Objective:Tegileridine is a novel selective μ-opioid receptor agonist. This exploratory dose‑finding study aimed to estimate the 50% effective dose (ED50) and secondarily the 95% effective dose (ED95) of tegileridine for suppressing the cervical dilation reflex during hysteroscopic surgery under propofol anesthesia, compare it with fentanyl, and evaluate perioperative safety in an exploratory manner. Methods:This prospective, randomized, single‑center trial enrolled 54 patients (ASA I‑II). Patients received tegileridine (initial dose 16.67 μg/kg) or fentanyl (initial dose 2 μg/kg) with propofol. Doses were adjusted using the Dixon sequential method. The primary endpoint was ED50 with its 95% confidence interval (CI), estimated using the percentile bootstrap method (2,000 replicates) as the primary inferential framework. ED95 was calculated secondarily via probit regression. Safety data are reported descriptively. Results:Twenty‑seven patients per group completed the study. The bootstrap‑based ED50 for tegileridine was 23.22 μg/kg (95% CI: 22.39‑24.19); for fentanyl, 1.51 μg/kg (95% CI: 0.97‑4.07). The ED50 potency ratio (tegileridine:fentanyl) was approximately 1:15 (95% uncertainty range derived from bootstrap CIs: 1:5.5 to 1:24.9). The ED95 values from probit regression were 23.89 μg/kg (95% CI: 23.68‑24.12) for tegileridine and 1.97 μg/kg (95% CI: 1.87‑2.07) for fentanyl. Respiratory depression/hypoxemia was observed in 14.8% of the tegileridine group and 59.3% of the fentanyl group; these exploratory findings should be interpreted with caution given the small sample and open‑label design. Conclusion:This exploratory study estimated the ED50 of tegileridine and fentanyl for hysteroscopic surgery. The ED50-based potency ratio and the observed differences in safety outcomes require confirmation in larger, adequately powered, blinded trials. The ED95 estimates are model‑based and carry substantial uncertainty. Trial Registration:Chinese Clinical Trial Registry, ChiCTR2500107995.
Background:Acetaminophen (APAP) overdose is a leading cause of acute liver injury and is frequently associated with oxidative stress, mitochondrial dysfunction, inflammation, and hepatocellular toxicity. R-α-lipoic acid (R-ALA) is a natural antioxidant and mitochondrial cofactor that provides protective effects against APAP-induced hepatic damage. Objective:To examine the protective effects of R-ALA against acute APAP-induced liver injury in mice. Methods:Adult male mice were randomly divided into five groups: control, APAP, R-ALA, repeated R-ALA pretreatment + APAP, and single R-ALA pretreatment + APAP. APAP was given orally at 500 mg/kg, while R-ALA was administered orally at 100 mg/kg. R-ALA was administered daily for 10 days, with a single dose given 1 hour before APAP. Twenty-four hours after APAP administration, blood and liver samples were collected. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), high mobility group box-1 (HMGB1), keratin-18 (K18), caspase-cleaved keratin-18 (ccK18), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. Liver malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase 3 (GPx3) were also assessed. Results:APAP administration increased serum markers of hepatocellular injury, mitochondrial injury, hepatocyte death, and inflammation, including ALT, AST, GLDH, HMGB1, K18, ccK18, IL-6, and TNF-α. APAP also increased hepatic MDA and decreased hepatic GSH, SOD, CAT, and GPx3. R-ALA pretreatment significantly attenuated these APAP-induced changes. APAP increased ALT from 7.49 to 29.46 and AST from 11.10 to 32.49, while R-ALA pretreatment significantly reduced both markers compared with the APAP group. Conclusion:R-ALA attenuated APAP-induced liver injury biomarker changes in mice, through antioxidant defenses and reduction of oxidative stress, inflammatory responses, mitochondrial injury markers, and hepatocyte death markers. These protective effects are mediated by antioxidant, anti-inflammatory, and mitochondrial-protective mechanisms. Further histological and pathway-focused molecular studies are needed to confirm the underlying mechanisms and translational relevance.
Management of glaucoma is now at an inflection point with a new generation of therapeutic candidates, whilst targeting intraocular pressure-independent strategies is challenged by the landmark Phase III failure of memantine regarding trial design and endpoint sensitivity. Preclinical research has identified promising targets including glutamate excitotoxicity, neurotrophic factor deprivation, and mitochondrial dysfunction, with nicotinamide emerging as a leading candidate due to its ability to robustly protect RGCs by supporting NAD levels and bioenergetics. Current clinical efforts are expanding into metabolic repurposing with agents (eg metformin and semaglutide), sustained-delivery systems with neurotrophic factors (eg ciliary neurotrophic factor implant), and functional enhancers (eg citicoline). To bridge the translational gap, the field is integrating new endpoints with higher sensitivity (eg advanced assessment of photopic negative response), AI-guided endpoint selection (eg graph attention neural network), novel biomarkers (eg detection of apoptotic retinal cells and neurofilament light chain in aqueous humor), and precision medicine frameworks (eg polygenic risk scores and multi-omics analysis) to develop the first clinically validated neuroprotective treatments for glaucoma.
Background:Colistin sulfate is effective against carbapenem-resistant Gram-negative bacilli but has a narrow therapeutic window, large pharmacokinetic variability, and high resistance risk. Clinical data remain limited, and individualized dosing guidance is urgently needed. This study aims to establish a population pharmacokinetic (PPK) model to optimize and guide precise individualized dosing of colistin sulfate in critically ill patients. Methods:Critically ill patients with confirmed CRO infections receiving intravenous colistin sulfate at the Second Hospital of Hebei Medical University from June 2021 to June 2023 were enrolled. A PPK model was developed using NONMEM. Goodness-of-fit (GOF) diagnostics and visual predictive check (VPC) were used to evaluate the predictive performance of the model, while the bootstrap method (BS) was used to assess its stability. Clinical efficacy, microbiological efficacy, and adverse reactions were assessed. Monte Carlo simulation calculated the probability of target attainment (PTA) across different MICs and renal function strata to optimize the colistin sulfate dosing regimen. Results:Among 51 patients, clinical efficacy was 60.78% (31/51), bacterial clearance 52.94% (27/51), and nephrotoxicity 3.92% (2/51). The PPK model included 123 concentration points (range: 0.12-4.40 mg/L).A one-compartment linear elimination model best described the PK profile. Typical values of clearance (CL) and volume of distribution (V) were 1.66 L/h and 10.10 L, respectively. Creatinine clearance (CrCL) was identified as a significant covariate affecting CL. Monte Carlo simulation showed that the recommended regimen achieved PTA ≥90% only when MIC ≤0.5 μg/mL with normal renal function. When MIC ≥1 μg/mL, there was a risk of insufficient exposure in patients with normal renal function. When MIC ≥2 μg/mL, no dosing regimen achieved PTA ≥90%. Conclusion:Renal function significantly impacts colistin sulfate clearance. Dose adjustment based on CrCL is necessary. The standard dosing regimen risks underexposure in patients with normal renal function and MIC ≥1 mg/L. Off-label high-dose regimens should be considered in such cases to ensure adequate drug exposure.
Objective:Laparoscopic sleeve gastrectomy (LSG) is associated with substantial postoperative pain and a high rate of postoperative nausea and vomiting. Tegileridine fumarate, a biased µ-opioid receptor agonist, may offer effective analgesia with fewer adverse effects than conventional opioids. This study compared the impact of tegileridine versus sufentanil analgesia on postoperative recovery quality in obese patients. Methods:Seventy-two patients were randomly assigned to either the tegileridine group (group T, n = 36) or the sufentanil group (group S, n = 36). The primary outcome was the Quality of Recovery-15 (QoR-15) score at 24 h postoperatively. Secondary outcomes included: the visual analogue scale (VAS), time to first rescue analgesia, rescue analgesia and antiemetic use, cumulative opioid consumption, incidence of adverse events, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6). Results:The median (IQR) total QoR-15 score of 105.5 (103-120.8) was higher (p < 0.0001) in the group T compared with the score of 100.5 (93.5-104) in the group S. Group T demonstrated superior early postoperative analgesia, with lower VAS scores at rest (3.61 ± 0.57 vs. 3.91 ± 0.61, P = 0.033) and during movement (4.86 ±0.76 vs. 5.23 ±0.72, P = 0.039). The time to first rescue analgesia was longer in group T compared with group S [38 (32.25-43.75) minutes vs. 21 (17.25-30) minutes, P < 0.001]. Group T had a lower incidence of nausea (36% vs. 23%, P < 0.05) and vomiting (11% vs. 33%, P < 0.05). Rescue analgesic demand, PCIA use and CRP or IL-6 levels at any measured time point showed no significant difference. Conclusion:In patients undergoing LSG, tegileridine demonstrated a modest improvement in recovery quality, comparable analgesia, and significantly fewer opioid-related adverse events versus sufentanil.
Purpose:This study aimed to determine the median effective dose (ED50) and 95% effective dose (ED95) of mivacurium for maintaining elicitable motor evoked potentials (MEP) under total intravenous anesthesia (TIVA) during adolescent scoliosis surgery, while fulfilling both muscle relaxation and intraoperative neurophysiological monitoring (IONM) requirements. Patients and Methods:26 adolescents scheduled for primary elective scoliosis surgery with MEP monitoring were enrolled. Anesthesia was maintained with TCI propofol to achieve BIS of 40-60. Infusing mivacurium to maintain train-of-four count 1-3 until surgical exposure was completed. After train-of-four ratio recovered to 75% and MEP waveforms were elicitable, modified Dixon up-and-down sequential method was employed, with an initial mivacurium infusion dose of 10 μg·kg-1·min-1, adjusted by 0.5 μg·kg-1·min-1 based on the presence or absence of reproducible MEP at predefined stimulation settings. Positive was defined as reproducible MEP waveform elicitable at a stimulus intensity of 100 V. Dose-finding proceeded until seven crossover pairs were obtained. Excluding cases prior to the first crossover, 21 patients contributed to ED estimation. Hemodynamic parameters, adverse reactions, vasoactive agents use, and L-SRS scores were recorded. Results:The ED50 was 7.24 μg·kg-1·min-1 (95% CI: 6.87-7.54). The probability of MEP waveform presence demonstrated a negative correlation with mivacurium infusion dose, with an ED95 of 6.70 μg·kg-1·min-1 (95% CI: 4.79-6.99). No patients experienced unintended body movements, spontaneous respiration recovery, or bronchospasm. No significant hemodynamic changes were observed after mivacurium administration. Transient skin flushing occurred in 6 patients, and low-dose ephedrine was required in 7 patients. L-SRS scores were higher during mivacurium infusion compared to post-discontinuation. Conclusion:Under this TIVA/IONM protocol, the ED50 and ED95 for continuous mivacurium infusion that preserves MEP are 7.24 μg·kg-1·min-1 and 6.70 μg·kg-1·min-1, respectively. These doses effectively achieve muscle relaxation while maintaining MEP signals without serious adverse events observed.
Background:Anlotinib, a multi-targeted tyrosine kinase inhibitor, has demonstrated anti-angiogenic and immunomodulatory activity in several solid tumors; however, its efficacy and predictive biomarkers in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remain unclear. Methods:This retrospective, single-center study included 68 patients with histologically confirmed R/M HNSCC who received anlotinib as third-line or later therapy (following failure of at least two prior systemic lines; 12 mg once daily on days 1-14 every 21 days, with dose reductions to 10 or 8 mg as needed) between January 2021 and October 2023. Tumor response was evaluated according to RECIST v1.1 in patients with available radiologic follow-up. Survival outcomes were analyzed in the overall treated population. Archived tumor tissues were subjected to next-generation sequencing (NGS) and multiplex immunofluorescence (mIF) to exploratorily assess genomic alterations and immune microenvironment features. Results:Among 68 treated patients, 14 achieved partial response, and 39 had stable disease, yielding an objective response rate (ORR) of 22.1% and a disease control rate (DCR) of 74.6% in treated patients. The median progression-free survival (PFS) and overall survival (OS) in the overall cohort were 6.3 and 8.4 months, respectively. Patients with oropharyngeal carcinoma and ECOG performance status 0-1 demonstrated improved outcomes. NGS analysis identified frequent alterations in TP53, PIK3CA, CDKN2A, PTEN, and FGF/FGFR pathways. PI3K pathway alterations were not associated with prolonged PFS. Tumors with PD-L1 CPS ≥ 1 and higher CD8⁺ T-cell infiltration exhibited an inflamed phenotype and were associated with improved response. Grade ≥3 adverse events occurred in 25.0% of patients, most commonly hypertension and hand-foot syndrome. Conclusion:Anlotinib demonstrated promising responses with manageable toxicity in a heavily pretreated R/M HNSCC population. Integration of genomic and immune microenvironment features may provide hypothesis-generating insights into patient selection.
Background:Hydromorphone and morphine are the primary opioids recommended for epidural analgesia following cesarean delivery. This study aimed to determine the 90% effective dose (ED90) of epidural hydromorphone and morphine in this patient population. Methods:In this dose-finding trial, 80 patients undergoing cesarean delivery under combined spinal-epidural anesthesia (CSEA) were randomized to receive a single epidural injection of either hydromorphone or morphine after uterine closure. The dose of each agent was determined using a biased-coin up-and-down sequential allocation method to estimate the ED90. In addition, all patients received standardized multimodal analgesia postoperatively. Satisfactory analgesia was defined as a visual analogue scale (VAS) score ≤3 within 12 hours after cesarean delivery, without the need for supplemental opioids. Results:The estimated ED90 was 500 µg (95% confidence interval [CI], 495.00-532.50 µg) for epidural hydromorphone and 3 mg (95% CI, 2.97-3.21 mg) for epidural morphine. Comparative analyses of postoperative VAS scores, adverse effects (nausea/vomiting and pruritus), and rescue hydromorphone consumption revealed no statistically significant differences between the two dosage groups. Conclusion:The ED90 for post-cesarean analgesia was estimated to be 500 µg for epidural hydromorphone and 3 mg for epidural morphine. There were no statistically significant differences in adverse effects between the two drugs at their respective ED90 doses. Clinical Trial Registration:ChiCTR2400084510.
Background:Remimazolam, a relatively newly developed ultrashort-acting benzodiazepine agent, is utilized for procedural sedation and general anesthesia, and was recently widely used in school-aged pediatric patients. However, few data could be available in obese pediatric patients. We compared the median effective dose (ED50) of remimazolam for procedural sedation in pediatric obese and normal weight patients based on the hypothesis that obese pediatric patients require a lower dose per body weight. Methods:Sixty pediatric patients were enrolled and allocated into the normal weight group (Group N) and the obese group (Group O). For the first pediatric patient, remimazolam was administered at an initial dose of 0.2 mg/kg. Subsequent doses were adjusted in increments of ±0.02 mg/kg, with an increase if the preceding dose was ineffective or a decrease if it achieved the desired effect, following a sequential up-and-down design. ED50 was estimated and compared using this approach. Results:The ED50 of remimazolam was significantly lower in Group O 0.17 mg/kg (95% CI: 0.14-0.19 mg/kg) than in Group N 0.23 mg/kg (95% CI: 0.19-0.24 mg/kg) (P < 0.001). The estimated relative median potency was 0.74 (95% CI: 0.41-0.91) via probit analysis. Conclusion:In summary, when administered in combination with remifentanil at a dosage of 2 μg/kg, the ED50 value for inducing sedation with remimazolam is reduced by approximately 26% in obese paediatric patients compared to normal-weight children.
Purpose:Osteoarthritis (OA) joints present abnormal mechanical environments that limit drug retention and therapeutic efficacy. Current intra-articular systems cannot provide both sustained anti-inflammatory delivery and mechanical support. A celecoxib (CXB)-loaded "Nano-in-Nano" Hierarchical Delivery System (NiN-HDS) was developed to simultaneously optimize drug release and joint reinforcement. Methods:In this study, celecoxib-loaded PLGA nanoparticles (CXB-NPs) were prepared by emulsion solvent evaporation and incorporated into an electrospun nanofiber membrane combined with a genipin-crosslinked gelatin layer to form NiN-HDS. The system was characterized for particle size, zeta potential, porosity, hydrophilicity, swelling, degradation, mechanical properties, and in vitro CXB release. Therapeutic potential was evaluated in a rat OA model using histological and immunohistochemical analyses of cartilage and inflammatory markers. Results:NiN-HDS maintained nanoparticle stability, with CXB-NPs showing an average particle size of 138.4 ± 4.3 nm and a zeta potential of -58.74 ± 16.58 mV. The system exhibited high porosity (87.16 ± 0.75%) and hydrophilicity (contact angle < 90°), achieved swelling equilibrium at 150 ± 10 min with a swelling ratio of 163.97 ± 9.76%, and degraded over 10 days with 88.53 ± 2.03% mass loss. Mechanical testing demonstrated high strength (Young's modulus 17.24 ± 2.65 MPa, elongation at break 307.48 ± 32.01%. NiN-HDS provided sustained CXB release over 7 days, reaching 67.16% cumulative release. In vivo, it reduced cartilage damage and suppressed IL-1β and MMP-13 expression, while maintaining mechanical support and controlled drug delivery. Conclusion:In conclusion, we successfully developed NiN-HDS. Our results show that NiN-HDS combines sustained drug delivery with mechanical support, improves cartilage preservation and reduces local inflammation in a rat OA model, indicating that it can serve as a promising strategy for intra-articular therapy of osteoarthritis.
Purpose:To investigate the effect of end-stage kidney disease (ESKD) factor on the sedative effects of ciprofol. Patients and Methods:Elective kidney transplant recipients aged 18-64 years, with a body mass index (BMI) of 18.5-24.0 kg/m2, Mallampati class I or II, interincisor distance ≥ 3.5 cm, and undergoing regular preoperative dialysis were enrolled. A matched control group with normal kidney function was included for comparison. The Dixon's up-and-down method was used to determine the median effective dose (ED50) of ciprofol required to suppress the response to I-gel insertion. Secondary outcomes included ciprofol consumption during anesthesia maintenance, recovery time, perioperative hemodynamic changes, and adverse events. The total dosage of ciprofol used for anesthesia maintenance was recorded, and average ciprofol consumption per unit time per body weight was calculated. Results:No statistically significant difference were observed in the ED50 or 95% confidence interval (CI) of ciprofol for suppressing the I-gel insertion response between the ESKD and control groups. Similarly, recovery time and mean ciprofol consumption during anesthesia maintenance were comparable between groups. Hemodynamic parameters remained stable throughout the perioperative period in both groups, with no significant intergroup differences. The incidence of adverse events, including hypotension, bradycardia, and respiratory depression, was also comparable between groups. Conclusion:ESKD appears to have no significant effect on the sedative efficacy, anesthetic consumption, recovery profile, or safety of ciprofol.
Background: Chronic obstructive pulmonary disease (COPD) frequently coexists with obesity, creating a vulnerable phenotype associated with increased exacerbations and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits in weight management and cardiovascular protection, but their effects in patients with COPD and obesity remain unclear. Methods: We conducted a retrospective cohort study using the TriNetX global research network. We identified adult patients with coexisting COPD and obesity who initiated GLP-1RA or other weight-loss medications. We performed 1:1 propensity-score matching to balance baseline characteristics between the study groups. The primary outcome was all-cause mortality. Secondary outcomes included COPD exacerbations, acute respiratory failure, pneumonia, and major adverse cardiovascular events (MACE). Results: After propensity score matching, the study included 10,487 patients in each group. During follow-up, all-cause mortality occurred in 237 patients (0.8 per 100 person-years) in the GLP-1RA group compared with 519 patients (2.2 per 100 person-years) in the control group (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.37 to 0.50). GLP-1RA use was also associated with reduced risk of COPD exacerbations (HR, 0.79; 95% CI, 0.71 to 0.88), acute respiratory failure (HR, 0.55; 95% CI, 0.49 to 0.62), pneumonia (HR, 0.72; 95% CI, 0.64 to 0.81), and MACE (HR, 0.71; 95% CI, 0.64 to 0.79). Results remained consistent across multiple sensitivity analyses and subgroup analyses. Conclusion: Among patients with coexisting COPD and obesity, GLP-1RA use was associated with lower risks of mortality and adverse respiratory and cardiovascular outcomes compared with other weight loss medication. However, given the observational nature of this study, these findings should be interpreted with caution, as residual confounding cannot be excluded. Randomized controlled trials are warranted to establish causality and confirm these findings.
Background: Providing safe sedation in pediatric patients remains challenging because of age-dependent physiological variations. This study aimed to identify the age-stratified 95% effective dose (ED95) of remimazolam tosilate for achieving moderate sedation in children. Methods: This study enrolled children aged 1-12 years with ASA physical status I-II scheduled for elective surgery. Participants were stratified into three age groups: toddlers (1-3 years), preschoolers (3-6 years), and school-aged children (6-12 years), with 40 patients in each group. The initial dose of remimazolam tosilate was 0.2 mg & centerdot;kg-1, with subsequent 0.05 mg & centerdot;kg-1 adjustments using a biased coin design up-and-down sequential method based on patient response. Sedation depth was evaluated using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale. An MOAA/S score <= 3 at 3 minutes after drug administration was defined as successful sedation. ED95 values were estimated using isotonic regression. Perioperative variables, including sedation onset time, operation time, total anesthesia time, and wake-up time, were recorded. Adverse events, including hypotension, bradycardia, and oxygen desaturation, were monitored during the observation period. Results: Of the 142 children screened, 120 completed the study. The estimated ED95 (95% confidence interval) of remimazolam tosilate was 0.415 mg & centerdot;kg-1 (0.311-0.437) in toddlers, 0.389 mg & centerdot;kg-1 (0.258-0.440) in preschoolers, and 0.362 mg & centerdot;kg-1 (0.228-0.396) in school-aged children. Toddlers had the longest median wake-up time (32.5 min; IQR: 25.3-40.8). Hypotension was reported in 0.8% of patients (n=1), whereas bradycardia and oxygen desaturation were each observed in 5.8% of patients (n=7). Conclusion: This study establishes age-specific ED95 reference doses of remimazolam tosilate for moderate sedation in children. Although remimazolam demonstrated an overall favorable safety profile, individualized dose titration remains essential, particularly given the 17.5% incidence of bradycardia observed in toddlers, which warrants closer monitoring. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2300075986).
Background:Inadequate post-cesarean analgesia remains a common clinical issue, associated with increased opioid use and risks of chronic pain and postpartum depression. Although the anterior quadratus lumborum block (QLB III) is more effective than transversus abdominis plane (TAP) block, it requires repeated positioning and may cause quadriceps numbness. To address these limitations, we designed a modified QLB to overcome these drawbacks. This study evaluated its analgesic efficacy and safety when combined with liposomal bupivacaine in cesarean delivery. Methods:This single-center, randomized, single-blind trial enrolled 70 patients undergoing elective cesarean delivery. Patients were randomized to modified QLB (Group Q) or TAP block (Group T). The primary outcome was postoperative Day 1 VAS pain score. Secondary outcomes included VAS scores on Days 2, 3, during uterine compression and oxytocin infusion, opioid consumption, recovery metrics, and adverse events. Results:Baseline characteristics were well balanced between the two groups (all p>0.05). The modified QLB group achieved significantly lower VAS pain scores at rest, during uterine palpation and oxytocin infusion throughout the first three postoperative days (all p<0.001), alongside fewer PCIA demands and reduced morphine-equivalent consumption. Recovery indicators and overall adverse event rates were comparable between groups, with no severe neurological or local complications observed in either cohort. Conclusion:Modified single lateral decubitus QLB combined with liposomal bupivacaine yields superior analgesia and reduces opioid consumption compared with the TAP block, demonstrating favorable safety and clinical value for enhancing postoperative recovery following cesarean delivery. Nevertheless, these findings are limited by the single-center design and relatively small sample size, and long-term follow-up of chronic pain and postpartum mental outcomes was not performed. Trial Registration Number:ChiCTR2400094584. The trial is publicly available and is registered at https://www.chictr.org.cn on December 25, 2024.
Purpose:To investigate whether oliceridine is more effective than morphine in reducing the incidence of moderate-to-severe catheter-related bladder discomfort (CRBD) in male patients after transurethral surgery. Patients and Methods:This prospective, randomized, double-blind trial enrolled 372 adult male patients undergoing elective transurethral surgery with urinary catheterization. Patients were randomized to receive oliceridine (1 mg) or morphine (2 mg) intravenously 5 minutes before surgery end. CRBD incidence/severity, Numerical Rating Scale. (NRS), Postoperative nausea and vomiting (PONV), Aldrete recovery scores, adverse events, and the Quality of Recovery-15 scale (QoR-15) score were assessed. Results:The incidence and severity of CRBD at 3 hours postoperatively were significantly lower in the oliceridine group than in the control group (21.5% vs 72.1%; RR 0.298, 95% CI: 0.220-0.403; P<0.001). QoR-15 scores were higher in the oliceridine group on postoperative days 1-3 (P≤0.005). No serious adverse events occurred, and nausea/vomiting incidence and pain score showed no significant difference. Conclusion:Intraoperative oliceridine (1 mg) effectively reduces moderate-to-severe CRBD incidence and severity, improves early postoperative recovery quality, and is well-tolerated in male transurethral surgery patients.
Purpose:Early-stage antibacterial candidate selection requires balancing antibacterial activity with broader developability-related properties. This study developed and applied a Fivefold Maximum Drug-Likeness strategy (5F-MDL) for prioritizing antibacterial candidates against Escherichia coli. Methods:An ensemble of deep learning models generated a 33-dimensional property spectrum covering physicochemical, pharmacokinetic, efficacy-related, safety, and stability endpoints. Approximately 16 million commercial molecules were screened, and fifteen candidates were experimentally evaluated by disk diffusion and broth microdilution. Molecular docking, molecular dynamics simulations, and a Bocillin-FL competition assay examined potential PBP2-associated interactions. Results:The fifteen prioritized candidates showed high property-spectrum similarity to reference antibiotics, with [Formula: see text] scores ranging from 0.929 to 0.971. Broth microdilution identified several molecules with measurable antibacterial activity, among which M2 showed the most balanced overall profile, including an MIC of 25.6 µg/mL and the largest inhibition zone among the candidates. Docking in the 549 Å3 active-site-associated cavity of PBP2 supported a plausible M2-PBP2 binding pose, and 200 ns molecular dynamics simulations supported the stability of the modeled complex. The Bocillin-FL assay further suggested that M2 could interfere with probe labeling of PBP2 in vitro. Conclusion:The 5F-MDL workflow provides a multidimensional property-spectrum-based approach for early-stage antibacterial candidate prioritization. M2 was identified as a preliminary lead-like hit, although its mechanism, safety profile, and broader applicability require further validation.
Background:Platinum-based chemotherapeutic agents are fundamental in the treatment of various malignancies, yet their long-term efficacy is often compromised by cumulative toxicity. This study investigates the association between platinum accumulation and length of hospital stay (LOS), and develops a predictive tool to optimize individualized platinum therapy. Methods:A total of 300 cancer patients receiving platinum-based chemotherapy were enrolled. Serum platinum concentration was measured on day 21 ± 3 after drug administration. The LOS and adverse events were recorded. Mediation analysis explored underlying mechanisms, and a classification and regression tree (CART) model was constructed for risk prediction. Results:Elevated serum platinum concentration significantly prolonged LOS, primarily mediated through reduced red blood cell count (mediation effect accounted for 32.3%). The CART model identified serum platinum concentration > 534.40 μg/L as a key threshold and major predictor of adverse reactions, alongside age > 60.5 years, serum creatinine > 94.50 μmol/L, and use of cisplatin or carboplatin. The model demonstrated an AUC of 0.782 and accuracy of 75.7%. Conclusion:A serum platinum concentration > 534.40 μg/L serves as a clinically meaningful cutoff for identifying patients at high risk of platinum‑related toxicity. The proposed decision‑tree model offers a clinically actionable framework for the early recognition of these high‑risk individuals, facilitating timely dose management and treatment optimization in clinical practice.
Glucagon-like peptide-1 receptor agonists, or GLP-1RAs, have been used for years to treat type 2 diabetes and obesity. More recently, it has become clear that these receptors are widely distributed throughout the central nervous system (CNS), which has raised the possibility of repurposing these drugs for neurological disorders. In this review we go through the evidence across a range of neurological conditions, discuss the main mechanisms thought to explain their neuroprotective effects, and point out the hurdles that still need to be cleared before they can be used in the clinic. Preclinical work has been fairly consistent. These drugs activate the cAMP/PKA/CREB pathway to boost BDNF expression. They also turn on the PI3K/Akt pathway, which reins in GSK-3β and cuts down tau hyperphosphorylation. At the same time, they put the brakes on NLRP3 inflammasome activation in microglia and get AMPK dependent mitochondrial biogenesis and autophagy going. In animal models of Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, intracerebral hemorrhage (ICH), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression, epilepsy, and spinal cord injury (SCI), these cellular changes add up to less protein aggregation, less neuron loss, and better functional outcomes. Clinical data are harder to interpret. Some trials have shown modest improvements in cognition or motor function, but others have found no meaningful effect on disease progression. One thing that does not get enough attention is that different GLP-1 receptor agonists cross the blood-brain barrier at widely varying rates, and these differences could well explain why trial results have been so mixed. Looking ahead, getting these drugs into the clinic will depend on choosing the ones that actually reach the CNS, developing biomarkers that can predict who will respond, and designing trials that take disease heterogeneity into account. Seen this way, this review offers a practical framework for turning mechanistic insights into real patient benefit.
Purpose: This study aimed to investigate the sedative interaction between the new benzodiazepine derivative remimazolam and etomidate during general anesthesia induction and determine the appropriate dose ratio for their combined use. Patients and Methods: Patients scheduled for general anesthesia, aged 18 to 60 years with a BMI of 18 to 28 kg/m2 and American Society of Anesthesiologists (ASA) physical status I-II, were randomly divided into five groups using a random number table. The modified Dixon up-and-down method was employed to determine the median effective dose (ED50) of remimazolam in Group A (remimazolam group) and etomidate in Group B (etomidate group). For the combined medication groups: Group C (0.25 ED50 remimazolam + 0.75 ED50 etomidate), Group D (0.5 ED50 remimazolam + 0.5 ED50 etomidate), and Group E (0.75 ED50 remimazolam + 0.25 ED50 etomidate), the dose of remimazolam was fixed in each group, and the ED50 of etomidate in each group was calculated. Isobolographic analysis was utilized to assess the sedative interaction between the two drugs, and the interaction index and optimal dose ratio for synergism were calculated. Results: The ED50 of remimazolam and its 95% confidence interval (95% CI) in Group A were 0.193 (0.167-0.253) mg/kg, while those of etomidate in Group B were 0.155 (0.118-0.20) mg/kg. Isobolographic analysis revealed remimazolam and etomidate produced a synergistic effect in Groups C and D, and an additive effect in Group E. When combined at 0.048 mg/kg remimazolam and 0.062 mg/kg etomidate, the optimal dose ratio for the strongest synergism was 1:1.29. Conclusion: During general anesthesia induction, when the dose ratios of remimazolam to etomidate are approximately 1:1.29 and 1:0.39, the two drugs exert a synergistic sedative effect, with the strongest synergism observed at the dose ratio of 1:1.29.
Purpose:This study aimed to design and characterize a novel dual-function floating-bioadhesive drug delivery system based on a hollow structure to extend gastroretentive time and enhance the bioavailability of ofloxacin. Methods:Hollow spherical shells were fabricated via fluidized-bed coating using a blended polymer film composed of (SuE (Surelease® E-7-19040) and EuN (Eudragit® NE 30D)). The system integrated a hollow spherical shell, a waterproof layer, a drug layer, a release-retarding ethylcellulose (EC) film, and an outer bioadhesive layer. The mechanical properties, in vitro floating and bioadhesive behavior, drug release profile, and in vivo pharmacokinetics were comprehensively evaluated. Results:The blended film at a SuE/EuN ratio of 4:4 exhibited optimal mechanical rigidity and strength for the hollow shell. Analysis of the release profile showed a zero-order release for the first 4 h, which was in accordance with the predicted value. The optimized formulation demonstrated excellent buoyancy with a floating rate of 96.3±0.5% and 100% bioadhesion on gastric mucosa. In vivo pharmacokinetic studies in New Zealand rabbits revealed that the test formulation had a prolonged elimination half-life (6.65±0.94 h) and a relative bioavailability of 112.2±14.9% compared to the reference tablet. Conclusion:The developed floating-bioadhesive system successfully combined hollow-structure buoyancy with mucoadhesion to achieve prolonged gastric retention and sustained drug release, offering a feasible approach for gastroretentive drug delivery systems.
