-
RMD Open May 2024To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs.
OBJECTIVE
To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting.
METHODS
Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression.
RESULTS
A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients.
CONCLUSION
Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.
Topics: Humans; Purines; Sulfonamides; Arthritis, Rheumatoid; Pyrazoles; Azetidines; Male; Female; Middle Aged; Antirheumatic Agents; Aged; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Treatment Failure; Adult; Patient Reported Outcome Measures; Severity of Illness Index
PubMed: 38816210
DOI: 10.1136/rmdopen-2024-004291 -
Frontiers in Microbiology 2024The spread of antimicrobial resistance (AMR) in animal husbandry is usually attributed to the use of antibiotics and poor hygiene and biosecurity. We therefore conducted...
The spread of antimicrobial resistance (AMR) in animal husbandry is usually attributed to the use of antibiotics and poor hygiene and biosecurity. We therefore conducted experimental trials to improve hygiene management in weaned pig houses and assessed the impact on the spread. For each of the two groups examined, the experimental group (EG) and the control group (CG), three replicate batches of piglets from the same pig breeder, kept in pre-cleaned flat decks, were analyzed. In the flat decks of the experimental groups, the hygiene conditions (cleaning, disinfection, dust removal and fly control) were improved, while regular hygiene measures were carried out in the control groups. The occurrence and spread of AMR were determined in (; resistance indicator) using cultivation-dependent (CFU) and -independent (qPCR) methods as well as whole genome sequencing of isolates in samples of various origins, including feces, flies, feed, dust and swabs. Surprisingly, there were no significant differences ( > 0.05) in the prevalence of resistant between the flat decks managed with conventional techniques and those managed with improved techniques. Selective cultivation delivered ampicillin- and sulfonamide-resistant proportions of up to 100% and 1.2%, respectively. While 0.5% resistant to cefotaxime and no ciprofloxacin resistance were detected. There was a significant difference ( < 0.01) in the abundance of the gene in fecal samples between EG and CG groups. The colonization of piglets with resistant pathogens before arrival, the movement of flies in the barn and the treatment of bacterial infections with antibiotics obscured the effects of hygiene improvement. Biocide tolerance tests showed no development of resistance to the farm regular disinfectant. Managing hygiene alone was insufficient for reducing antimicrobial resistances in piglet rearing. We conclude that the complex factors contributing to the presence and distribution of AMR in piglet barns underscore the necessity for a comprehensive management strategy.
PubMed: 38812683
DOI: 10.3389/fmicb.2024.1393923 -
Frontiers in Immunology 2024Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment...
characterization of acute myeloid leukemia patients undergoing hypomethylating agents and venetoclax regimen reveals a venetoclax-specific effect on non-suppressive regulatory T cells and PD-1TIM3 exhausted CD8 T cells.
Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment response. The therapies available for AML can affect lymphocyte function, limiting the efficacy of immunotherapy while hindering leukemia-specific immune reactions. Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. To better understand the immunological effect of VEN treatment, we characterized the phenotype and immune checkpoint (IC) receptors' expression on CD4 and CD8 T cells from AML patients after the first and second cycle of HMA in combination with VEN. HMA and VEN treatment significantly increased the percentage of naïve CD8 T cells and TIM-3 CD4 and CD8 T cells and reduced cytokine-secreting non-suppressive T regulatory cells (Tregs). Of note, a comparison between AML patients treated with HMA only and HMA in combination with VEN revealed the specific contribution of VEN in modulating the immune cell repertoire. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8 T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4 and CD8 T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients.
Topics: Humans; Leukemia, Myeloid, Acute; Sulfonamides; CD8-Positive T-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hepatitis A Virus Cellular Receptor 2; Programmed Cell Death 1 Receptor; Middle Aged; Aged; T-Lymphocytes, Regulatory; Female; Male; Antineoplastic Combined Chemotherapy Protocols; Adult; Aged, 80 and over
PubMed: 38812504
DOI: 10.3389/fimmu.2024.1386517 -
Indian Journal of Pharmacology Mar 2024Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and...
Off-target effect of high-dose sildenafil on adenosine 5'- diphosphate and collagen-induced platelet activation through mitogen-activated protein kinase pathway in treated BALB/C mice and in vitro experiments: A preliminary study.
Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and sudden cardiac death in a few case reports. Therefore, we investigated the in vitro and in vivo effect of sildenafil treatment and dosage on platelet activation and mitogen-activated protein kinase (MAPK) phosphorylation. BALB/C mice were segregated into four groups, each having four mice each (control, low [3.25 mg/kg], medium [6.5 mg/kg], and high [13 mg/kg] sildenafil), and after the treatment, blood was drawn from each mouse and washed platelets prepared. Washed platelets were incubated with CD41 PE-Cy7 and Phospho-p38 MAPK PE antibodies and analyzed using a flow cytometer for platelet activation and adenosine 5'- diphosphate (ADP)/collagen-induced MAPK phosphorylation. Washed platelets obtained from the venous blood of 18 human volunteers, were incubated with PAC-1 FITC and Phospho-p38 MAPK PE antibodies, and platelet activation (ADP and collagen), followed by flow cytometry analysis. There was a significant increase in both platelet activation as well as MAPK phosphorylation in the presence of collagen in the high-dose (13 mg/kg) sildenafil group (P = 0.000774). Further, increased platelet activation was observed in samples that were treated with high-dose sildenafil as compared to the untreated samples (P < 0.00001). These studies show the risk of prothrombotic episodes in patients on high-dose sildenafil (100 mg), in those with even mild endothelial dysfunction due to ADP, and collagen-induced platelet activation through MAPK phosphorylation, which was not seen in the low-and intermediate-dose cohorts.
Topics: Animals; Sildenafil Citrate; Platelet Activation; Mice, Inbred BALB C; Male; Humans; Collagen; Mice; Adenosine Diphosphate; Blood Platelets; Phosphorylation; Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Phosphodiesterase 5 Inhibitors; Dose-Response Relationship, Drug; Adult
PubMed: 38808925
DOI: 10.4103/ijp.ijp_312_23 -
World Journal of Urology May 2024To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center... (Comparative Study)
Comparative Study
BACKGROUND
To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center experience switching from ciprofloxacin to fosfomycin trometamol (FMT) alone and to an augmented prophylaxis combining fosfomycin and trimethoprim/sulfamethoxazole (TMP/SMX).
METHODS
Between 01/2019 and 12/2020 we compared three different regimes. The primary endpoint was the clinical diagnosis of an infection within 4 weeks after biopsy. We enrolled 822 men, 398 (48%) of whom received ciprofloxacin (group-C), 136 (16.5%) received FMT (group-F) and 288 (35%) received the combination of TMP/SMX and FMT (group-BF).
RESULTS
Baseline characteristics were similar between groups. In total 37/398 (5%) postinterventional infections were detected, of which 13/398 (3%) vs 18/136 (13.2%) vs 6/288 (2.1%) were detected in group-C, group-F and group-BF respectively. The relative risk of infectious complication was 1.3 (CI 0.7-2.6) for group-C vs. group-BF and 2.8 (CI 1.4-5.7) for group-F vs. group-BF respectively.
CONCLUSION
The replacement of ciprofloxacin by fosfomycin alone resulted in a significant increase of postinterventional infections, while the combination of FMT and TMP/SMX had a comparable infection rate to FQ without apparent adverse events. Therefore, this combined regimen of FMT and TMP/SMX is recommended.
Topics: Humans; Male; Fosfomycin; Ciprofloxacin; Trimethoprim, Sulfamethoxazole Drug Combination; Antibiotic Prophylaxis; Aged; Middle Aged; Prostate; Anti-Bacterial Agents; Drug Therapy, Combination; Biopsy; Retrospective Studies; Rectum; Postoperative Complications
PubMed: 38806739
DOI: 10.1007/s00345-024-05048-4 -
Scientific Reports May 2024This article explores the structural properties of eleven distinct chemical graphs that represent sulfonamide drugs using topological indices by developing python...
This article explores the structural properties of eleven distinct chemical graphs that represent sulfonamide drugs using topological indices by developing python algorithm. To find significant relationships between the topological characteristics of these networks and the characteristics of the associated sulfonamide drugs. We use quantitative structure-property relationship (QSPR) approaches. In order to model and forecast these correlations and provide insights into the structure-activity relationships that are essential for drug design and optimization, linear regression is a vital tool. A thorough framework for comprehending the molecular characteristics and behavior of sulfonamide drugs is provided by the combination of topological indices, graph theory and statistical models which advances the field of pharmaceutical research and development.
Topics: Sulfonamides; Algorithms; Quantitative Structure-Activity Relationship; Models, Theoretical; Drug Design
PubMed: 38806587
DOI: 10.1038/s41598-024-62819-0 -
Current Research in Toxicology 2024Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and...
Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of () as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC:EC = 1:1) and non-equitoxic ratios (EC:EC = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure-activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy () between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.
PubMed: 38803613
DOI: 10.1016/j.crtox.2024.100172 -
Diabetes & Metabolism Journal May 2024
Topics: Humans; Rosuvastatin Calcium; Diabetes Mellitus, Type 2; Ezetimibe; Anticholesteremic Agents; Drug Therapy, Combination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Blood Glucose; Azetidines; Sulfonamides; Pyrimidines
PubMed: 38802118
DOI: 10.4093/dmj.2024.0168 -
Frontiers in Chemistry 2024A novel series of dihydropyrimidine/sulphonamide hybrids with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. assay,...
A novel series of dihydropyrimidine/sulphonamide hybrids with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. assay, results showed that compounds , , , and were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound was the most potent dual inhibitor with IC values of 0.92 µM and 1.98 µM, respectively. anti-inflammatory studies demonstrated that compounds , , and had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds and were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds and significantly reduced the levels of pro-inflammatory cytokines (PGE, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.
PubMed: 38800576
DOI: 10.3389/fchem.2024.1387923 -
Narra J Apr 2024Second-degree burn, the most common among burn degrees, underscores the importance of timely and proper treatment in influencing prognosis. Nutmeg (), renowned for its...
Second-degree burn, the most common among burn degrees, underscores the importance of timely and proper treatment in influencing prognosis. Nutmeg (), renowned for its potent antibacterial and antifungal properties, also serves as an effective antiseptic for open wounds. The aim of this study was to identify the phytochemical constituents of nutmeg essential oil and analyze the wound healing effect of nutmeg cream on second-degree burns in an animal model. An experimental study with a completed randomized design was conducted on strain Wistar rats with second-degree burn. This study had four groups and each group consisting of four rats: B (burn-treated base cream), B+N (burn-treated 3% nutmeg cream), B+SSD (burn-treated silver sulfadiazine (BSS)), and B+N+SSD (burn-treated 3% nutmeg cream and SSD in a 1:1 ratio). The phytochemical analysis of nutmeg essential oil was conducted by gas chromatography and mass spectroscopy (GC-MS). The burn diameter and burn wound healing percentage were measured from day 0 to 18. One-way ANOVA followed by post hoc analysis using the least significant difference (LSD) was employed to analysis the effect. The phytochemical analysis of nutmeg essential oil found that myristicin, terpinene-4-ol, terpinene, safrole and terpinolene were the most abundant putative compounds in nutmeg essential oil. On day 0, the average burn wound diameters were 1.4 cm in all groups and increases were observed in all groups on day 3. The wound diameter decreased until day 18 with the smallest burn wound diameter was found in the B+N group (0.86±0.37 cm), followed by B+SSD (0.93±0.29 cm). The B+SSD group exhibited the highest percentage of burn wound healing (56.80±14.05%), which was significantly different from the base cream (<0.05). The percentage of burn wound healing in rats given 3% nutmeg cream was 41.88±13.81%, suggesting that nutmeg cream could promote burn wound healing in rats induced by second-degree burns.
Topics: Animals; Myristica; Wound Healing; Burns; Rats, Wistar; Rats; Disease Models, Animal; Oils, Volatile; Skin Cream; Male; Gas Chromatography-Mass Spectrometry; Anti-Infective Agents, Local; Silver Sulfadiazine
PubMed: 38798873
DOI: 10.52225/narra.v4i1.621