Drug Target Insights最新文献

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implementing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to conduct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields-cardiovascular, cancer, and diabetes-and to further underscore the potential risks associated with the emergence of antimicrobial resistance (AMR) when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By comprehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

Immunotherapy has become an integral part of a comprehensive treatment approach to metastatic colorectal cancer (mCRC). Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that blocks the interaction between the programmed cell death 1 (PD-1) receptor and its ligands 1/2 (PD-L1/PD-L2), leading to inhibition of T-cell proliferation, cytokine secretion, and enhanced immune response. The US Food and Drug Administration (FDA) has approved this drug for use in high microsatellite instability (MSI-high)/deficiencies in mismatch repair (dMMR) advanced CRC patients. However, its efficacy is extremely limited in microsatellite stability (MSS)/mismatch repair proficient (pMMR) patients. We report a case of a 42-year-old man diagnosed with MSS/pMMR mCRC who has achieved a durable response to nivolumab after a progression under chemotherapy with antiangiogenic treatment. We observed for the first time an atypical response after 8 months of nivolumab treatment, with the regression of previous primary pulmonary lesions and the presence of new para-aortic lymph node lesions. This report demonstrates that a subset of pretreated mCRC patients with the MSS/pMMR phenotype may benefit from nivolumab and these patients need more attention.

Background: Non-compliance in the drafting of examination bulletins makes it difficult to perform them and interpret the results. With the aim of continuously improving laboratory services and guaranteeing the quality of urine cytobacteriological examination (ECBU) results, we initiated this study to evaluate non-compliance in the drafting of ECBU reports.

Materials and methods: This was a retrospective descriptive cross-sectional study which focused on non-compliance in the drafting of ECBU reports analysed in the laboratory from January to December 2022.

Results: During the study period, we collected 383 non-compliant ECBU reports out of 672, with a frequency of 56.99%. Non-compliances were related to age (2.68%), profession (24.40%), clinical information (6.70%) and residence (52.08%). The majority of non-compliant reports came from the medicine (35.51%) and urology (25.85%) departments.

Conclusion: The high frequency of non-compliance is a cause for concern and is of concern to all prescribers in this hospital.

Urinary tract infections (UTIs) are among the most common infections globally, imposing a substantial personal and economic burden on individuals and health resources. Despite international health concerns and sustained public awareness campaigns about the emergence of resistant microorganisms through the inappropriate therapeutic use of antimicrobial agents, the problem of antimicrobial resistance (AMR) is worsening, and AMR in UTIs represents a critical global healthcare issue. This narrative review summarizes evidence-based scientific material, recommendations from the current medical literature, and the latest clinical guidelines on antibiotic and antibiotic-sparing strategies for managing urological infections, including practical approaches to improve the management of patients with acute and recurrent UTIs (rUTIs) in routine clinical practice. Novel emerging therapies and prophylaxis options are described as potential alternatives to overcome the abuse and overuse of antibiotics and the practical application of the guideline recommendations and issues relating to best practice in managing UTIs.

Background: Antibiotic misuse is a major public health issue with long-term repercussions.

Objective: The purpose of this investigation was to evaluate the effects of pneumonia and diarrhea, with an emphasis on antibiotic misuse.

Methodology: This study included 410 participants (217 fathers and 193 mothers), of whom 239 purchased antibiotics for their children without a prescription, whereas 171 had a prescription or were unsure if one was required.

Results: Antibiotics were used incorrectly by 58.1% of respondents. About 51.2% of participants said they were taking two antibiotics at the same time. Around 30% of people admitted to using antibiotics inefficiently. The most prevalent reason for use was "viral and bacterial," followed by "viral," and then "bacterial," with 35%, 21%, and 20%, respectively. In addition, 22.4% of patients have used antibiotics for an unknown reason.

Conclusion: Saudi parents of children with pneumonia and diarrhea abuse antibiotics. Saudi legislation banning medications without a prescription has helped reduce antibiotic abuse, but more community-based education and awareness are needed.

Optimal treatment for metastatic non-small cell lung cancer (NSCLC) with mesenchymal epithelial transition gene (MET) exon 14 skipping mutation has not been established yet. MET inhibitors were demonstrated to be effective and tolerated in patients with this condition, while evidence on safety and efficacy of immunotherapy and/or chemotherapy in this population is limited. Here we report the case of an 86-year-old male with metastatic NSCLC harboring MET exon 14 skipping mutation and with high programmed cell death ligand 1 (PD-L1) expression (tumor proportion score ≥50%). The patient received the MET inhibitor tepotinib as first-line treatment, achieving a partial response, with G2 peripheral edema as adverse event that was successfully managed with temporary discontinuation, dose reduction, diuretics and physical therapy. After 31 months, the patient is still receiving tepotinib, with an ongoing response. Tepotinib is a valuable therapeutic option for first-line treatment of older patients with NSCLC harboring MET exon 14 skipping mutation, even in the presence of high PD-L1 expression.

Introduction: Antibiotic-resistant Pseudomonas aeruginosa strains cause considerable morbidity and mortality globally. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents against it. This study attempted to identify small-molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in P. aeruginosa. 'Las' system can be said to be the 'master' regulator of quorum sensing in P. aeruginosa, whose receptor protein is LasR. Similarly, NOR is crucial to detoxification of reactive nitrogen species.

Methods: In silico identification of potential LasR or NOR inhibitors was attempted through a virtual screening platform AtomNet® to obtain a final subset of <100 top scoring compounds. These compounds were evaluated for their in vivo anti-pathogenic activity by challenging the model host Caenorhabditis elegans with P. aeruginosa in the presence or absence of test compounds. Survival of the worm population in 24-well assay plates was monitored over a period of 5 days microscopically.

Results: Of the 96 predicted LasR inhibitors, 11 exhibited anti-Pseudomonas activity (23%-96% inhibition of bacterial virulence as per third-day end-point) at 25-50 µg/mL. Of the 85 predicted NOR inhibitors, 8 exhibited anti-Pseudomonas activity (40%-85% inhibition of bacterial virulence as per second-day end-point) at 25-50 µg/mL.

Conclusion: Further investigation on molecular mode of action of compounds found active in this study is warranted. Virtual screening can be said to be a useful tool in narrowing down the list of compounds requiring actual wet-lab screening, saving considerable time and efforts for drug discovery.

Background: Antimicrobial resistance (AMR) is a global health concern, with extended-spectrum β-lactamases (ESBLs) and carbapenemases being major contributors. Pleural infection (PI) is a severe condition in West Africa, complicated by AMR. This study aimed to investigate the prevalence and molecular characteristics of ESBL and carbapenemase-producing enterobacteria in pleural effusions in Mali.

Materials and methods: Pleural fluid samples from 526 patients with pleuritis were analyzed. Enterobacterial species were isolated and identified, and the prevalence of resistance genes (bla_OXA-48, bla_NDM-1, bla_KPC, bla_TEM, bla_SHV) and virulence factors was determined.

Results: Among the patients, 110 were diagnosed with enterobacterial pleuritis. Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were the main pathogens identified. Resistance to β-lactams and cephalosporins was high, while carbapenems showed good activity. ESBL production was detected in 33.6% of isolates, with bla_TEM being the most common gene. Carbapenemase gene (bla_NDM-1) was found in three isolates.

Conclusion: The study highlights the high prevalence of multidrug-resistant bacteria and the need for appropriate antibiotic selection based on local resistance patterns. Understanding the molecular characteristics of resistance is crucial for optimizing patient care and developing effective therapeutic strategies. Further research is needed to monitor and control AMR in PIs in Mali.