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.
