Pharmacological management has been the backbone of treatment for disorders of central hypersomnolence despite challenges in drug administration due to intolerable side effects, development of tolerance, and addiction potential. Recent advances in drug therapies for central hypersomnolence disorders, namely sodium oxybate and orexin agonists, have either changed or increased the potential to significantly improve the quality of life of individuals with narcolepsy and idiopathic hypersomnia. Mechanisms of action, pharmacodynamics and pharmacokinetics of previously and commonly used medications, along with the evidence behind their use, are discussed. In addition, oveporexton, an orexin receptor 2 agonist (OX2R) will be discussed as it marks an important first step in directly counteracting the pathology behind narcolepsy with cataplexy and has completed Phase 2 trials with Phase 3 underway. Early clinical data is promising; however, its long term efficacy and safety data is insufficient to garner US Food & Drug Administration approval, though additional trials are ongoing in narcolepsy with cataplexy, and non-orexin deficient central hypersomnolence disorders as well. Regardless, new drug developments may lead expanded treatment options and may have the potential to decrease or potentially eliminate the need for polypharmacy in the treatment algorithm for narcolepsy and idiopathic hypersomnia.
Background:Lenacapavir (LEN), a first-in-class HIV-1 capsid inhibitor administered subcutaneously twice yearly, has demonstrated near-perfect efficacy in Phase 3 trials, generating justified enthusiasm for its potential to reconfigure HIV prevention. However, its revolutionary success obscures critical spatiotemporal vulnerabilities. We critically examined the protective envelope of LEN, specifically focusing on the gap between systemic pharmacokinetics (PK) and mucosal distribution, the dynamics of the prolonged PK tail, and the clinical emergence of capsid resistance. Methods:A systematic narrative synthesis was conducted through April 2026. We integrated screening and data parameters from the PURPOSE and CAPELLA trials alongside advanced PK-PD modeling and structural biology datasets to comprehensively map the spatiotemporal parameters of lenacapavir-based PrEP. Findings:We characterize the Limitations of Systemic Surrogacy, highlighting that no published empirical data exist characterizing LEN concentrations in human mucosal sanctuary sites; the sole registered tissue distribution trial (Pro00043856) remains unpublished four years post-registration. While modeling baseline assumptions establish a wild-type 95% preventive plasma concentration (EC95) of 5.8 ng/mL, the terminal absorption-limited elimination phase creates a definitive 106-235 day Mutant Selection Window (MSW) following drug discontinuation. Based on the 58 studies included in the full synthesis, falling sub-therapeutic drug concentrations during this tail phase exert selective pressure that favors high-fitness capsid substitutions (eg, Q67H), lowering the genetic barrier for complex, high-level resistance mutations (eg, N74D). Clinical breakthrough infections observed across the CAPELLA trial (19%) and rare PURPOSE infections (0.07 per 100 person-years) validate this corridor of vulnerability, highlighted by a recorded seroconversion occurring 16 months post-injection. Conclusion:Optimizing the public health impact of lenacapavir requires transitioning from simple serum-based monitoring toward tissue-informed clinical stewardship. Unlike conventional oral PrEP, twice-yearly lenacapavir involves an extended pharmacological commitment of nearly 12 months, requiring pre-planned clinical protocols for bridging therapy during drug discontinuation. Implementation requires the evaluation of high-sensitivity viral surveillance tools (LOD ≤ 10 copies/mL) and global access reconfigurations to resolve the economic and licensing barriers separating low-cost generic synthesis from international list prices, protecting the long-term viability of the capsid inhibitor class across all implementation sectors.
Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of paclitaxel therapy. The inflammasome complex, including apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and NOD-like receptor family pyrin domain-containing 3 (NLRP3), is implicated in inflammatory signaling pathways related to neuropathy. This study aimed to evaluate transcriptomic changes in genes involved in the inflammasome pathway in breast cancer patients, with a specific focus on metformin treatment initiated after the onset of neuropathy. Materials and Methods: A total of 51 breast cancer patients receiving paclitaxel were included (26 controls, 25 metformin). Metformin was initiated following the clinical onset of neuropathy. Plasma samples were collected at baseline, cycle 6, and cycle 12. Expression levels of ASC, Caspase-1, and NLRP3 were quantified as fold-change. Statistical analyses included normality testing (Shapiro-Wilk), temporal comparisons (Friedman or repeated-measures ANOVA), group comparisons (Mann-Whitney U-test), correlation (Spearman), and Receiver Operating Characteristic (ROC) analysis. Results: No significant baseline differences were observed between groups. In the control group, ASC expression increased over time (p = 0.0005), while Caspase-1 and NLRP3 showed no significant temporal changes. In neuropathic patients, ASC (p < 0.0001), Caspase-1 (p = 0.0007), and NLRP3 (p = 0.04) expression levels were higher in the metformin group. ROC analysis demonstrated moderate discriminatory ability for ASC (AUC = 0.74) and Caspase-1 (AUC = 0.70), whereas NLRP3 showed weaker performance (AUC = 0.62). Correlation analysis revealed positive associations between ASC and Caspase-1, suggesting coordinated gene expression. These findings reflect transcriptomic modulation rather than functional inflammasome activation. Conclusion: Metformin administration after neuropathy onset was associated with transcriptomic changes in genes involved in the inflammasome pathway. However, these findings should be interpreted cautiously, as plasma RNA may not reflect protein activity or neural tissue processes, and further validation studies are required.
Background:Chemotherapy-induced nausea and vomiting (CINV) remains a significant and distressing adverse effect of cancer treatment, adversely affecting patients' quality of life. Despite well-established international guidelines for antiemetic prophylaxis, variability in CINV incidence and guideline adherence persists across different regions and healthcare settings, particularly in low- and middle-income countries (LMICs). Objective:This study determined the incidence and associated factors of chemotherapy-induced nausea and vomiting (CINV) among adult cancer patients at Mbarara Regional Referral Hospital. Methods:A prospective observational study was conducted among 237 adult cancer patients receiving chemotherapy at the Mbarara Regional Referral Hospital. The MASCC Antiemesis Tool (MAT) was used to assess acute nausea and vomiting (≤24 hours) and delayed nausea and vomiting (>24 hours to 5 days), as well as any chemotherapy-induced nausea and vomiting (CINV; nausea and/or vomiting). A 5-day follow-up using the MAT tool for acute (≤24hours) and delayed (>24hours-5 days) CINV was conducted. Results:Among 237 participants, 66 (27.8%) and 136 (57.4%) experienced acute and delayed nausea, and 53 (22.4%) and 101 (42.6%) experienced acute and delayed vomiting; 67 (28.3%) and 136 (57.4%) had combined acute and delayed nausea and vomiting. Antiemetic prophylaxis guideline adherence was 73.4%, with 26.6% receiving non-guideline-compliant regimens. Independent associated factors for CINV were female sex (AOR = 2.0, 95% CI: 1.1-3.8; p = 0.026), moderate- (AOR = 21.2, 95% CI: 9.1-49.0; p < 0.001) and high-emetogenic chemotherapy (AOR = 22.6, 95% CI: 8.6-59.2; p < 0.001), and prior CINV (AOR = 6.1, 95% CI: 2.8-12.9; p < 0.001). Conclusion:Over half of the participants experienced delayed chemotherapy-induced nausea and vomiting, while nearly one-third experienced acute CINV. Adherence to guidelines for antiemetic prophylaxis was high at 73.4%. Key identified associated factors included female gender, moderate to highly emetogenic potential of chemotherapy regimens, and a history of CINV in this study population.
Multidrug-resistant Pseudomonas aeruginosa (MDRP) is usually induced by inappropriate use of broad-spectrum antibiotics, and pre-multidrug-resistant Pseudomonas aeruginosa (pre-MDRP) is defined as resistance to any two of three antibiotics, such as carbapenems, fluoroquinolones, and aminoglycosides. Two cases of infections with such organisms are reported. Case 1 was a 78-yearold man with esophageal cancer who had pneumonia, treated by meropenem (MEPM) for two weeks because P. aeruginosa, which showed good susceptibility to most antibiotics, was isolated. He improved, but his inflammation status and chest X-ray findings worsened on day 21. MDRP was isolated, and he was treated using tazobactam/ceftolozane (TAZ/CTLZ) for 10 days. After improvement, clarithromycin (CAM) 200 mg once per day was then started as long-term, low-dose macrolide therapy. His condition has remained stable for more than six months. Case 2 was a 5-year-old girl with congenital heart abnormalities. She had pneumonia due to P. aeruginosa that showed good susceptibility to antibiotics and was treated by MEPM for 10 days. However, MDRP was isolated, and then ciprofloxacin (CPFX), to which MDRP showed good susceptibility, with only intermediate susceptibility to levofloxacin (LVFX), was started. Ten days later, her pneumonia improved, and half-dose (5 mg/kg) CAM three times per day was started as longterm, low-dose macrolide therapy. Her condition has remained stable for more than six months. These two cases, one adult MDRP infection and one pediatric pre-MDRP infection, that were maintained by long-term, half-dose macrolide administration, which might have affected pathogen colonization and host immunomodulation, are presented.
Background:Treatment of elderly acute myeloid leukemia (AML) remains challenging, and intensive chemotherapy is often poorly tolerated in elderly patients due to comorbidities and frailty, thereby necessitating low‑intensity alternatives. This study compared the efficacy and safety of venetoclax combined with a hypomethylating agent (VEN-HMA) against HMA plus low-intensity induction chemotherapy (HMA-LIIC) and low-intensity induction chemotherapy alone (LIIC) in a real-world elderly AML cohort. Methods:In this retrospective study, 136 newly diagnosed elderly AML patients (≥60 years) were categorized into three groups: VEN-HMA (n=45), HMA-LIIC (n=38), and LIIC (n=53). LIIC was defined as low‑dose cytarabine ‑based regimens given without a concomitant VEN or HMA. Key endpoints included morphologic response, measurable residual disease (MRD) negativity, early mortality, and overall survival (OS). Results:The VEN-HMA group demonstrated a significantly higher overall response rate (82.2%) than the HMA-LIIC (39.4%) and LIIC (54.7%) groups (p=0.010). While the complete remission (CR) rate was comparable across groups, the VEN-HMA group had a notably higher CR with incomplete hematologic recovery (CRi) rate (33.3% vs 10.5% vs 11.3%) (p=0.007). The MRD negativity rate was significantly superior in the VEN-HMA group (65.5%) compared to HMA-LIIC (18.8%) and LIIC (41.7%) (p=0.010), an advantage particularly pronounced in intermediate-risk patients (68.8% vs 12.5% vs 30.8%, p=0.021). The VEN-HMA group also had a numerically lowest 30-day early mortality (4.44% vs 7.97% vs 17.0%). With a median follow-up, the median OS was 11.0 months in the VEN-HMA group, 7.2 months in the HMA-LIIC group, and 10.1 months in the LIIC group. The VEN-HMA group showed a numerically higher 1-year OS rate (55.0%) than the HMA-LIIC group (35.0%) and comparable to the LIIC group (47.9%) (p=0.153). Conclusion:In this real-world analysis, VEN-HMA demonstrated superior response rates and deeper molecular remissions (MRD) compared to HMA-LIIC and LIIC in elderly AML patients, further supporting its use as an effective and feasible frontline option for this population, especially in the intermediate-risk group.
Background: Chronic Cardiorenal Syndrome (CRS types 2/4) involves the mutual exacerbation of heart failure and chronic kidney disease, with over half of heart failure patients affected by renal impairment that increases mortality and rehospitalization. Despite advances in management, prospective evidence for Traditional Chinese Medicine in chronic CRS is lacking. Qishen Yiqi Dropping Pills (QSYQ) have proven safe in cardiovascular care, but their concurrent renoprotective effects remain unconfirmed. Based on preliminary cardiorenal protective findings, this study evaluates QSYQ combined with standard therapy on symptoms, function, biomarkers, and outcomes in chronic CRS. Methods: This is a prospective, multicenter, observational cohort study. Patients will be stratified into two groups based on whether or not they receive QSYQ treatment: an "Exposure Group" (standard background pharmacotherapy plus QSYQ; n=60) and a "Non-exposure Group" (standard background pharmacotherapy alone; n=60). The study duration is 270 days, with the exposure period set to the initial 90 days. Follow-up assessments will be conducted at baseline, and on days 90, 120, 180, and 270. The primary outcome measure is the 6-Minute Walk Test (6MWT). Secondary outcome measures include the New York Heart Association (NYHA) functional classification, N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum creatinine (Cr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), trimethylamine N-oxide (TMAO), major adverse renal and cardiovascular events (MARCE), the Veterans Specific Activity Questionnaire (VSAQ), and the Kansas City Cardiomyopathy Questionnaire (KCCQ). Throughout the entire study period, adverse events will be recorded to facilitate safety assessments. Discussion: This study will comprehensively assess QSYQ's clinical utility for chronic CRS, evaluating functional capacity, quality of life, biomarkers, and long-term outcomes to provide prospective evidence for integrating Traditional Chinese Medicine into chronic CRS management.
Purpose:Chronic pain is a debilitating condition faced among the geriatric population, contributing to reduced mobility, impaired daily function, and increased dependence on healthcare services. This review explores the current landscape of chronic pain in the elderly, providing a comprehensive overview of treatment options, with the goal of exploring more effective, individualized care. Patients and Methods:This narrative review draws on a range of studies and clinical publications accessible through the National Center for Biotechnology Information (NCBI) database. The literature reviewed includes research on the underlying mechanisms, diagnostic challenges, and treatment strategies for chronic pain in older adults. Clinical relevance and practical approaches were explored, where risks and benefits of pharmacologic, non-pharmacologic, and interventional therapies were explored. Results:Chronic pain in the elderly is often undertreated, likely due to unaccounted comorbidities and age-related changes in drug metabolism. While acetaminophen remains the recommended first-line agent, the use of NSAIDs and opioids in this population carries significant risks and demands careful consideration. Adjuvant medications such as SNRIs and gabapentinoids offer additional options for neuropathic pain, but may require dose adjustments or close adverse effect monitoring. Non-pharmacologic interventions-such as physical therapy and cognitive behavioral therapy- often are underutilized despite a strong safety profile and evidence of benefit. In cases refractory to conservative measures, interventional procedures including epidural steroid injections, radiofrequency ablation, and spinal cord stimulation may offer meaningful relief for select patients. Conclusion:Managing chronic pain in older adults requires a thoughtful, individualized approach that balances effectiveness with safety. As the population ages, there is a growing need for more inclusive research, better integration of non-drug therapies, and greater access to interdisciplinary care. Tailoring treatment to individual goals can help improve outcomes and preserve independence and function in this vulnerable group.
Background:Delirium is a frequent complication in critically ill patients and is associated with increased mortality, prolonged hospitalization, and long-term cognitive impairment. Montelukast, a leukotriene receptor antagonist commonly used in respiratory diseases, has been associated with neuropsychiatric adverse effects, including delirium. Evidence regarding its safety in critically ill adults is limited. This study aimed to investigate the association between montelukast use during ICU stay and the development of delirium and further evaluate its safety in the ICU. Methods:This retrospective cohort study was conducted at King Abdulaziz Medical City, Saudi Arabia, between January 2018 and December 2021. Adult critically ill patients (18-79 years) who were admitted to ICUs for respiratory symptoms and categorized based on montelukast exposure during ICU stay. The primary outcome was assessing the incidence of delirium during ICU stay. Secondary outcomes included delirium duration, recurrence of delirium, delirium-free days, ventilator-free days, length of stay (LOS), safety outcomes (liver and kidney injury), 30-day and in-hospital mortality. Propensity score (PS) matching with a 1:4 ratio was performed to minimize baseline differences between the groups. Results:Out of 1590 screened patients, 1469 were included, and 44 received montelukast during ICU stay. After PS matching (1:4), montelukast use was associated with a significantly higher incidence of delirium (OR 4.66, 95% CI 1.63 to 13.34; P < 0.004). Among patients who developed delirium, mixed delirium was the most frequent subtype in the montelukast group (50% vs 12.5% in controls). There were no notable differences found in terms of delirium-free days, recurrence of delirium, liver or kidney injury, length of stay, ventilator-free days, or overall mortality. Conclusion:Our study demonstrates an association between montelukast use during ICU admission and a higher incidence of delirium. Prospective randomized studies are needed to confirm these findings.
Hydrogels are widely used in clinical medicine for drug delivery and tissue repair; however, they exhibit limited mechanical strength, suboptimal degradation profiles, and variable biocompatibility. In order to address inherent shortcomings in conventional hydrogels, hybrid hydrogels were engineered by incorporating nanoparticles, bioactive materials, and polymer networks. This review explores the use of hybrid hydrogels in pain management, specifically emphasizing their localized and sustained drug delivery, their modulation of inflammation, and their regenerative effects on tissue. Hybrid hydrogels allow for targeted delivery of analgesics, NSAIDs, and biologics to localized tissues therefore reducing systemic exposure and toxicity. Their tunable release makes them responsive to physiological cues like body pH, temperature, and enzymatic activity which makes them tailored to the environment they are in. In addition to their multifunctional pharmacological application, hybrid hydrogels exhibit regenerative properties that can be used to repair tissues in a safe and effective manner. Despite the advantages of hybrid hydrogels, there are limitations in their biodegradation variability, potential cytotoxicity, and reproducibility for regulation into clinical use. Current and continued research is needed to optimize hybrid hydrogel formulations to address these limitations while maintaining the many benefits they provide. In conclusion, hybrid hydrogels are a promising medium for pain management by integrating advantageous aspects of conventional hydrogels while incorporating localized drug delivery, anti-inflammatory therapy, and regenerative capabilities, however, further research is needed to validate its adoption into clinical use.
Objective:To investigate the roles of age and renal function in optimizing enoxaparin dosage for achieving target anti-Xa levels in Asian patients. Methods:A total of 135 patients subjected to enoxaparin therapy were retrospectively enrolled. Baseline demographic characteristics, clinical indicators, and laboratory test results were collected. The distribution patterns of weight-adjusted doses and anti-Xa levels were analyzed. Dose-response curves were employed to evaluate the probability of achieving therapeutic anti-Xa levels in different age groups (<80 years vs ≥80 years) and estimated glomerular filtration rate (eGFR) categories (eGFR <60 mL/min vs ≥60 mL/min). Results:The dose distribution revealed discrepancies between actual weight-adjusted doses and manufacturer-recommended doses in some patients. Age significantly influenced the attainment of target anti-Xa levels, whereas renal function exhibited no significant impact. Dose-response curves demonstrated that patients aged ≥80 years required lower doses to achieve 90-95% target anti-Xa levels compared to those <80 years. No significant difference was observed in target attainment between patients with eGFR <60 mL/min and those with eGFR ≥60 mL/min. Conclusion:Within the range of eGFR ≥30 mL/min/1.73 m2, advanced age, rather than mild-to-moderate renal impairment, emerged as the critical factor for achieving target anti-Xa levels with enoxaparin in Asian patients. Patients aged ≥80 years required lower doses compared to younger patients. These findings still need prospective validation.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterised by irreversible fibrosis of the lung parenchyma and a steady decline in respiratory function. Its pathogenesis remains incompletely understood, and despite advances in diagnosis and disease management, therapeutic options remain limited and largely palliative. Emerging evidence suggests that phosphodiesterase-4 (PDE4) inhibitors may represent a novel therapeutic approach in IPF through modulation of cyclic adenosine monophosphate-dependent signalling pathways. Preclinical and clinical studies indicate that PDE4 inhibition can attenuate key pathological processes implicated in IPF, including macrophage-driven inflammatory responses, dysregulated epithelial repair, and fibroblast proliferation and differentiation. Through these mechanisms, PDE4 inhibitors demonstrate combined anti-inflammatory and antifibrotic effects in experimental models of lung fibrosis. Among this class, the PDE4B-selective inhibitor nerandomilast has shown encouraging signals of efficacy in clinical trials of IPF, supporting continued investigation of subtype-selective targeting strategies. Other PDE4 inhibitors, including roflumilast, rolipram, and structurally novel derivatives such as 2-arylbenzofurans, have also demonstrated antifibrotic activity, predominantly in preclinical studies. This review synthesises current evidence on the role of PDE4 signalling in IPF pathogenesis and critically evaluates the pharmacological rationale, therapeutic potential, and translational challenges of PDE4 inhibitors in the treatment of IPF. Future perspectives, including subtype-selective inhibition and optimised drug delivery strategies, are discussed as potential avenues to improve efficacy and tolerability in this patient population.
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.
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.
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.
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.
