Frontiers in Pharmacology最新文献

Snakebite is a major public health concern in many parts of the world, including India, where over 58,000 deaths occur annually due to snake envenoming. The common krait (Bungarus caeruleus) is responsible for the second-highest number of snakebite-related mortalities in the country. However, despite its notoriety, little is known about its venom ecology, functions and compositional variation across bioclimatic zones, partly because these nocturnal snakes are highly elusive, making it difficult to find them in the wild. We aim to address this knowledge gap by characterising the venom composition and toxicity profiles of the pan-Indian populations (n = 8) of B. caeruleus using a combination of proteomics, receptor-toxin interaction assays, biochemical experiments, pharmacological tests and preclinical evaluations. We reveal considerable variation in venom composition, functions, and pharmacological activities among the geographically distinct populations of B. caeruleus. Furthermore, toxin-receptor interaction assays provide insights into their feeding ecology and prey-predator interactions. Finally, in vitro and in vivo experiments revealed the poor neutralising potencies of Indian antivenoms towards most populations of the common krait. Our findings highlight the alarming need to develop efficacious snakebite therapy in India to treat bites from this medically most important elapid snake.

Voriconazole, a broad-spectrum antifungal agent, is considered the first-line treatment for invasive aspergillosis. In this article, we report three cases of patients who experienced visual disturbances and hallucinations following voriconazole therapy for invasive pulmonary aspergillosis. These symptoms appeared within 1 week after initiating voriconazole administration and resolved upon discontinuation or dose reduction of the drug. Considering the absence of any identifiable alternative cause and the temporal relationship with voriconazole initiation, these symptoms were attributed to the adverse effects of voriconazole. All three patients had trough concentrations exceeding 5 μg/mL at the time of adverse reactions, leading to subsequent therapeutic drug monitoring and dose adjustment. The clinical characteristics and management strategies of voriconazole-induced hallucinations and/or visual disturbances have been rarely reported previously. Therefore, our study reviewed and analyzed relevant case reports since 2014. This study highlights the importance of recognizing the potential risk of hallucinations and visual disturbances associated with voriconazole. Furthermore, our findings indicate that the route of voriconazole administration does not influence the frequency of these adverse events. Additionally, special attention should be given to monitoring adverse events related to voriconazole in Asian populations due to their higher prevalence of CYP2C19 poor metabolizers. In the event of adverse reactions to voriconazole, diligent monitoring of therapeutic drug levels and dosage adjustments is crucial. These clinical characteristics and management strategies offer advantages in terms of enhancing drug efficacy, ensuring treatment continuity, and minimizing the incidence of other severe adverse reactions.

Background: This study analyzed the FDA's Adverse Event Reporting System (FAERS) data to investigate the correlation between oral bisphosphonates (BPs) and oesophageal adverse events (AEs).

Methods: We systematically extracted data on adverse reactions to oral alendronate, risedronate, and ibandronate from the FAERS database, covering the period from the 2004 Q1 to the 2023 Q4. The role_code of AEs mainly includes primary suspect (PS), secondary suspect (SS), concomitant (C), and interaction (I). This study targeted reports with a role_code of "PS." According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is selected when the CASEID and FDA_DT are the same. Our analysis leveraged four statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS), to assess the relationship between oral bisphosphonates and oesophageal AEs. The Kaplan-Meier method was utilized to evaluate the cumulative incidence of oesophageal toxicity, while the log-rank test examined the temporal onset profiles of these toxicities. Additionally, the Pearson chi-squared test was employed to identify any significant differences in mortality and hospitalization rates associated with the oesophageal AEs caused by these medications.

Results: The FAERS database had 41,590 AE reports for oral BPs, with 3,497 (8.41%) related to oesophageal AEs. Our findings indicate that oral BPs are disproportionately associated with an increased incidence of gastrointestinal system AEs at the system organ class (SOC) level. The adverse events identified at the preferred terms (PTs) level encompassed conditions such as gastroesophageal reflux disease, oesophagitis, and oesophageal pain. A significant divergence in the cumulative incidence of oesophageal AEs was observed among patients treated with the three different oral bisphosphonates, as confirmed by the log-rank test (p < 0.0001). Hospitalization rates varied significantly among patients receiving different BPs (p < 0.05), but no significant difference in mortality rates was found.

Conclusion: The study establishes a significant link between oral BPs and oesophageal toxicity, highlighting the need for further research into the mechanisms of BP-induced oesophageal toxicity and potential preventive measures.

Introduction: With the onset of the COVID-19 pandemic, the incidence and prevalence of acute pharyngitis (AP) have increased significantly. Tinosporae Radix (TR) is a vital medication utilized in the treatment of pharyngeal and laryngeal ailments, especially AP. The study endeavors to explore unclear molecular mechanisms of TR in addressing AP.

Methods: Network pharmacology and metabolomics analyses of effect of TR on AP were conducted, and apossible pathway was validated both in vivo using the acute pharyngitis rat model and in vitro using the LPS-induced RAW264.7 cells model, through techniques such as histopathological examinations, immunohistochemical technology, ELISA, RT-qPCR, and Western blotting to systematically explore the possible mechanisms underlying the inhibition of AP by TR.

Results and discussion: Network pharmacology analysis identified several key targets, including PIK3CA, IL6, AKT1, TNF, and PTGS2, alongside pivotal signaling pathways such as IL-17, TNF, Hepatitis B, nuclear factor kappa B (NF-κB), Influenza A, and the PI3K-Akt pathway. Most of them are closely associated with inflammation. Then, wide-target metabolomics analysis showed that TR downregulated substances within the glycerophospholipid metabolic pathway, and modulated the PI3K-Akt pathway. The integrated findings from network pharmacology and metabolomics underscored the pivotal role of the PI3K-Akt signaling pathway and the attenuation of inflammatory responses. Finally, in vitro and in vivo experiments have shown that TR can inhibit inflammatory factors such as IL-6, TNF - α, and COX-2, downregulate targets such as PI3K and AKT on the PI3K-Akt signaling pathway, and thereby alleviate the inflammatory response of AP. Our study demonstrated that TR exerts an anti-AP effect through suppression of release of inflammatory factors and modulation of glycerophospholipid metabolism via suppressing the PI3K-Akt signaling pathway.

[This corrects the article DOI: 10.3389/fphar.2024.1459408.].

Drug-related problems (DRPs) are prevalent in critically ill patients and may significantly increase mortality risks. The participation of critical care pharmacists (CCPs) in the medical team has demonstrated a benefit to healthcare quality. Research indicates that CCP medication order evaluations can reduce DRPs, while their participation in rounds can reduce adverse drug events and shorten hospital stays. Pharmacist medication reconciliation often proves more effective than physicians, and CCPs play a crucial role in antimicrobial management and reducing treatment costs. Despite these benefits, there is a noticeable lack of practical guidance for implementing CCP roles effectively. Their workflow heavily influences the efficiency of CCPs. Integrating results from the literature with our practical experience, we have detailed workflows and critical entry points that CCPs can refer to. Pharmacists should be proactive rather than passive consultants. Pre-round medication order evaluations are crucial for determining the depth of a pharmacist's involvement in patient care. These evaluations should cover the following aspects: medication indication, dosage, treatment duration, detection of DRPs, implementation of therapeutic drug monitoring, dosing of sedatives and analgesics, and pharmaceutical cost containment. Beyond identifying medication issues, a primary task during rounds is gathering additional information and building trust with the medical team. Post-round responsibilities for CCPs include patient and caregiver education on medication, medication reconciliation for transitioning patients, and follow-up care for post-ICU patients. Establishing a rationalized and standardized workflow is essential to minimize daily work omissions and maximize the pharmacist's value. A multidisciplinary pharmacist-led team can significantly promote the rational use of antibiotics. Participation in post-ICU outpatient follow-ups can reduce drug-induced injuries after discharge. This review provides a detailed overview of the tasks performed by CCPs before, during, and after medical rounds, serving as a valuable reference for establishing an efficient workflow for CCPs.

Objectives: Literature data are scarce on concurrent chemoradiotherapy (CCRT) with S-1 for locally advanced nasopharyngeal carcinoma (LANPC) treatment. This study compared the efficacy and safety of the S-1 versus platinum-based CCRT in LANPC treatment. Methods: This study enrolled 547 patients newly diagnosed with LANPC who underwent CCRT with S-1 or platinum at three institutions. Propensity score matching in a 1:1 ratio balancing baseline features was performed. Survival and adverse effects were compared between groups.

Results: Of 160 patients in the cohort, 100 eligible were propensity score matched. Matched dataset analyses showed a higher 5-year overall survival rate (87.1% vs. 84.7%, P = 0.833), progression-free survival (79.6% vs. 75.5%, P = 0.669), locoregional recurrence-free survival (87.0% vs. 84.7%, P = 0.518), and distant metastasis-free survival (84.8% vs. 83.0%, P = 0.780) in the S-1 group than in the platinum-based CCRT group, although not statistically significant. Objective response rate (98.0% vs. 88.0%, P = 0.117) was significantly higher in the S-1 than in the platinum-based regimen, although it was not statistically reflected. Compared with platinum-based, those undergoing S-1-based chemotherapy demonstrated a higher incidence of grade 3 mucositis (20.0% vs. 2.0%, P = 0.016) in the S-1 group and a lower incidence of leukopenia (44.0% vs. 68.0%, P = 0.033), neutropenia (28.0% vs. 52.0%, P = 0.032), anemia (22.0% vs. 44.0%, P = 0.040), nephrotoxicity (4.0% vs. 20.0%, P = 0.028), and nausea/vomiting (30.0% vs. 56.0%, P = 0.019).

Conclusion: The results suggest that S-1 can be used as a concurrent chemotherapy regimen during radiotherapy for patients with LANPC, since it presents a noninferior survival benefit compared with platinum and shows tolerable adverse effects.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation.

Methods: The recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio K_p,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. K_p,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites.

Results: Based on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., K_p,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001).

Discussion: In the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX.

Background: Postmenopausal osteoporosis (PMOP) is a serious condition that affects elderly individuals. Our previous study revealed that Yigu decoction (YGD) effectively improved bone mineral density (BMD) in elderly individuals, but the mechanism underlying this effect remains unclear. In this study, we investigated the relationships among YGD, microRNAs (miRNAs), and bone metabolism by assessing the effects of YGD on the miRNA levels in patient plasma to provide a scientific basis for treating PMOP with YGD.

Methods: In this clinical trial, 60 patients were randomly assigned to the YGD group or the control group (ratio of 1:1) and treated for 3 months. The primary outcome measure was BMD, and the secondary outcome measures included plasma miRNA levels, visual analogue scale (VAS) scores, alkaline phosphatase (ALP) levels, anti-tartrate acid phosphatase (TRACP-5b) levels and traditional Chinese medicine (TCM) syndrome scores. We assessed the regulatory roles of miRNAs in PMOP patients by analysing publicly available data from the Gene Expression Omnibus (GEO) database. Bioinformatics methods were also used to explore the mechanism by which YGD regulates miRNAs that are involved in bone metabolism.

Results: Compared with those before treatment, the BMD, ALP levels, TRACP-5b levels, TCM syndrome scores and VAS scores improved in both groups after 3 months of treatment (P < 0.05). A total of 82 miRNAs differed between the groups. After analysing data from the GEO database, we confirmed that miR-133a-3p is the key molecule that mediates the effects of YGD intervention on PMOP. GO analysis of key genes suggested that gene enrichment was more pronounced in response to hormones, cellular response to growth factor stimulation, and positive regulation of physiological and metabolic processes. KEGG analysis revealed that these genes were enriched mainly in the PI3K-Akt, FOXO, and JAK-STAT pathways and other pathways. The results of the protein‒protein interaction (PPI) network analysis revealed that epidermal growth factor receptor (EGFR), Insulin-like growth factor 1 (IGF-1), Caveolin-1 (Cav-1) and others were core proteins.

Conclusion: This study demonstrated that YGD is beneficial in the treatment of PMOP, ameliorating clinical symptoms and bone turnover indices. Moreover, the inhibition of miR-133a-3p expression may be the key mechanisms by which YGD regulates bone metabolism in the treatment of PMOP, although YGD regulates bone metabolism in a multitarget and multipathway manner.

The kidney plays a crucial role in maintaining the body's microenvironment homeostasis. However, current treatment options and therapeutic agents for chronic kidney disease (CKD) are limited. Fortunately, the advent of kidney organoids has introduced a novel in vitro model for studying kidney diseases and drug screening. Despite significant efforts has been leveraged to mimic the spatial-temporal dynamics of fetal renal development in various types of kidney organoids, there is still a discrepancy in cell types and maturity compared to native kidney tissue. The extracellular matrix (ECM) plays a crucial role in regulating cellular signaling, which ultimately affects cell fate decision. As a result, ECM can refine the microenvironment of organoids, promoting their efficient differentiation and maturation. This review examines the existing techniques for culturing kidney organoids, evaluates the strengths and weaknesses of various types of kidney organoids, and assesses the advancements and limitations associated with the utilization of the ECM in kidney organoid culture. Additionally, it presents a discussion on constructing specific physiological and pathological microenvironments using decellularized extracellular matrix during certain developmental stages or disease occurrences, aiding the development of kidney organoids and disease models.