tract Infections
PubMed: 32597580
DOI: No ID Found -
Spectrochimica Acta. Part A, Molecular... Oct 2020Three univariate and two multivariate spectrophotometric methods were developed and subsequently validated to determine phenazopyridine HCl (PHZ) and trimethoprim (TMP)...
Simultaneous determination of phenazopyridine HCl and trimethoprim in presence of phenazopyridine HCl impurity by univariate and multivariate spectrophotometric methods - Quantification of phenazopyridine HCl impurity by univariate methods.
Three univariate and two multivariate spectrophotometric methods were developed and subsequently validated to determine phenazopyridine HCl (PHZ) and trimethoprim (TMP) in the presence of 2,6-Diaminopyridine (2,6-DAP). The first univariate method depends on direct determination of phenazopyridine by measuring its absorbance at 412 nm and performed in concentration range of 1.00-10.00 μg/mL. Then the contribution of phenazopyridine is removed by dividing the mixture spectrum with PHZ divisor (5 μg/mL) after that the constant is mathematically subtracted and finally the generated spectrum is multiplied with the PHZ divisor. These steps eliminate PHZ contribution and the recovered spectrum is that of TMP and 2,6-DAP only where different methods can be applied to determine TMP and 2,6-DAP through this binary mixture spectrum. The first method to determine both components depends on measuring both TMP and 2,6-DAP through their first derivative (DD) spectra at 244.70 and 259.60 nm for TMP and 2,6-DAP, respectively with concentration ranges of 4.00-24.00 μg/mL TMP and 4.00-26.00 μg/mL 2,6-DAP. The second method depends on application of the isoabsorptive method which was used for TMP determination at its isoabsorptive point with 2,6-DAP at 242.64 nm with concentration range 1.00-20.00 μg/mL for TMP. The developed univariate methods were successfully applied to determine PHZ, TMP and PHZ impurity (2,6-DAP). Two multivariate methods were applied for determination of PHZ and TMP in presence of 2,6-DAP namely, Principle Component Regression (PCR) and Partial Least Squares (PLS). The results of the two models show that simultaneous determination of PHZ and TMP in presence of PHZ impurity can be performed in the concentration ranges of 6.00-14.00 μg/mL PHZ and 24.00-56.00 μg/mL TMP. All the proposed methods were successfully applied to analyze PHZ and TMP in pharmaceutical formulations without interference from the dosage form additives and the results were statistically compared with the reported method.
Topics: Least-Squares Analysis; Phenazopyridine; Spectrophotometry; Trimethoprim
PubMed: 32492634
DOI: 10.1016/j.saa.2020.118516 -
Journal of Separation Science Jul 2020Magnetic dispersive solid-phase extraction followed by dispersive liquid-liquid microextraction coupled with gas chromatography/mass spectrometry was applied for the...
Quantitative determination of trace phenazopyridine in human urine samples by hyphenation of dispersive solid-phase extraction and liquid-phase microextraction followed by gas chromatography/mass spectrometry analysis.
Magnetic dispersive solid-phase extraction followed by dispersive liquid-liquid microextraction coupled with gas chromatography/mass spectrometry was applied for the quantitative analysis of phenazopyridine in urinary samples. Magnetic dispersive solid-phase extraction was carried out using magnetic graphene oxide nanoparticles modified by poly(thiophene-pyrrole) copolymer. The eluting solvent of this step was used as the disperser solvent for the dispersive liquid-liquid microextraction procedure. To reach the maximum efficiency of the method, effective parameters including sorbent amount, adsorption time, type and volume of disperser and extraction solvents, pH of the sample solution, and ionic strength as well as desorption time, and approach were optimized, separately. Characterization of the synthesized sorbent was studied by utilizing infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray analysis. Calibration curve was linear in the range of 0.5-250 ng/mL (R = 0.9988) with limits of detection and quantification of 0.1 and 0.5 ng/mL, respectively. Intra- and interday precisions (RSD%, n = 3) of the method were in the range of 4.6-5.4% and 4.0-5.5%, respectively, at three different concentration levels. Under the optimal condition, this method was successfully applied for the determination of phenazopyridine in human urine samples. The relative recoveries were obtained in the range of 85.0-89.0%.
Topics: Gas Chromatography-Mass Spectrometry; Humans; Liquid Phase Microextraction; Magnetic Phenomena; Phenazopyridine; Solid Phase Extraction
PubMed: 32396240
DOI: 10.1002/jssc.202000055 -
Journal of Environmental Management Jan 2020In the present study, the potential of Azolla filiculoides (A. filiculoides) was first investigated for degradation of Phenazopyridine (PhP), an analgesic drug. The...
In the present study, the potential of Azolla filiculoides (A. filiculoides) was first investigated for degradation of Phenazopyridine (PhP), an analgesic drug. The effects of main variables such as initial pharmaceutical concentration, amount of plant, and pH were studied on the efficiency of the biological process. It was observed that A. filiculoides was able to remove pharmaceuticals from contaminated water up to 85.90% during 48 h. Then, the electro-Fenton (EF) method was applied for further removal of PhP yielding a removal rate of about 98.72% under optimum conditions during 2 h. The effects of variables including the current, amount of catalyst, and pH were also studied in this phase. Also, the probability of adsorption was investigated during this step. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis were performed for the used magnetite nanoparticles, total organic carbon (TOC) were performed to investigate PhP removal efficiency during the reaction time and Gas chromatography-mass spectrometry (GC-MS) were performed to analyze degradation byproducts of PhP. Based on the results, it was found that a combination of these bioremediation and electrochemical removal steps were capable of PhP removal from contaminated water. Therefore, this approach may be effective for phytoremediation of pharmaceutical-contaminated aquatic ecosystems.
Topics: Ecosystem; Hydrogen Peroxide; Iron; Oxidation-Reduction; Phenazopyridine; Wastewater; Water Pollutants, Chemical
PubMed: 31731027
DOI: 10.1016/j.jenvman.2019.109802 -
Pharmaceutical Research Nov 2019The intracellular fraction of unbound compound (f) is an important parameter for accurate prediction of drug binding to intracellular targets. f is the result of a...
PURPOSE
The intracellular fraction of unbound compound (f) is an important parameter for accurate prediction of drug binding to intracellular targets. f is the result of a passive distribution process of drug molecules partitioning into cellular structures. Initial observations in our laboratory showed an up to 10-fold difference in the f of a given drug for different cell types. We hypothesized that these differences could be explained by the phospholipid (PL) composition of the cells, since the PL cell membrane is the major sink of unspecific drug binding. Therefore, we determined the f of 19 drugs in cell types of different origin.
METHOD
The cells were characterized for their total PL content and we used mass spectrometric PL profiling to delineate the impact of each of the four major cellular PL subspecies: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI). The cell-based experiments were compared to cell-free experiments that used beads covered by PL bilayers consisting of the most abundant PL subspecies.
RESULTS
PC was found to give the largest contribution to the drug binding. Improved correlations between the cell-based and cell-free assays were obtained when affinities to all four major PL subspecies were considered. Together, our data indicate that f is influenced by PL composition of cells.
CONCLUSION
We conclude that cellular PL composition varies between cell types and that cell-specific mixtures of PLs can replace cellular assays for determination of f as a rapid, small-scale assay covering a broad dynamic range. Graphical Abstract.
Topics: Biological Availability; Biological Transport; Caffeine; Cell Line; Cell Membrane; Computer Simulation; Cytoplasm; Drug Interactions; Humans; Models, Biological; Phenazopyridine; Phospholipids
PubMed: 31701258
DOI: 10.1007/s11095-019-2717-1