The objective of this study is to determine the magnitude and clinical relevance of a potential drug-drug interaction of GSK3882347 with midazolam (MDZ) in healthy participants. This study assesses the effect of GSK3882347 as an inducer of Cytochrome P450 3A4 (CYP3A4) using MDZ, a sensitive substrate of hepatic and intestinal CYP3A4. The study will investigate MDZ pharmacokinetic (PK) effect in two dosing periods:
Period 1: A single dose of MDZ Period 2: 14-days of once daily repeat dosing of GSK3882347 followed by single dose of MDZ co-administered with GSK3882347 on Day 15 (14-days has been selected as this duration is required in order to maximize any potential CYP3A4 enzyme induction).

开始日期2023-04-11

申办/合作机构

GSK Plc

NCT05138822 / Recruiting临床1期

A Double-Blind, Double Dummy, Randomized, Phase 1b, Nitrofurantoin Controlled, Repeat Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Microbiological Response of GSK3882347 in Female Participants With Acute Uncomplicated Urinary Tract Infection

This phase 1b study is a double-blind, double-dummy, nitrofurantoin-controlled study designed to evaluate microbiological response at the test of cure (ToC) visit along with safety, tolerability and pharmacokinetic (PK) response following daily oral dosing for 5 days of GSK3882347 in an adult female with uncomplicated urinary tract infections (uUTI). Comparator nitrofurantoin will be included in the study to ensure unbiased reporting of safety events. The study will be separated into 2 cohorts. Cohort 1 consists of an inpatient treatment period and PK analysis at frequent timepoints. Cohort 2 includes an outpatient treatment period and PK analysis conducted less frequently, at key trough timepoints.

开始日期2022-05-18

申办/合作机构

GSK Plc

NCT04488770 / Completed临床1期

A Double-Blind Randomized, Placebo-Controlled, Single and Repeated Oral Dose Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics (Including Food Effect) of GSK3882347 in Healthy Participants

This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, first time in human (FTIH) study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetics (PK) of GSK3882347 in healthy adult men and Woman of Non Childbearing Potential (WONCBP). Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each participant in the SAD cohort will receive a single dose of GSK3882347 or placebo (PBO) in 3:1 ratio and in Part 2 (MAD), participants will be randomized in a 4:1 ratio to receive active treatment and placebo. Part 1 will consist of two cohorts with a maximum of four-period for each cohort, the food effect evaluation will be conducted in last period (Period 4) in only one of the cohorts based on the observed human pharmacokinetics (PK). Part 2 will consist of maximum of four cohorts for each of the MAD dose or placebo.

开始日期2020-08-24

申办/合作机构

GSK Plc

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100 项与 fimH蛋白相关的临床结果

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100 项与 fimH蛋白相关的转化医学

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0 项与 fimH蛋白相关的专利（医药）

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项与 fimH蛋白相关的文献（医药）

2024-08-01·Food Microbiology

It takes two to attach - endo-1,3-β-d-glucanase as a potential receptor of mannose-independent, FimH-dependent Salmonella Typhimurium binding to spinach leaves

Article

作者: Dutkiewicz, Agata ; Klasa, Beata ; Grzymajlo, Krzysztof ; Czajkowska, Joanna ; Aleksandrowicz, Adrianna ; Waszczuk, Wiktoria ; Carolak, Ewa

Currently, fresh, unprocessed food has become a relevant element of the chain of transmission of enteropathogenic infections. To survive on a plant surface and further spread the infections, pathogens like Salmonella have to attach stably to the leaf surface. Adhesion, driven by various virulence factors, including the most abundant fim operon encoding type 1 fimbriae, is usually an initial step of infection, preventing physical removal of the pathogen. Adhesion properties of Salmonella's type 1 fimbriae and its FimH adhesin were investigated intensively in the past. However, there is a lack of knowledge regarding its role in interaction with plant cells. Understanding the mechanisms and structures involved in such interaction may facilitate efforts to decrease the risk of contamination and increase fresh food safety. Here, we applied Salmonella genome site-directed mutagenesis, adhesion assays, protein-protein interactions, and biophysics methods based on surface plasmon resonance to unravel the role of FimH adhesin in interaction with spinach leaves. We show that FimH is at least partially responsible for Salmonella binding to spinach leaves, and this interaction occurs in a mannose-independent manner. Importantly, we identified a potential FimH receptor as endo-1,3-β-d-Glucanase and found that this interaction is strong and specific, with a dissociation constant in the nanomolar range. This research advances our comprehension of Salmonella's interactions with plant surfaces, offering insights that can aid in minimizing contamination risks and improving the safety of fresh, unprocessed foods.

2023-10-01·Journal of pediatric urology

Effect of thymol on antimicrobial susceptibility, and adhesion genes expression of uropathogenic Escherichia coli isolated from pediatric urinary tract infection.

Article

作者: Sedighi, Iraj ; Moradi, Abbas ; Goodarzi, Rezvan ; Taheri, Mohammad ; Yousefimashouf, Rasoul

BACKGROUNDUropathogenic Escherichia coli (UPEC) is a common cause of urinary tract infections (UTI) in children and currently is one of the leading medical problems. Due to the increase in antibiotic resistance rate, herbal medicines with lower side effects were considered.OBJECTIVEThis study aimed to identify the afa, fimH, and sfa genes of UPEC bacteria isolated from pediatric UTI to investigate the effect of the thyme on the expression of fimH gene.STUDY DESIGNIn this cross-sectional study, 160 UPEC were isolated from pediatric UTIs. An antibiotic susceptibility test was performed on six families of antibiotics, including beta-lactams, quinolones, aminoglycosides, carbapenems, sulfonamides, and nitrofurantoin. The micro-broth dilution method was used to determine MIC of thymol. The biofilm production ability of isolated strains was quantified by the microtiter plate method. The PCR technique was used to detectfimH, afa, and sfa adhesion genes, and real-time PCR was used to measure the fimHgene expression.RESULTSThe results of the antibiogram showed that the lowest and highest resistance related to meropenem and imipenem (zero), and 72.5% for cephalothin. MIC showed 80.7% of the isolates were sensitive to thymol. The biofilm production results showed that 3.12%, 53.75%, and 43.12% of the isolates were strong, weak, and no-biofilm (Zero) producers, respectively. After thymol treatment, 26.25% and 73.75% of isolates were weak and no-producer (Zero) biofilms, respectively and there was a significant correlation (P-value = 0.042) compared to the control group. The frequency of fimH, sfa, and afa genes was 53.1%, 49.4%, and 29.4%, respectively. The expression of fimHgene after 48 h thymol treatment decreased significantly (P-value< 0.05).CONCLUSIONDue to the significant effects of thymol in preventing the expression of the adhesion gene (fimH) of UPEC bacteria, our study is a proof-of-concept study evaluating bacterial sensitivity to Thymol and its effect on biofilm production in vitro. Given the demonstrated promising results of Thymol's effectiveness and the increase in bacterial antibiotic resistance, further studies should be undertaken to determine the safety and effectiveness of Thymol use in the clinical treatment of urinary tract infection. We believe that Thymol may prove to be an effective adjunct to the treatment of bacterial urinary tract infections.

2023-06-13·Journal of Biomolecular Structure and Dynamics

Elucidating novel antibacterial compounds from the NPASS database against the FimH lectin domain for the treatment of urinary tract infections: an in-silico study

Article

作者: Al-Zrkani, Mrtatha K. ; Al-Fahad, Dhurgham ; Abdulkareem, Rafid A. ; Al-Khdhairawi, Ahmad ; Nasr, Amaal Mohammed Salih ; Al Shouber, Marwah

The increase in multidrug-resistant pathogens in urinary tract infections (UTIs) among communities and hospitals threatens our ability to treat these common pathogens. Uropathogenic Escherichia coli (UPEC) strains are the most frequent uropathies linked to the development of UTIs. This work aims to introduce bioactive natural products via virtual screening of small molecules from a public database to prevent biofilm formation by inhibiting FimH, a type 1 fimbriae that plays a crucial role in UPEC pathogenicity. A total of 30926 small molecules from the NPASS database were subjected to screening via molecular docking. Followed by performing in silico ADME studies, seven molecules showed promising docking results ranging from -6.8 to -8.7 kcal/mol. As a result of the docking score findings, 100 ns Molecular dynamics (MD) simulations were performed. Based on MM-PBSA analysis, NPC313334 ligand showed high binding affinity -42 and stability with the binding pocket of FimH protein during molecular dynamic simulations. DFT calculations were also performed on the ligands to calculate the HOMO-LUMO energies of the compounds in order to an idea about their structure and reactivity. This research suggests that NPC313334 may be a possible antibacterial drug candidate that targets FimH to reduce the number of UPEC-related urinary tract infections.Communicated by Ramaswamy H. Sarma.

项与 fimH蛋白相关的新闻（医药）

2023-05-11

·Firstwordpharma

Takeda guides for fall in annual sales, profit on headwinds from generics

Headline results for the fourth fiscal quarter: Revenue: JPY 956.2 billion ($7.1 billion), up 9.5% Profit: JPY 31.1 billion ($231 million), versus a loss of JPY 11.4 billionNote: All changes are versus the prior-year period unless otherwise statedWhat the company said:Chief financial officer Costa Saroukos noted that "our top-line and profit performance was driven by our growth and launch products, which grew 19% at constant exchange rate." Saroukos added "I'm pleased to report that Takeda delivered or exceeded management guidance in FY2022 and booked a record core operating profit of almost JPY 1.2 trillion."Other results: Gastroenterology product sales: JPY 237 billion, up 12.9% Entyvio: JPY 154.9 billion, up 22.5% Takecab/Vocinti: JPY 24.2 billion, up 0.6% Rare diseases product sales: JPY 169.8 billion, up 14.5% Rare haematology product sales: JPY 72.1 billion, flat versus the prior year Advate: JPY 26.1 billion, down 10.6% Rare genetics product sales: JPY 97.8 billion, up 28.3% Takhzyro: JPY 34.9 billion, up 40.7% Plasma-derived therapy/immunology sales: JPY 176 billion, up 22.5% Neuroscience product sales: JPY 160.6 billion, up 34.2% Vyvanse/Elvanse: JPY 123.8 billion, up 50.9% Trintellix: JPY 20.4 billion, up 5.7% Oncology product sales: JPY 93.8 billion, down 14.5% Ninlaro: JPY 16.8 billion, down 18.1% Adcetris: JPY 18.2 billion, up 4.3% Velcade: JPY 3 billion, down 88.2% Full-year revenue: JPY 4 trillion, up 12.8% Full-year profit: JPY 317 billion, up 37.8%Looking ahead:CEO Christophe Weber said "while we expect to face temporary headwinds in FY2023 from generic entrants and lower demand for coronavirus vaccines, we are confident that strong momentum in our growth and launch products will drive a return to growth in the near-term."Takeda expects sales in fiscal year 2023 of JPY 3.8 trillion ($28.2 billion), representing a 4.7% decline versus the prior 12-month period, with revenue from Entyvio jumping 15% to JPY 788 billion ($5.8 billion). Meanwhile, operating profit is forecast to fall 28.8% to JPY 349 billion ($2.6 billion).($1 = JPY 134.730)

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