Clinical Pharmacology : Advances and Applications最新文献

Opioid-induced respiratory depression (OIRD) and sedation are significant perioperative complications that limit safe and effective use of opioid analgesia. Current reversal agents, such as naloxone, are effective at treating OIRD but may negatively affect pain management, leaving a critical clinical gap in perioperative pain management. The orexin system has a pivotal role in wakefulness and respiratory drive. Danavorexton is a selective orexin-2 receptor agonist that targets this system to promote arousal and respiratory function. It has emerged as a pharmacological option for OIRD and reversal for opioid sedation without compromising analgesia. Additionally, studies have shown that danavorexton can enhance tidal volume and minute ventilation in patients who are being managed with opioids. This narrative review discusses the pathophysiology of OIRD, current reversal strategies, and the emerging evidence supporting the use of Danavorexton in perioperative care. Danavorexton represents a novel and potentially transformative adjunct that could improve postoperative recovery, reduce adverse opioid-related events, and enhance patient safety in the surgical setting.

Postoperative pain is a common consequence of spinal operations related to tissue trauma, manipulation of neural structures, and lengthy procedures. While opioid medications are frequently used for pain control, their side effects, such as nausea, vomiting, tolerance, and dependency, have led to increased interest in multimodal analgesic techniques. This review aims to examine effectiveness and safety of liposomal bupivacaine (LB, EXPAREL) in erector spinae plane blocks (ESPB) for postoperative pain management following spinal surgery. Regional anesthesia methods, particularly ESPB, have gained attention in reducing opioid requirements. The ESPB technique involves ultrasound-guided administration of local anesthetics beneath the erector spinae muscles and above the transverse process, effectively inhibiting ventral and dorsal rami of spinal nerves. Despite its popularity for versatility and safety, the analgesic effects of ESPB with conventional local anesthetics are relatively short-lived. LB, which releases the drug gradually as liposomes are degraded, offers extended pain control. Early clinical applications in pediatric scoliosis surgery and transforaminal lumbar interbody fusion have revealed that ESPB with LB adequately outperformed the control analgesic in terms of opioid consumption (30% and 50% decrease in mentioned studies) and length of stay (24%, 32%, and 12% decrease in mentioned studies). These findings indicate that LB in ESPB represents a promising strategy for enhanced perioperative pain management in spinal procedures. However, further research with larger and more diverse patient populations and outcome measurements are needed to overcome the current limitations of current research. In the present investigation, current evidence regarding the implementation of LB in ESPB during spine surgeries is summarized, focusing on safety and potential to improve patient outcomes by prolonging analgesia, minimizing opioid use, and promoting faster recovery.

Remimazolam is a novel ultra-short-acting benzodiazepine sedative, which has shown great promise in clinical scenarios such as outpatient surgeries, endoscopic examinations, intensive care units, and emergency departments due to its rapid onset, adjustable sedation level, and fast metabolic clearance. Currently, there is no consensus on the clinical application of remimazolam in non-operating room anesthesia. This article provides a comprehensive overview of its pharmacological properties and metabolic characteristics, with a particular focus on its application in special populations such as the elderly, patients with high cardiovascular risk, and children. The main purpose is to evaluate its safety and sedative effect in non-operating room settings by comparing it with traditional sedatives, and to provide insights for future research directions, thereby offering theoretical basis and practical guidance for the rational clinical application of this drug outside the operating room.

In this narrative review we describe the recent updates regarding anti-obesity medications as of February 2025. We describe the physiologic mechanisms underpinning the development of hunger, satiation, and maintenance of satiety to address targets for anti-obesity medications. The efficacy, mechanism, and additional beneficial effects of anti-obesity medications are then further detailed. For this review, we focus on FDA-approved medications for obesity and on select medications currently under development and undergoing Phase 2 and 3 trials. We start by focusing on the non-incretin anti-obesity medications orlistat, phentermine, phentermine-topiramate, and naltrexone-bupropion. We also highlight setmelanotide for heritable obesity. The mechanism of action and comparative efficacy of the GLP-1 receptor agonists liraglutide and semaglutide are reviewed. Tirzepatide, the GLP-1 and GIP-receptor dual agonist is described, and weight loss is compared to alternative anti-obesity medications. Additional incretin targets in the pipeline include dual co-agonists to glucagon and GLP-1 receptors, triple agonists targeting glucagon, GLP-1 and GIP, novel GLP-1 agonists, oral formulations of GLP-1 agonists, and amylin agonists. Finally, we provide best practices for adjuncts to pharmacologic treatments of obesity, monitoring efficacy of obesity treatments, and adjusting medication regimens for providers.

Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic approaches. Fungi are a rich source of bioactive metabolites, some of which exhibit potent anticancer properties. This scoping review evaluates the current research on fungal metabolites with anticancer potential, focusing on species native to Saudi Arabia's unique ecosystem. Following PRISMA 2020 guidelines, a comprehensive literature search was conducted using PubMed, Google Scholar, and Web of Science. Out of approximately 14,000 records, 11 studies met the inclusion criteria (2000-2024). A total of 16 distinct fungal species were identified, with their metabolites tested against various human cancer cell lines. Compounds derived from Penicillium sp. RO-11, Fusarium venenatum, Chaetomium globosum, Bipolaris sorokiniana, and Aspergillus sydowii demonstrated notable cytotoxic effects. Reported IC₅₀ values ranged from as low as 0.2 µg/mL to over 600 µg/mL, indicating varying levels of potency. Penicillium sp. RO-11 (emodin, IC₅₀ = 2 ± 7.6 µM) and Fusarium venenatum (IC₅₀ = 0.3779 µg/mL against HCT8 cells) emerged as the most potent candidates. These metabolites exerted their effects by inducing apoptosis, inhibiting proliferation, and disrupting oncogenic signaling pathways. The findings underscore the therapeutic potential of fungal-derived compounds and highlight the importance of further research to isolate and characterize the most effective strains for biomedical applications. Expanding investigations into Saudi Arabia's fungal diversity may yield promising candidates for future cancer treatments.

Red yeast rice (RYR) is an Asian indigenous medicine that ferments Oryza sativa grains using the Monascus fungi, specifically Monascus purpureus. Monacolins, pigments, phenols, sterols, and benzopyrans, such as the mycotoxin citrinin, were proven to be present in RYR, contributing to its numerous effects. This study aims to provide a thorough overview of the in vitro and in vivo pharmacological activities of M. purpureus red yeast rice, its studies in humans, and a summary of recent case reports. A literature search was conducted on the PubMed database, using the keywords: "pharmacology activity of red yeast rice" filtered to free full text and articles published from 2014 to 2024 for in vitro and in vivo studies, to ensure the newest developments. In vitro and in vivo pharmacological activity studies of RYR and/or metabolites have confirmed antidyslipidemia, anti-inflammatory, and anticancer activities, whereas studies in humans have evidenced its activity in improving lipid profiles. Furthermore, case reports on red yeast rice supplements, published between 2020 and 2025, revealed Fanconi syndrome and kidney dysfunction as the main adverse events, mostly reported from Japan.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an established class of agents in the treatment of type 2 diabetes mellitus (T2DM), with proven cardiovascular and renal benefits. However, their precise mechanisms of action remain incompletely understood. Metabolomics offers a powerful approach to uncovering drug-induced alterations in metabolic pathways.

Aim: This narrative review summarizes the available human evidence on the metabolomic effects of SGLT2 inhibitors, with a focus on their potential implications for metabolic adaptation and cardiorenal protection.

Methods: We performed a comprehensive literature search of human studies that applied metabolomic analyses to evaluate the effects of SGLT2 inhibitors in T2DM. Both targeted and untargeted metabolomic approaches were considered.

Results: Across studies, SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates. Key metabolite changes include increases in ketone bodies, alterations in branched-chain amino acids, and modulation of intermediates of the tricarboxylic acid cycle.

Conclusion: SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates, including ketone bodies, fatty acids, and certain amino acids. These metabolomic adaptations may underlie their observed cardiovascular and renal protective effects. While these findings support the "thrifty fuel" hypothesis, additional longitudinal studies with standardized methodologies and precision medicine approaches are needed to fully define the clinical significance of these metabolic adaptations.

Background: 5-Fluorouracil (5-FU) is a chemotherapy drug used to treat breast cancer. Monitoring 5-FU levels in blood is essential due to its narrow therapeutic range, high individual variability, nonlinear pharmacokinetics, dosage calculations based on body surface area, and susceptibility to toxicity influenced by individual factors such as enzyme polymorphisms.

Methods: An observational study was conducted in 2 types of patients: patients receiving intravenous 5-FU chemotherapy and those receiving oral chemotherapy with capecitabine as the 5-FU prodrug. 5-Fluorouracil blood levels in those patients were monitored using dried blood spots (DBS) as a biosampling method to correlate them with adverse events experienced by patients. Samples from DBS were analyzed using LC-MSMS which has been fully validated with propylthiouracil as an internal standard. All patients were also interviewed to determine adverse events experienced during 5-FU treatment. These adverse events were evaluated based on Common Terminology Criteria for Adverse Events version 5.0.

Results: Among the five patients who received intravenous 5-FU, only one patient had concentrations within the target range of 2-3 µg/mL, two patients were below the target range, and two patients were slightly above the target range. For the patients receiving oral capecitabine, 5-FU concentrations were detectable in only 3 out of 8 patients, with values near the LLOQ. The most common adverse events observed in intravenous chemotherapy patients were constipation, fatigue, and alopecia. Hand-foot syndrome was the most common syndrome in patients receiving oral chemotherapy.

Conclusion: The validated DBS method can be applied for therapeutic drug monitoring of 5-FU, offering advantages such as reduced invasiveness compared to traditional venipuncture. However, no significant relationship was found between the administered drug dosage, 5-FU blood levels, and adverse events. This study's limitations include its small sample size, which requires further research with larger cohorts to validate these observations and their clinical relevance.

Background: Immune checkpoint inhibitors (ICIs) are antibodies that activate the immune system to kill tumor cells and have been widely used in oncology. However, dysregulated immune activation may result in the attack of normal tissues and organs, leading to immune-related adverse events (irAEs). Corticosteroid-refractory irAE pneumonitis severely threatens patient survival and is characterized by a lack of high-level evidence-based management guidelines, highlighting the need for increased scrutiny in this area.

Case presentation: This article presents the diagnosis and treatment of a patient with lung squamous cell carcinoma who developed recurrent corticosteroid-refractory grade 3 checkpoint inhibitor- related pneumonitis (CIP) during treatment with the ICI tislelizumab. The management approach included the use of intravenous immunoglobulin (IVIG) and mycophenolate mofetil (MMF). The case is thoroughly analyzed and discussed, accompanied by a review of relevant literature.

Conclusion: IVIG and MMF showed effectiveness in corticosteroid-refractory CIP, and further investigation is warranted to establish standardized guideline and to optimize therapeutic drug monitoring for immunosuppressive agents.

Antimicrobial stewardship has gained momentum in Japan, prompting the adoption of various strategies to optimize antimicrobial use. Key recommendations include individualized dosing, dosing intervals, and treatment regimens tailored to the patient's condition, causative pathogens, and affected organs. Combination therapy is advised for empiric treatment of severe infections and suspected multidrug-resistant organisms. Early initiation of antimicrobial therapy followed by de-escalation may enhance clinical outcomes and reduce resistance development. Additionally, while clear criteria for intravenous-to-oral switch therapy remain undefined, its implementation could play a crucial role in optimizing antimicrobial administration. The duration of therapy should be guided by disease pathophysiology rather than isolated inflammatory markers, including C-reactive protein, with adherence to established guidelines and clinical recommendations. These strategies have been incorporated at the bedside, and optimized antibiotics use are now advanced in Japan.