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Nature Communications Sep 2021Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these...
Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these compounds are rare. Here we report an efficient method for enantioselective construction of bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter via Rh-catalyzed asymmetric hydroformylation/intramolecular cyclization/pyridium chlorochromate (PCC) oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols are transformed into corresponding γ-hydroxyl aldehydes with specific syn-selectivity. Then, hemiacetals form in situ and oxidation with PCC in one-pot affords bridged [2,2,1] bicyclic lactones in high yields and excellent enantiomeric excess. Replacing the hydroxyl group by an ester group, cyclopentanecarbaldehydes with a chiral all-carbon quaternary stereocenter in the γ-position can be generated efficiently.
Topics: Aldehydes; Bridged Bicyclo Compounds, Heterocyclic; Cyclization; Cyclopentanes; Formates; Humans; Lactones; Oxidation-Reduction; Phenazopyridine; Phosphines; Phosphites; Stereoisomerism; Water
PubMed: 34489434
DOI: 10.1038/s41467-021-25569-5 -
Molecular Pharmaceutics Apr 2023The purpose of the present study was to evaluate whether the population balance model (PBM) could be a suitable model for the precipitation of weak base and zwitterionic...
The purpose of the present study was to evaluate whether the population balance model (PBM) could be a suitable model for the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment. Five poorly soluble drugs were used as model drugs (dipyridamole, haloperidol, papaverine, phenazopyridine, and tosufloxacin). PBM consists of the equations for primary nucleation, secondary nucleation, and particle growth. Each equation has two empirical parameters. The pH shift (pH-dumping) precipitation test (pH 3.0 to 6.5) was used to determine the model parameters for each drug. It was difficult to determine all six parameters by simultaneously fitting them to the precipitation profiles. Therefore, the number of model parameters was reduced from six to three by neglecting the secondary nucleation process and applying a common exponent number for the particle growth equation. Despite reducing the parameter number, PBM appropriately described the precipitation profiles in the pH shift tests. The constructed PBM model was then used to predict the precipitation profiles in an artificial stomach-intestine transfer (ASIT) test. PBM appropriately predicted the precipitation profiles in the ASIT test. These results suggested that PBM can be a suitable model to represent the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment for biopharmaceutics modeling and simulation.
Topics: Solubility; Administration, Oral; Gastrointestinal Tract; Stomach; Computer Simulation; Hydrogen-Ion Concentration; Models, Biological; Chemical Precipitation; Intestinal Absorption
PubMed: 36929729
DOI: 10.1021/acs.molpharmaceut.3c00088 -
WMJ : Official Publication of the State... Sep 2023Trimethoprim-sulfamethoxazole (TMP-SMX) and phenazopyridine are individually associated with methemoglobinemia through a series of altered reduction-oxidation reactions....
A Case That Will Take Your Breath Away: Acquired Methemoglobinemia Related to Trimethoprim-Sulfamethoxazole and Phenazopyridine Ingestion for Treatment of Urinary Tract Infection.
Trimethoprim-sulfamethoxazole (TMP-SMX) and phenazopyridine are individually associated with methemoglobinemia through a series of altered reduction-oxidation reactions. We report a case of methemoglobinemia associated with concurrent use of TMP/SMX and phenazopyridine in a 70-year-old woman with recurrent urinary tract infections. She presented to the emergency department for worsening back pain in the setting of recurrent urinary tract infections, concerning for pyelonephritis. During her workup, she became acutely hypoxic. The emergency department provider suspected the presence of abnormal hemoglobin. An arterial blood gas showing elevated levels of methemoglobinemia confirmed the suspicion. The combined use of TMP/SMX and phenazopyridine was thought to be the likely etiology of hypoxia. This case highlights the importance of medication management in the geriatric population, as well as the judicious use of antibiotics for urinary tract infections-a common chief complaint in the primary care setting.
Topics: Aged; Female; Humans; Trimethoprim, Sulfamethoxazole Drug Combination; Phenazopyridine; Methemoglobinemia; Urinary Tract Infections; Eating
PubMed: 37768772
DOI: No ID Found -
Archives of Biochemistry and Biophysics Jul 2024Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in...
Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in incubations with cell cultures or ex vivo gut microbiome samples and contributes to the xenobiotic metabolism of drugs and food additives. Applying metagenomic studies to personalized medicine requires knowledge of the genes responsible for sulfasalazine and other drug metabolism, and candidate genes and proteins for drug modifications are understudied. A representative gut-abundant azoreductase from Anaerotignum lactatifermentan DSM 14214 efficiently reduces sulfasalazine and another drug, phenazopyridine, but could not reduce all azo-bonded drugs in this class. We used enzyme kinetics to characterize this enzyme for its NADH-dependent reduction of these drugs and food additives and performed computational docking to provide the groundwork for understanding substrate specificity in this family. We performed an analysis of the Flavodoxin-like fold InterPro family (IPR003680) by computing a sequence similarity network to classify distinct subgroups of the family and then performed chemically-guided functional profiling to identify proteins that are abundant in the NIH Human Microbiome Project dataset. This strategy aims to reduce the number of unique azoreductases needed to characterize one protein family in the diverse set of potential drug- and dye-modifying activities found in the human gut microbiome.
Topics: Humans; Nitroreductases; Gastrointestinal Microbiome; NADH, NADPH Oxidoreductases; Coloring Agents; Molecular Docking Simulation; Substrate Specificity; Sulfasalazine; Bacterial Proteins; Kinetics; Clostridiales; Azo Compounds
PubMed: 38740275
DOI: 10.1016/j.abb.2024.110025 -
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 -
Journal of Hazardous Materials Jun 2021High-performance novel iron oxyhydroxide (limonite) nanostructure, with improved surface reactive sites, was prepared via one-pot, eco-friendly, free precursor and cold...
Efficient oxidation/mineralization of pharmaceutical pollutants using a novel Iron (III) oxyhydroxide nanostructure prepared via plasma technology: Experimental, modeling and DFT studies.
High-performance novel iron oxyhydroxide (limonite) nanostructure, with improved surface reactive sites, was prepared via one-pot, eco-friendly, free precursor and cold glow discharge N-plasma technique. Natural and plasma treated (PTNL/N) limonite samples were characterized by FESEM, XPS, XRD, FTIR, AAS, EDX, BET/BJH and pH to confirm the successful synthesis. Central composite design (CCD) and artificial neural network (ANN, topology of 4:8:1) methods were utilized to study the oxidation/mineralization of phenazopyridine (PhP) as a hazardous contaminant by heterogeneous catalytic ozonation process (HCOP). The obtained results indicated that PTNL/N had the highest catalytic performance in PhP degradation (98.6% in 40 min) and mineralization (80.4% in 120 min). The degradation mechanism in different processes was investigated by dissolved ozone concentration, various organic scavengers (BQ and TBA) and inorganic salts (NaNO, NaCl, NaCO and NaHPO). Moreover, reusability-stability, Fe and nitrogen (NO and NH) ions release were assessed during different AOPs. Furthermore, toxicity tests indicated that the HCOP using PTNL/N was able to detoxify the PhP solutions efficiently. Finally, Density Functional Theory (DFT) studies were employed to introduce the most plausible contaminant degradation pathway, reactive sites and byproducts. This research provided a new insight into the improvement of wastewater treatment studies by a combination of experiment and computer simulation.
PubMed: 33461011
DOI: 10.1016/j.jhazmat.2021.125074 -
Fundamental & Clinical Pharmacology Dec 2021The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any...
The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.
Topics: Alkylating Agents; Carcinogenicity Tests; Carcinogens; DNA; Humans; Intercalating Agents; Mutagenicity Tests; Pharmaceutical Preparations; Poisons; Probability; Topoisomerase Inhibitors
PubMed: 33772863
DOI: 10.1111/fcp.12674 -
The Journal of Biological Chemistry Jun 2024Menstrual toxic shock syndrome (mTSS) is a rare but severe disorder associated with the use of menstrual products such as high-absorbency tampons and is caused by...
Menstrual toxic shock syndrome (mTSS) is a rare but severe disorder associated with the use of menstrual products such as high-absorbency tampons and is caused by Staphylococcus aureus strains that produce the toxic shock syndrome toxin-1 (TSST-1) superantigen. Herein, we screened a library of 3920 small bioactive molecules for the ability to inhibit transcription of the TSST-1 gene without inhibiting growth of S. aureus. The dominant positive regulator of TSST-1 is the SaeRS two-component system (TCS), and we identified phenazopyridine hydrochloride (PP-HCl) that repressed production of TSST-1 by inhibiting the kinase function of SaeS. PP-HCl competed with ATP for binding of the kinase SaeS leading to decreased phosphorylation of SaeR and reduced expression of TSST-1 as well as several other secreted virulence factors known to be regulated by SaeRS. PP-HCl targets virulence of S. aureus, and it also decreases the impact of TSST-1 on human lymphocytes without affecting the healthy vaginal microbiota. Our findings demonstrate the promising potential of PP-HCl as a therapeutic strategy against mTSS.
PubMed: 38852884
DOI: 10.1016/j.jbc.2024.107455 -
Hematology Reports May 2023Methemoglobinemia is an acute medical emergency that requires prompt correction. Physicians should have a high degree of suspicion of methemoglobinemia in cases that...
Phenazopyridine-Induced Methemoglobinemia in a Jehovah's Witness Treated with High-Dose Ascorbic Acid Due to Methylene Blue Contradictions: A Case Report and Review of the Literature.
Methemoglobinemia is an acute medical emergency that requires prompt correction. Physicians should have a high degree of suspicion of methemoglobinemia in cases that present with hypoxemia that does not resolve with supplemental oxygenation, and they should confirm this suspicion with a positive methemoglobin concentration on arterial blood gas. There are multiple medications that can induce methemoglobinemia, such as local anesthetics, antimalarials, and dapsone. Phenazopyridine is an azo dye used over-the-counter as a urinary analgesic for women with urinary tract infections, and it has also been implicated in causing methemoglobinemia. The preferred treatment of methemoglobinemia is methylene blue, but its use is contraindicated for patients with glucose-6-phosphatase deficiency or those who take serotonergic drugs. Alternative treatments include high-dose ascorbic acid, exchange transfusion therapy, and hyperbaric oxygenation. The authors report a case of a 39-year-old female who took phenazopyridine for 2 weeks to treat dysuria from a urinary tract infection and subsequently developed methemoglobinemia. The patient had contraindications for the use of methylene blue and was therefore treated with high-dose ascorbic acid. The authors hope that this interesting case promotes further research into the utilization of high-dose ascorbic acid for managing methemoglobinemia in patients who are unable to receive methylene blue.
PubMed: 37367083
DOI: 10.3390/hematolrep15020034 -
Journal of Community Hospital Internal... 2023Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic disorder which commonly affects males. It is due to a defect in the red blood cell...
Syncope Following Treatment of UTI: A Case of Acute Hemolytic Anemia, Methemoglobinemia and Acute Renal Dysfunction Following Phenazopyridine Use in a Patient With G6PD Deficiency.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic disorder which commonly affects males. It is due to a defect in the red blood cell enzyme, G6PD. Lack of G6PD makes the RBCs vulnerable to oxidant stress resulting in hemolysis. The severity of hemolytic anemia varies among individuals with G6PD deficiency. Here we present a case of an 80-year-old man admitted with syncope and jaundice. He was treated with phenazopyridine for a UTI 2 weeks ago. Subsequent investigation revealed G6PD deficiency as well as methemoglobinemia. Historically, phenazopyridine has been associated with causing methemoglobinemia and triggering hemolysis in G6PD deficient individuals. However, only a few cases have been reported in the last 60 years, making it a very rare occurrence.
PubMed: 36817304
DOI: 10.55729/2000-9666.1144