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BMC Nephrology Jun 2022Asymptomatic hyperuricemia was found to be associated with increased cardiovascular disease risk but the potential benefits of urate-lowering therapy (ULT) remain... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Asymptomatic hyperuricemia was found to be associated with increased cardiovascular disease risk but the potential benefits of urate-lowering therapy (ULT) remain controversial. We conducted a systematic review and network meta-analysis (NMA) with frequentist model to estimate the efficacy and safety of ULT in asymptomatic hyperuricemia.
METHODS
MEDLINE, Embase, and Scopus were searched without language restrictions. Randomized controlled trials (RCT) of adults with asymptomatic hyperuricemia were eligible if they compared any pair of ULTs (i.e., allopurinol, febuxostat, probenecid, benzbromarone, sulfinpyrazone, rasburicase, lesinurad, and topiroxostat) and placebo or no ULT, and had outcomes of interest, including composite renal events, major adverse cardiovascular events, serum urate levels, estimated glomerular filtration rate (eGFR), systolic blood pressure, and adverse events.
RESULTS
NMA with frequentist approach was applied to estimate relative treatment effects, i.e., risk ratio (RR) and mean difference (MD). A total of 23 RCTs were eligible. NMA identified beneficial effects of ULT on composite renal events and eGFR but not for other outcomes. Allopurinol and febuxostat had significantly lower composite renal events than placebo (RR 0.39, 95% confidence interval [CI] 0.23 to 0.66, and RR 0.68, 95% CI 0.46 to 0.99, respectively). Both treatments also resulted in significantly higher eGFR than placebo (MD 3.69 ml/min/1.73 m, 95% CI 1.31 to 6.08, and MD 2.89 ml/min/1.73 m, 95% CI 0.69 to 5.09, respectively). No evidence of inconsistency was identified.
CONCLUSIONS
Evidence suggests that allopurinol and febuxostat are the ULTs of choice in reducing composite renal events and improving renal function.
TRIAL REGISTRATION
This study was registered with PROSPERO: CRD42019145908. The date of the first registration was 12 November 2019.
Topics: Adult; Allopurinol; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Network Meta-Analysis; Randomized Controlled Trials as Topic; Uric Acid
PubMed: 35739495
DOI: 10.1186/s12882-022-02850-3 -
International Journal For Parasitology.... Aug 2022Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus...
Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.
Topics: Albendazole; Animals; Anthelmintics; Glycosides; Glycosyltransferases; Haemonchus; Nematoda; Phenobarbital; Sheep; Sheep Diseases; Sulfinpyrazone; Uridine Diphosphate
PubMed: 35738156
DOI: 10.1016/j.ijpddr.2022.06.001 -
Medicine Jun 2023Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for severe COVID-19, but the mechanism remains unknown. This study used bioinformatics to help...
Nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for severe COVID-19, but the mechanism remains unknown. This study used bioinformatics to help define the relationship between these diseases. The GSE147507 (COVID-19), GSE126848 (NAFLD), and GSE63067 (NAFLD-2) datasets were screened using the Gene Expression Omnibus. Common differentially expressed genes were then identified using a Venn diagram. Gene ontology analysis and KEGG pathway enrichment were performed on the differentially expressed genes. A protein-protein interaction network was also constructed using the STRING platform, and key genes were identified using the Cytoscape plugin. GES63067 was selected for validation of the results. Analysis of ferroptosis gene expression during the development of the 2 diseases and prediction of their upstream miRNAs and lncRNAs. In addition, transcription factors (TFs) and miRNAs related to key genes were identified. Effective drugs that act on target genes were found in the DSigDB. The GSE147507 and GSE126848 datasets were crossed to obtain 28 co-regulated genes, 22 gene ontology terms, 3 KEGG pathways, and 10 key genes. NAFLD may affect COVID-19 progression through immune function and inflammatory signaling pathways. CYBB was predicted to be a differential ferroptosis gene associated with 2 diseases, and the CYBB-hsa-miR-196a/b-5p-TUG1 regulatory axis was identified. TF-gene interactions and TF-miRNA coregulatory network were constructed successfully. A total of 10 drugs, (such as Eckol, sulfinpyrazone, and phenylbutazone) were considered as target drugs for Patients with COVID-19 and NAFLD. This study identified key gene and defined molecular mechanisms associated with the progression of COVID-19 and NAFLD. COVID-19 and NAFLD progression may regulate ferroptosis through the CYBB-hsa-miR-196a/b-5p-TUG1 axis. This study provides additional drug options for the treatment of COVID-19 combined with NAFLD disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Systems Biology; Gene Expression Profiling; COVID-19; MicroRNAs; Computational Biology; Gene Regulatory Networks
PubMed: 37335656
DOI: 10.1097/MD.0000000000033912 -
Insects Apr 2021UDP-glycosyltransferases (UGTs) are major phase II detoxification enzymes that catalyze the transfer of glycosyl residues from activated nucleotide sugars to acceptor...
UDP-glycosyltransferases (UGTs) are major phase II detoxification enzymes that catalyze the transfer of glycosyl residues from activated nucleotide sugars to acceptor hydrophobic molecules and play very important roles in the biotransformation of various endogenous and exogenous compounds. Our previous studies demonstrated that UGTs participated in the detoxification of insecticides in . However, the potential roles of UGTs in resistance to sulfoxaflor are still unclear. In this study, two inhibitors of UGT enzymes, sulfinpyrazone and 5-nitrouracil, significantly increased the toxicity of sulfoxaflor to a resistant strain of , whereas there were no synergistic effects in the susceptible strain. Based on the transcriptome sequencing results, the expression levels of 15 UGTs were analyzed by quantitative real-time PCR, and we found that seven UGT genes were highly over-expressed in a sulfoxaflor-resistant strain compared to the susceptible strain, including , , , , and . Further suppressing the expression of , , and by RNA interference significantly increased the sensitivity of resistant aphids to sulfoxaflor, indicating that the overexpression of UGT genes is potentially associated with sulfoxaflor resistance. These results could provide valuable information for further understanding the mechanisms of insecticide resistance.
PubMed: 33923504
DOI: 10.3390/insects12040356 -
PLoS Neglected Tropical Diseases Sep 2019Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people...
Lymphatic filariasis (LF), a morbid disease caused by the tissue-invasive nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori, affects millions of people worldwide. Global eradication efforts have significantly reduced worldwide prevalence, but complete elimination has been hampered by limitations of current anti-filarial drugs and the lack of a vaccine. The goal of this study was to evaluate B. malayi intestinal UDP-glucuronosyltransferase (Bm-UGT) as a potential therapeutic target. To evaluate whether Bm-UGT is essential for adult filarial worms, we inhibited its expression using siRNA. This resulted in a 75% knockdown of Bm-ugt mRNA for 6 days and almost complete suppression of detectable Bm-UGT by immunoblot. Reduction in Bm-UGT expression resulted in decreased worm motility for 6 days, 70% reduction in microfilaria release from adult worms, and significant reduction in adult worm metabolism as detected by MTT assays. Because prior allergic-sensitization to a filarial antigen would be a contraindication for its use as a vaccine candidate, we tested plasma from infected and endemic normal populations for Bm-UGT-specific IgE using a luciferase immunoprecipitation assay. All samples (n = 35) tested negative. We then tested two commercially available medicines known to be broad inhibitors of UGTs, sulfinpyrazone and probenecid, for in vitro activity against B. malayi. There were marked macrofilaricidal effects at concentrations achievable in humans and very little effect on microfilariae. In addition, we observed that probenecid and sulfinpyrazone exhibit a synergistic macrofilaricidal effect when used in combination with albendazole. The results of this study demonstrate that Bm-UGT is an essential protein for adult worm survival. Lack of prior IgE sensitization in infected and endemic populations suggest it may be a feasible vaccine candidate. The finding that sulfinpyrazone and probenecid have in vitro effects against adult B. malayi worms suggests that these medications have promise as potential macrofilaricides in humans.
Topics: Albendazole; Animals; Antigens, Helminth; Brugia malayi; Drug Therapy, Combination; Elephantiasis, Filarial; Female; Filaricides; Glucuronosyltransferase; Humans; Immunoglobulin E; Intestines; Microfilariae; Movement; Probenecid; RNA, Small Interfering; Sulfinpyrazone
PubMed: 31513587
DOI: 10.1371/journal.pntd.0007687 -
The Cochrane Database of Systematic... Jul 2021People with end-stage renal disease (ESRD) often require either the formation of an arteriovenous fistula (AVF) or an interposition prosthetic arteriovenous graft... (Meta-Analysis)
Meta-Analysis
BACKGROUND
People with end-stage renal disease (ESRD) often require either the formation of an arteriovenous fistula (AVF) or an interposition prosthetic arteriovenous graft (AVG) for haemodialysis. These access sites should ideally have a long life and a low rate of complications (e.g. thrombosis, infection, stenosis, aneurysm formation and distal limb ischaemia). Although some of the complications may be unavoidable, any adjuvant technique or medical treatment aimed at decreasing complications would be welcome. This is the fourth update of the review first published in 2003.
OBJECTIVES
To assess the effects of adjuvant drug treatment in people with ESRD on haemodialysis via autologous AVFs or prosthetic interposition AVGs.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and ClinicalTrials.gov trials register to 6 August 2020.
SELECTION CRITERIA
Randomised controlled trials of active drug versus placebo in people with ESRD undergoing haemodialysis via an AVF or prosthetic interposition AVG.
DATA COLLECTION AND ANALYSIS
For this update, two review authors (IM, MFAK) independently selected trials for inclusion, extracted data, assessed risk of bias and assessed the certainty of the evidence according to GRADE. We resolved disagreements by discussion or consultation with another review author (ADS). The primary outcome was the long-term fistula or graft patency rate. Secondary outcomes included duration of hospital stay; complications such as infection, aneurysm formation, stenosis and distal limb ischaemia; and number of related surgical or radiological interventions.
MAIN RESULTS
For this update, one additional study was suitable for inclusion, making a total of 13 trials with 2080 participants. Overall the certainty of the evidence was low or moderate due to short follow-up periods, heterogeneity between trials, small sample sizes, and risk of bias due to incomplete reporting. Medical adjuvant treatments used in the included trials were aspirin, ticlopidine, dipyridamole, dipyridamole plus aspirin, warfarin, fish oil, clopidogrel, sulphinpyrazone and glyceryl trinitrate (GTN) patch. All included studies reported on graft patency by measuring graft thrombosis. There was insufficient evidence to determine if there was a difference in graft patency in studies comparing aspirin versus placebo (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.07 to 2.25; 3 studies, 175 participants; low-certainty evidence). The meta-analysis for graft patency comparing ticlopidine versus placebo favoured ticlopidine (OR 0.45, 95% CI 0.25 to 0.82; 3 studies, 339 participants; moderate-certainty evidence). There was insufficient evidence to determine if there was a difference in graft patency in studies comparing fish oil versus placebo (OR 0.24, 95% CI 0.03 to 1.95; 2 studies, 220 participants; low-certainty evidence); and studies comparing clopidogrel and placebo (OR 0.40, 95% CI 0.13 to 1.19; 2 studies, 959 participants; moderate-certainty evidence). Similarly, there was insufficient evidence to determine if there was a difference in graft patency comparing the effect of dipyridamole versus placebo (OR 0.46, 95% CI 0.11 to 1.94; 1 study, 42 participants, moderate-certainty evidence) and dipyridamole plus aspirin versus placebo (OR 0.64, CI 0.16 to 2.56; 1 study, 41 participants; moderate-certainty evidence); comparing low-intensity warfarin with placebo (OR 1.76, 95% CI 0.78 to 3.99; 1 study, 107 participants; low-certainty evidence); comparing sulphinpyrazone versus placebo (OR 0.43, 95% CI 0.03 to 5.98; 1 study, 16 participants; low-certainty evidence) and comparing GTN patch and placebo (OR 1.26, 95% CI 0.63 to 2.54; 1 study, 167 participants; moderate-certainty evidence). The single trial evaluating warfarin was terminated early because of major bleeding events in the warfarin group. Only two studies published data on the secondary outcome of related interventions (surgical or radiological); there was insufficient evidence to determine if there was a difference in related interventions between placebo and treatment groups. None of the included studies reported on the duration of hospital stay. Most studies reported complications ranging from mortality to nausea. However, data on complications were limited and reporting varied between studies.
AUTHORS' CONCLUSIONS
The meta-analyses of three studies for ticlopidine (an antiplatelet treatment), which all used the same dose of treatment but with a short follow-up of only one month, suggest ticlopidine may have a beneficial effect as an adjuvant treatment to increase the patency of AVFs and AVGs in the short term. There was insufficient evidence to determine if there was a difference in graft patency between placebo and other treatments such as aspirin, fish oil, clopidogrel, dipyridamole, dipyridamole plus aspirin, warfarin, sulphinpyrazone and GTN patch. The certainty of the evidence was low to moderate due to short follow-up periods, the small number of studies for each comparison, small sample sizes, heterogeneity between trials and risk of bias due to incomplete reporting. Therefore, it appears reasonable to suggest further prospective studies be undertaken to assess the use of these antiplatelet drugs in renal patients with an AVF or AVG.
Topics: Arteriovenous Shunt, Surgical; Chemotherapy, Adjuvant; Fish Oils; Graft Occlusion, Vascular; Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Ticlopidine; Vascular Access Devices; Vascular Patency
PubMed: 34298589
DOI: 10.1002/14651858.CD002786.pub4 -
International Journal of Molecular... Jul 2019Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are major phase II detoxification enzymes involved in glycosylation of lipophilic endobiotics and xenobiotics,...
Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are major phase II detoxification enzymes involved in glycosylation of lipophilic endobiotics and xenobiotics, including phytoalexins. Nicotine, one of the most abundant secondary plant metabolites in tobacco, is highly toxic to herbivorous insects. Plant-herbivore competition is the major impetus for the evolution of large superfamilies of and other detoxification enzymes. However, UGT functions in green peach aphid () adaptation are unknown. In this study, we show that UGT inhibitors (sulfinpyrazone and 5-nitrouracil) significantly increased nicotine toxicity in , suggesting that UGTs may be involved in nicotine tolerance. In total, 101 transcripts identified in the genome/transcriptome were renamed according to the UGT Nomenclature Committee guidelines and grouped into 11 families, UGT329, UGT330, UGT339, UGT341-UGT345, and UGT348-UGT350, with UGT344 containing the most (57). Ten (, , , , , , , , , and ) were highly expressed in compared to sensu stricto. Knockdown of four UGTs (, , , and ) significantly increased sensitivity to nicotine, suggesting that expression in this subspecies may be associated with nicotine tolerance and thus host adaptation. This study reveals possible relevant to nicotine adaptation in tobacco-consuming , and the findings will facilitate further validation of the roles of these in nicotine tolerance.
Topics: Adaptation, Biological; Amino Acid Sequence; Animals; Aphids; Conserved Sequence; Drug Resistance; Gene Expression; Gene Knockdown Techniques; Glucuronosyltransferase; Multigene Family; Nicotine; Phylogeny; Protein Domains
PubMed: 31349586
DOI: 10.3390/ijms20153637 -
Frontiers in Medicine 2020Gout is the most common form of inflammatory arthritis and was found to be independently associated with incident dementia in the elderly. However, the associations...
Gout is the most common form of inflammatory arthritis and was found to be independently associated with incident dementia in the elderly. However, the associations between anti-gout preparations and dementia were not well-studied. Data were collected from Taiwan's National Health Insurance Research Database (NHIRD). A 2005-2013 retrospective cohort study was conducted, and all investigated subjects were identified by International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification. Conditional logistic regression was used to evaluate the odds ratio of dementia in relation to different gout preparations (benzbromarone, allopurinol, sulfinpyrazone, probenecid) and number of days of anti-gout preparation use, after adjustment for potential confounding variables. A total of 3,242 gout patients with and without dementia were selected from the NHIRD and included in the final analysis after 1:1 matching for age, gender, and diagnosis year of gout. In the anti-gout preparations, only use of Benzbromarone decreased the risk of dementia (adjusted OR, 0.81; 95% CI, 0.68-0.97). The result of the subgroup analysis revealed a trend toward a lower risk of dementia with longer use of benzbromarone. Use of benzbromarone for ≥180 days showed a significantly lower risk of dementia (adjusted OR, 0.72; 95% CI, 0.58-0.89). Moreover, the protective effect was more pronounced in males compared with females. This cohort study reveals that gout patients taking benzbromarone are at a decreased risk of developing incident dementia, especially with longer use and in male. Further prospective trials are warranted to confirm our findings.
PubMed: 33511144
DOI: 10.3389/fmed.2020.607808 -
PloS One 2019Changes in treatment choice of therapy and size of treated population that can lead to under- or overestimate of payer's budget are less likely to be reassured after...
OBJECTIVES
Changes in treatment choice of therapy and size of treated population that can lead to under- or overestimate of payer's budget are less likely to be reassured after reimbursement adoption of a new drug. The aim of this study was to evaluate the effects of febuxostat introduction and the modifications in its insurance coverage on the utilization and expenditure of urate-lowering therapy (ULT).
METHODS
Electronic medical records for adults patients prescribed any ULT during 2010-2015 was derived from the largest medical organization in Taiwan. Aggregated estimates of ULT use and costs were assessed per 3-month and per patient per month (PPPM). Factors associated with total ULT expenditure were assessed using a time series design with factored Autoregressive Integrated Moving Average (ARIMA) models.
RESULTS
ULT prevalent users increased 34.1% from 2010 to 2015 and a 123% increase in total ULT expenditure. Numbers on allopurinol and sulfinpyrazone both declined 31%, and on benzbromarone and febuxostat gradually increased to 38.21% and 22.89% of all users in 2015. Insurance payments PPPM ($4.44 to $9.22) and total monthly ULT cost ($32,946 to $ 85,732) growth more than doubled in 6 years, trend changes generated mostly by individuals switching to febuxostat.
CONCLUSIONS
ULT use moved to favor benzbromarone and febuxostat; greater expensive uptake for febuxostat led to a rapid rise in ULT cost. Marginal values of increasing access to febuxostat for asymptomatic hyperuricemia should be focus on future studies to facilitate drug prices negotiation and ensure appropriate ULT use.
Topics: Febuxostat; Female; Health Expenditures; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Prescription Drugs; Regression Analysis; Uric Acid
PubMed: 31449565
DOI: 10.1371/journal.pone.0221504 -
ACS Omega Jun 2022Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are...
Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies.
Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.
PubMed: 35721972
DOI: 10.1021/acsomega.2c00518