<p>Treatment of Recurrent Urinary Tract Infection Symptoms with Urinary Antiseptics Containing Methenamine and Methylene Blue: Analysis of Etiology and Treatment Outcomes</p>

Abstract

Purpose Urinary antiseptics including methenamine and methylene blue are used in the symptomatic treatment of urinary tract infections (UTIs). Patients and Methods This was a prospective, double-blind, randomized, double-dummy safety and efficacy study of 2 urinary antiseptic combinations in the symptomatic treatment of recurrent cystitis: methenamine 120mg + methylene blue 20mg (Group A) versus acriflavine 15mg + methenamine 250mg + methylene blue 20mg + Atropa belladonna L. 15mg (Group B). All subjects underwent pretreatment urine culture and antibiotic sensitivity tests prior to 3-day oral treatment with study drug, followed by 3 days of antibiotic therapy (based on urine culture) + study drug treatment. Efficacy was evaluated using the Urinary Tract Infection Symptoms Assessment Questionnaire (UTISA). The primary endpoint was the percentage of patients presenting improvement in cystitis manifestations on the UTISA domain “Urination Regularity” at Visit 2. The primary safety variable was the incidence of treatment-related adverse events. Results A total of 144 subjects were randomized per group and 272 completed the study. Primary endpoint analysis demonstrates homogeneity between treatment groups, with 69.4% and 72.2% subjects, respectively, showing improvement in the score of the urinary regularity UTISA domain after 3 days of treatment ( p = 0.87). At Visit 2, incidence of treatment-related adverse events was higher in Group B (Group A: n= 11, Group B: n= 31, p = 0.0057). Conclusion Both treatments were effective in reducing UTI symptoms assessed by UTISA questionnaire after 3 days of treatment. The two regimens were comparable in incidence of adverse events, but the combination of methenamine + methylene blue resulted in fewer treatment-related adverse effects.

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

“…It has to be considered, however, that the aromatic acridine rings in ACF are linked with DNA-intercalating properties and thus exhibit mutagenic potential. On the other hand, a substantial amount of long-term clinical data is available for systematic applications of ACF ( Gama et al., 2020 ; Mathé et al., 1996 , 1998 ), thus alleviating concerns related to the potential mutagenic effects, especially for short-term antiviral therapy. Importantly, the antiviral effects are observed at concentrations of 2–3 orders of magnitude lower than those used in experiments assessing in vitro mutagenicity of ACF ( Obstoy et al., 2015 ; Rees et al., 1989 ).…”

“…Importantly, in some countries, ACF is currently available as an over-the-counter medicine (e.g., Brazil; EMS Cystex) against urinary tract infections. Its safety and efficacy were tested in a recently completed clinical trial ( Gama et al., 2020 ; NCT03379389, 2020 ). In other countries, ACF is used as an ingredient in mouthwash advised for children (“Michino” gargle in Japan) ( Lee et al., 2009 ).…”

Inhibitors of SARS-CoV-2 PLpro

“…Confounding its on-target specificity, ACF has been shown to reduce tumour growth by directly inhibiting HIF-1a dimerization ( Lee et al, 2009 ). ACF appears to be under investigation for its use in treating diseases such as cancer ( Cheloni et al, 2017 ; Mangraviti et al, 2017 ; Nehme et al, 2020 ) and malaria ( Dana et al, 2014 ); or as a topical ointment for treating chronic urinary tract infections ( Gama et al, 2020 ). The myriad of indications points towards the polypharmacology of Acriflavine and it is important to note that this compound is not currently approved by the FDA for any of these indications.…”

Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art

“…Proflavine has been found to bind better to alternating purine–pyrimidine DNA sequences than ACF. , Other studies highlight the toxicity of ACF after exposure to light at 448 nm, also related to the induction of DNA damage . In addition, adding ACF to the treatment of infections of the urinary tract with methanamine and methylene blue resulted in an increase in the number of side effects . There are also reports of the effectiveness of ACF (e.g., against HIV1) with little to no toxicity. , …”

“…68 In addition, adding ACF to the treatment of infections of the urinary tract with methanamine and methylene blue resulted in an increase in the number of side effects. 69 There are also reports of the effectiveness of ACF (e.g., against HIV1) with little to no toxicity. 14,70 ACF is an effective inhibitor of HIF-1α aimed primarily at the treatment of solid tumors.…”