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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 -
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 -
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 -
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 -
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 -
European Urology Focus Jul 2023The rise in antimicrobial resistance means that alternative approaches for the treatment and prevention of urinary tract infection (UTIs) are required. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The rise in antimicrobial resistance means that alternative approaches for the treatment and prevention of urinary tract infection (UTIs) are required.
OBJECTIVE
To evaluate the safety and efficacy of a D-mannose-based dietary supplement (D-mannose, citric acid, prebiotic fibers, Astragalus, and dandelion; DAPAD complex) for the treatment of uncomplicated acute E. coli UTIs.
DESIGN, SETTING, AND PARTICIPANTS
This was a single-center, randomized, double-blind, placebo-controlled trial conducted from April 2021 to October 2021 in Rajalakshmi Hospital and Research Centre (Bangalore, India). The participants were nonmenopausal women with an acute uncomplicated E. coli UTI. UTI was diagnosed according to the presence of at least one urinary symptom and bacteriuria (>100 000 CFU/ml).
INTERVENTION
The DAPAD complex was administered twice a day for 5 d, with phenazopyridine and alkalizing agents as the standard of care (SOC). The control group received placebo with SOC.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Subjective (clinical resolution/response) and objective (midstream bacteriuria) outcomes were evaluated at the end of therapy (day 6) and at day 35 of follow-up. Adverse events were recorded. Categorical variables were analyzed using χ and Fisher's exact tests; a p value <0.05 was considered significant.
RESULTS AND LIMITATIONS
Seventy women were enrolled and equally randomized to the two groups. Clinical resolution was higher in the DAPAD group at 6 d (34.3% vs 0%; p < 0.0001) and 35 d from baseline (88.6% vs 20%, p < 0.0001). At day 35, no patients in the DAPAD group had moderate or severe symptoms, whereas 25.7% (nine/35) and 11.4% (four/35) of patients in the placebo group had moderate and severe symptoms, respectively. Bacteriological resolution was also higher in the DAPAD group at day 6 (85.7% vs 14.3%; p < 0.0001) and day 35 (100% vs 40%; p < 0.0001). Three mild adverse events (4.26%) unrelated to the investigated product were recorded, all of which were medically treated.
CONCLUSIONS
The DAPAD complex dietary supplement is effective and safe for treatment of acute uncomplicated E. coli UTIs.
PATIENT SUMMARY
Our results show that for nonmenopausal women with an uncomplicated Escherichia coli urinary tract infection, those treated with a dietary supplement (containing D-mannose, citric acid, prebiotic fibers, Astragalus, and dandelion) had a higher rate of clinical resolution or response than women who received a placebo.
Topics: Female; Humans; Mannose; Bacteriuria; Escherichia coli; Treatment Outcome; India; Urinary Tract Infections; Escherichia coli Infections; Dietary Supplements; Prebiotics
PubMed: 36621376
DOI: 10.1016/j.euf.2022.12.013