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Pharmaceutics Jan 2024Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of but limited activity against the...
Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study, we have examined the anti- activity of a range of existing FDA-approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against adult male parasites using a concentration of 1.25 × 10 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate and rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti- drug candidates worthy of further investigation.
PubMed: 38399264
DOI: 10.3390/pharmaceutics16020210 -
Nature Communications Sep 2023Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic...
Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic platform for the efficient asymmetric alkylation of α-keto acids. First, guided by our recently obtained crystal structures, we develop SgvM as a general biocatalyst for the enantioselective methylation, ethylation, allylation and propargylation of a range of α-keto acids with total turnover numbers (TTNs) up to 4,600. Second, we mine a family of bacterial HMTs from Pseudomonas species sharing less than 50% sequence identities with known HMTs and evaluated their activities in SAM regeneration. Our best performing HMT from P. aeruginosa, PaHMT, displays the highest SAM regeneration efficiencies (TTN up to 7,700) among HMTs characterized to date. Together, the synergistic use of SgvM and PaHMT affords a fully biocatalytic protocol for asymmetric methylation featuring a record turnover efficiency, providing a solution to the notorious problem of asymmetric alkylation.
Topics: Methyltransferases; Alkylation; Biocatalysis; Engineering; Keto Acids; Methenamine; Pseudomonas aeruginosa
PubMed: 37709735
DOI: 10.1038/s41467-023-40980-w -
BMJ Open Apr 2024To estimate the cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis in the management of recurrent urinary tract infections. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis for the management of recurrent urinary tract infections in secondary care: a multicentre, open-label, randomised, non-inferiority trial.
OBJECTIVES
To estimate the cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis in the management of recurrent urinary tract infections.
DESIGN
Multicentre, open-label, randomised, non-inferiority trial.
SETTING
Eight centres in the UK, recruiting from June 2016 to June 2018.
PARTICIPANTS
Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment.
INTERVENTIONS
Women were randomised to receive once-daily antibiotic prophylaxis or twice-daily methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary economic outcome was the incremental cost per quality-adjusted life year (QALY) gained at 18 months. All costs were collected from a UK National Health Service perspective. QALYs were estimated based on responses to the EQ-5D-5L administered at baseline, 3, 6, 9, 12 and 18 months. Incremental costs and QALYs were estimated using an adjusted analysis which controlled for observed and unobserved characteristics. Stochastic sensitivity analysis was used to illustrate uncertainty on a cost-effectiveness plane and a cost-effectiveness acceptability curve. A sensitivity analysis, not specified in the protocol, considered the costs associated with antibiotic resistance.
RESULTS
Data on 205 participants were included in the economic analysis. On average, methenamine hippurate was less costly (-£40; 95% CI: -684 to 603) and more effective (0.014 QALYs; 95% CI: -0.05 to 0.07) than antibiotic prophylaxis. Over the range of values considered for an additional QALY, the probability of methenamine hippurate being considered cost-effective ranged from 51% to 67%.
CONCLUSIONS
On average, methenamine hippurate was less costly and more effective than antibiotic prophylaxis but these results are subject to uncertainty. Methenamine hippurate is more likely to be considered cost-effective when the benefits of reduced antibiotic use were included in the analysis.
TRIAL REGISTRATION NUMBER
ISRCTN70219762.
Topics: Humans; Urinary Tract Infections; Cost-Benefit Analysis; Female; Hippurates; Middle Aged; Methenamine; Quality-Adjusted Life Years; Adult; Antibiotic Prophylaxis; Recurrence; United Kingdom; Anti-Bacterial Agents; Aged
PubMed: 38684270
DOI: 10.1136/bmjopen-2023-074445 -
Archives of Pathology & Laboratory... Feb 2024The diagnosis of some infectious diseases requires their identification in tissue specimens. As institutions adopt digital pathology for primary diagnosis, the limits of...
Digital Pathology in the Detection of Infectious Microorganisms: An Evaluation of Its Strengths and Weaknesses Across a Panel of Immunohistochemical and Histochemical Stains Routinely Used in Diagnostic Surgical Pathology.
CONTEXT.—
The diagnosis of some infectious diseases requires their identification in tissue specimens. As institutions adopt digital pathology for primary diagnosis, the limits of microorganism detection from digital images must be delineated.
OBJECTIVE.—
To assess the reliability of microorganism detection from digitized images of histochemical and immunohistochemical stains commonly used in pathology.
DESIGN.—
Original glass slides from 620 surgical pathology cases evaluated for the presence of infectious microorganisms were digitized. Immunohistochemical stains included those for herpes simplex virus (n = 100), cytomegalovirus (n = 100), Helicobacter pylori (n = 100), and spirochetes (n = 80). Histochemical stains included mucicarmine for Cryptococcus spp (n = 20), Grocott methenamine silver for fungi (n = 100), Giemsa for H pylori (n = 100), and Ziehl-Neelsen for acid-fast bacilli (n = 20). The original diagnosis based on the glass slides was regarded as the reference standard. Six pathologists reviewed the digital images.
RESULTS.—
Digital review was generally associated with high (ie, ≥90%) specificity and positive predictive value owing to a low percentage of false positive reads, whereas a high percentage of false negatives contributed to low sensitivity and negative predictive value for many stains. Fleiss κ showed substantial interobserver agreement in the interpretation of Grocott methenamine silver and immunostains for herpes simplex virus, H pylori, and cytomegalovirus; moderate agreement for spirochete, Ziehl-Neelsen, and mucicarmine; and poor agreement for Giemsa.
CONCLUSIONS.—
Digital immunohistochemistry generally outperforms histochemical stains for microorganism detection. Digital interpretation of Ziehl-Neelsen and mucicarmine stains is associated with low scores for interrater reliability, accuracy, sensitivity, and negative predictive value such that it should not substitute for conventional review of glass slides.
PubMed: 38385999
DOI: 10.5858/arpa.2023-0214-OA -
Cureus Sep 2023Disseminated histoplasmosis is a progressive granulomatous disease caused by , which is an intracellular dimorphic fungus endemic to the Ohio and Mississippi River...
Disseminated histoplasmosis is a progressive granulomatous disease caused by , which is an intracellular dimorphic fungus endemic to the Ohio and Mississippi River valleys in the United States. It is usually thought to be due to the failure of the activation of the T-cell-mediated immune response. Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition, in which histiocytes and lymphocytes build up in and damage organs and other blood cells. We present a 37-year-old man with a past medical history of systemic lupus erythematosus (SLE) complicated by lupus nephritis on immunosuppressive therapy who presented to the emergency department with hypotension and was admitted for acute kidney injury. Prior to the presentation, he had persistent fever, myalgias, cough, mild shortness of breath, and back pain. Computed tomography (CT) chest shows "eggshell" calcification; microbiology evaluation of peripheral blood smear revealed intracellular organism, morphologically consistent with ; and urine histoplasmosis antigen test confirmed the diagnosis of histoplasmosis. HLH diagnosis was made clinically after "clinical and testing criteria" were evaluated. Despite further management, he developed coagulopathy and sepsis, which led to his death. At autopsy, we found organomegaly of the liver, spleen, and kidneys. Microscopically, these enlarged organs show old fibrotic granulomas and granulomatous inflammation with suspected fungal organisms. Gomori's methenamine silver special stain confirmed these fungal organisms to be consistent with species (3-5 micron budding yeasts). This case highlights that physicians should be aware of the diagnostic challenge that disseminated histoplasmosis with HLH could pose in a patient with SLE, especially in patients on immunosuppression. Failure to recognize the infection promptly could lead to grievous complications and possibly death.
PubMed: 37900471
DOI: 10.7759/cureus.46068 -
The Journal of Antimicrobial... May 2024Despite a lack of conclusive evidence of effect, methenamine hippurate is widely prescribed as preventive treatment for recurrent urinary tract infections (UTIs) in...
BACKGROUND
Despite a lack of conclusive evidence of effect, methenamine hippurate is widely prescribed as preventive treatment for recurrent urinary tract infections (UTIs) in Norway. A national discontinuation of methenamine hippurate treatment due to a 4-month drug shortage in 2019 presented an opportunity to evaluate its preventive effect on UTIs among regular users.
OBJECTIVE
To estimate the impact of the methenamine hippurate drug shortage on prescription frequency of UTI antibiotics.
METHODS
Data from The Norwegian Prescription Database was analysed using an interrupted time series design. The time series consisted of 56 time periods of 14 days. The model included two naturally occurring interruptions: (i) the methenamine hippurate drug shortage, and (ii) reintroduction of the drug. The study population were 18 345 women ≥50 years receiving ≥2 prescriptions of methenamine hippurate in the study period before the shortage. Main outcome measure was number of prescriptions of UTI antibiotics per 1000 methenamine hippurate users. Prescription rates of antibiotics for respiratory tract infections were analysed to assess external events affecting antibiotic prescribing patterns.
RESULTS
We found a significant increase of 2.41 prescriptions per 1000 methenamine hippurate users per 14-day period during the drug shortage (95%CI 1.39, 3.43, P < 0.001), followed by a significant reduction of -2.64 prescriptions after reintroduction (95%CI -3.66, -1.63, P < 0.001).
CONCLUSIONS
During the methenamine hippurate drug shortage, we found a significant increase in prescribing trend for UTI antibiotics followed by a significant decrease in prescribing trend after reintroduction. This change in trend seems to reflect a preventive effect of the drug on recurrent UTIs.
Topics: Humans; Urinary Tract Infections; Norway; Anti-Bacterial Agents; Interrupted Time Series Analysis; Female; Hippurates; Methenamine; Middle Aged; Aged; Drug Prescriptions; Practice Patterns, Physicians'; Aged, 80 and over; Drug Utilization
PubMed: 38635298
DOI: 10.1093/jac/dkae078 -
Journal of Cardiology Cases Jan 2024infection is infrequently considered in the differential diagnoses for acute pericarditis in immunocompetent hosts when presenting with tamponade physiology, given its...
UNLABELLED
infection is infrequently considered in the differential diagnoses for acute pericarditis in immunocompetent hosts when presenting with tamponade physiology, given its gradual infective nature. We describe a case of a young male presenting solely with acute pericarditis with pericardial effusion and early cardiac tamponade physiology secondary to a pulmonary histoplasmosis infection. Our patient had no pulmonary symptoms; the only pulmonary manifestation of histoplasmosis included incidental findings of subcarinal lymphadenopathy and a left lingular nodule abutting the pericardium. Given failure of symptom improvement with pericardiocentesis and first-line therapy for idiopathic/viral pericarditis, further workup of the pulmonary nodule was pursued. Histopathologic analysis of tissue showed caseating granulomas and fungal Grocott-Gömöri's methenamine silver stain revealed yeast consistent with species. The patient improved with itraconazole therapy.
LEARNING OBJECTIVE
Pulmonary histoplasmosis has potential to present as a pericardial effusion in the immunocompetent individual. In addition to pericardiocentesis, antifungal therapy can be curative.
PubMed: 38188317
DOI: 10.1016/j.jccase.2023.10.002 -
The Science of the Total Environment Mar 2024Among personal care products, quaternium-15 is prominently featured as a preservative in items such as shampoos, soaps, shaving products, and cosmetics. The widespread...
Among personal care products, quaternium-15 is prominently featured as a preservative in items such as shampoos, soaps, shaving products, and cosmetics. The widespread use of these products in people's daily routines contributes to quaternium-15 release into aquatic ecosystems. In this context, the primary aim of the study was to assess the physiological and cellular responses of the digestive gland and gills in Mytilus galloprovincialis to quaternium-15 exposure. Cell viability and the ability of digestive gland cells to regulate their volume were evaluated. Additionally, the expression of the genes involved in oxidative stress response was assessed to further substantiate the compound's harmful effects. Results indicated a significant decrease in both the viability of digestive gland cells and their RVD (regulatory volume decrease) capacity when exposed to a hypotonic solution. Furthermore, impairment of digestive gland cell function was corroborated by the modulation of oxidative stress-related gene expression, including SOD, Cat, as well as Hsp70 and CYP4Y1. Similar gene expression alterations were observed in the gills, reflecting impaired functionality in this vital organ as well. In summary, the outcomes of the study provide conclusive evidence of the toxicity of quaternium-15. This underscores the urgent need to further investigate the toxicological effects of this contaminant on aquatic ecosystems and emphasises the necessity of limiting the use of products containing quaternium-15.
Topics: Humans; Animals; Mytilus; Ecosystem; Oxidative Stress; Digestion; Water Pollutants, Chemical; Gills; Biomarkers; Methenamine
PubMed: 38309339
DOI: 10.1016/j.scitotenv.2024.170568 -
Clinical, Cosmetic and Investigational... 2024Protothecosis, an infrequent human infection, is caused by achlorophyllic algae belonging to the genus Prototheca, particularly Prototheca wickerhamii. The skin stands...
Protothecosis, an infrequent human infection, is caused by achlorophyllic algae belonging to the genus Prototheca, particularly Prototheca wickerhamii. The skin stands as the most commonly affected organ. This report documents a case involving an 82-year-old male with Protothecosis. Histopathological analysis revealed granulomatous inflammation in the dermis, exhibiting necrotic features and hosting numerous non-budding spherical organisms. These organisms were positively stained using methenamine silver and periodic acid-Schiff stains, confirming identification as after validation through tissue culture and sequencing procedures. Initially, the patient received oral itraconazole at a dosage of 200 mg daily, accompanied by topical 1% naftifine-0.25% ketoconazole cream for a duration of 4 weeks, resulting in significant improvement. Subsequently, due to gastrointestinal discomfort presumably linked to itraconazole, terbinafine was administered. Over a span of 3 months, the patient received oral terbinafine at a dosage of 250 mg/day alongside the application of topical 1% naftifine-0.25% ketoconazole cream, leading to complete healing of the skin lesion, leaving behind a fibrotic scar.
PubMed: 38689756
DOI: 10.2147/CCID.S453620