Drug Design, Development and Therapy最新文献

Purpose: The effect of esketamine on perioperative inflammatory factors and postoperative analgesic outcomes in patients with Obstructive sleep apnea syndrome (OSAS) remains unclear. This trial assesses whether 0.25 mg · kg^- esketamine during general anesthesia can reduce the inflammatory level and relieve postoperative pain in OSAS patients.

Patients and methods: 96 adult patients with OSAS underwent palatopharyngoplasty under general anesthesia was included in our research. Following anesthetic introduction, subjects were randomized to either 0.25 mg · kg^- esketamine (in 20mL solution; esketamine group) or an equivalent volume of saline (Control group). The primary result was the level of IL-6 and TNF-α before the infusion of esketamine, 40min, 4h, and 24h after the esketamine infusion. Secondary outcomes was NRS scores immediately after tracheal extubation, 4h after the infusion, postoperative day 1 (POD1), postoperative day 2 (POD 2) and postoperative day 7 (POD 7).

Results: The esketamine group demonstrated significantly reduced IL-6 and TNF-α levels at 40 minutes post-infusion (P<0.001) and showed lower the numerical rating scale(NRS)scores with less rescue analgesia immediately after extubation (P<0.001) compared to the control group, despite prolonged extubation and post-anesthesia care unit (PACU) stay (P<0.001). Across POD1-2, the esketamine group maintained reduced NRS scores (P<0.001) and analgesic doses (P=0.021), higher quality of recovery-15 (QoR-15) scores and patient satisfaction scores (P<0.001) relative to control group. It is important to note that the significant differences in inflammatory markers and pain scores between groups were not sustained at the 24-hour assessment and on postoperative day 7, respectively, indicating transient effects.

Conclusion: Intraoperative infusion of 0.25 mg·kg^- esketamine provided transient suppression of inflammatory responses and reduced early postoperative pain in OSAS patients. However, these benefits were exploratory and time-limited, and must be weighed against prolonged extubation and PACU stay.

Objective: To determine the efficacy and safety of clobazam, a benzodiazepine derivative endorsed for adjunctive therapy in drug-resistant epilepsy due to its broad-spectrum efficacy and tolerability profile, as an adjunctive treatment for pediatric patients with drug-resistant epilepsy.

Methods: This was a multicenter, real-world, self-controlled study. Pediatric drug-resistant epilepsy patients receiving clobazam adjunctive treatment at three centers were retrospectively included. The primary outcomes were response rates and seizure-free rates at 6 and 12 months of treatment. The secondary outcomes included retention rates at months 6 and 12 of treatment and adverse events that occurred during the addition of clobazam therapy.

Results: A total of 146 patients were included. The retention rates were 87.67% (128/146) and 81.51% (119/146) at 6 and 12 months, respectively. The response rates were 58.99% (82/139) and 62.41% (83/133), and the seizure-free rates were 36.69% (51/139) and 35.34% (47/133) at 6 and 12 month, respectively. Clobazam has shown good efficacy in patients with epilepsy due to genetic variants (60.42%, 29/48) and its significantly better efficacy for the SCN1A genotype than for other genotypes (P=0.048). The independent factor associated with clinical response was a lower baseline seizure frequency (seizure frequency <1 seizure/day). Adverse reactions occurred in 24 (24/146, 16.64%) patients, with excessive salivation/hypersalivation (4/146, 2.74%) and loss of appetite (4/146, 2.74%) being the most common.

Conclusion: Clobazam adjunctive therapy is effective, safe and well tolerated in pediatric patients with drug-resistant epilepsy.

Purpose: To investigate the optimal dose of butorphanol for patient-controlled intravenous analgesia (PCIA) by evaluating its effects on perioperative pain control and immune function in patients undergoing ovarian cancer surgery.

Patients and methods: Patients undergoing ovarian cancer surgery between May 2023 and March 2025 were randomized into four PCIA groups: Group S (sufentanil 0.04 μg·kg^-1·h^-1), B1 (low-dose butorphanol 3.0 μg·kg^-1·h^-1), B2 (medium-dose butorphanol 3.5 μg·kg^-1·h^-1), and B3 (high-dose butorphanol 4.0 μg·kg^-1·h^-1). Postoperative pain visual analog scale scores (VAS) were recorded for each group at T1 (2 h), T2 (6 h), T3 (12 h), T4 (24 h), and T5 (48 h). The number of PCIA button presses, rescue analgesia frequency, adverse reactions, inflammatory biomarkers, postoperative recovery indicators, and the level of lymphocyte subsets and NK cells were recorded.

Results: VAS score at T3 was lower in group B3 than in S (P = 0.042). VAS scores at T3 and T4 were lower in groups B2 (P = 0.007 and P < 0.001) and B3 (P = 0.005 and P < 0.001) than in B1. Compared to group S, B1 showed an increased area under the curve of VAS time (AUC_VAS-time) over 48 hours (P = 0.010), whereas group B3 exhibited a decrease in AUC_VAS-time (P = 0.004). Group B3 had shorter postoperative time to ambulate than group S (P = 0.041). In group S, NK cells at T5 were lower than those at T0 (P = 0.007). In group B1, levels of CD4+ T cells, and CD4+/CD8+ ratio were higher at T5 than at T0 (P = 0.007 and P = 0.014), whereas CD8+ T cell count was lower (P = 0.011).

Conclusion: High-dose butorphanol PCIA effectively relieves postoperative pain and reduces time to early ambulation without affecting immune indicators within 48 h postoperatively.

Background: Anlotinib and bevacizumab have demonstrated efficacy in treating HER-2 (human epidermal growth factor receptor 2)-negative metastatic breast cancer (MBC), yet no comparative studies have been conducted to access their effectiveness in MBC patients. Accordingly, this study aimed to evaluate the safety and effectiveness of anlotinib versus bevacizumab when combined with taxane/capecitabine for second-line or subsequent treatment of HER-2-negative MBC.

Methods: Patients with pathologically confirmed HER-2-negative MBC that underwent second-line or subsequent treatment of anlotinib or bevacizumab plus taxane/capecitabine between April 2020 and October 2021 were retrospectively reviewed. Outcomes including the objective response rates (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were analyzed.

Results: A total of 130 patients were included for this study, with 67 in the anlotinib + chemotherapy group and 63 in the bevacizumab + chemotherapy group. The ORRs were 40.30% for the anlotinib + chemotherapy group and 30.16% for the bevacizumab + chemotherapy group (P = 0.27), while the DCRs were 86.57% and 69.84%, respectively (P = 0.03). Patients in the anlotinib + chemotherapy group showed significantly longer median PFS and OS compared to the bevacizumab + chemotherapy group (mPFS: 8.57 vs 5.90 months, HR 0.55 [95% CI 0.36-0.85], P = 0.04; mOS: 22.76 vs 16.50 months, HR 0.63[95% CI 0.43-0.93], P = 0.02). The most common treatment-related adverse events (TRAE) were grade 1/2 alopecia, peripheral neuropathy, hypertension, and granulocytopenia, with both groups exhibiting tolerable TRAE profiles.

Conclusion: In this retrospective analysis, anlotinib combined with taxane/capecitabine demonstrated a manageable safety profile. This regimen was associated with improved DCR, PFS, and OS compared to bevacizumab plus chemotherapy in patients with HER2-negative MBC. These findings suggest that anlotinib may represent a promising therapeutic option for patients for whom ADC drugs are inaccessible or unsuitable; however, further prospective, randomized studies are warranted to confirm.

Background: Cervical dilation during ambulatory hysteroscopy often triggers somatic responses that challenge patient comfort and procedure smoothness. While esketamine's unique analgesic profile could address this, its effective dose within a dexmedetomidine-remifentanil monitored anesthesia care (MAC) protocol is undefined.

Methods: In this prospective, double-blind, dose-finding study, 30 women received a standardized MAC protocol (dexmedetomidine 0.6 μg∙kg^-1 loading dose followed by 0.4 μg∙kg^-1∙h^-1, with remifentanil 5 μg∙kg^-1∙h^-1). Esketamine was administered via Dixon's up-and-down sequential design (initial dose 0.3 mg∙kg^-1; increments/decrements 0.02 mg∙kg^-1) before cervical dilation. Positive response is defined as the absence of purposeful movement. The median effective dose (ED50) and 95% effective dose (ED95) were calculated using probit regression.

Results: 30 patients completed the study. The ED50 of esketamine was 0.36 mg∙kg^-1 (95% CI 0.35-0.37) and the ED95 was 0.39 mg∙kg^-1 (95% CI 0.37-0.42). Hemodynamic stability was maintained (mean arterial pressure change ≤15% from baseline) with no respiratory depression. Adverse events were self-limiting dizziness (66.7%) and nausea (6.7%). Recovery was swift, with a time to meet post-anesthesia care unit (PACU) discharge criteria of 17.93±3.30 min, and patient satisfaction was high (median score 9/10, IQR 8-10).

Conclusion: Under dexmedetomidine-remifentanil MAC, esketamine 0.39 mg∙kg^-1 (ED95) effectively suppresses the cervical dilation response, promotes hemodynamic and respiratory stability, and facilitates a rapid, enhanced recovery after surgery (ERAS)-compliant recovery. This dose-finding study provides a practical and effective anesthetic combination for clinical implementation in ambulatory hysteroscopy.

Clinical trial registration: ClinicalTrials.gov (identifier: NCT07034963). Principal Investigator: Lijuan Yan.

Purpose: Postoperative delirium (POD) is frequent and consequential in older adults, especially those with preexisting sleep disorders. While perioperative intravenous dexmedetomidine may lower POD risk, the benefit of preoperative intranasal administration is unknown. This study aimed to determine whether preoperative intranasal dexmedetomidine reduces POD in elderly patients with sleep disorders undergoing major noncardiac surgery.

Patients and methods: In this randomized, triple-blind, placebo-controlled trial, 348 elderly patients (≥60 years) with a Pittsburgh Sleep Quality Index >7 undergoing major noncardiac surgery were enrolled between November 2023 and August 2024. Participants received either intranasal dexmedetomidine (n=174) or placebo (n=174) the night before surgery (20:30-00:00). Dexmedetomidine was administered using a weight-based regimen (≤45 kg: 45 μg; 45-75 kg: 60 μg; ≥75 kg: 75 μg), with a rescue dose of 30 μg allowed if sleep onset did not occur within 30 minutes. The primary outcome was the incidence of POD within 5 days postoperatively. Secondary outcomes included preoperative sleep quality, delayed neurocognitive recovery (dNCR) at 7 and 30 days postoperatively, and adverse events on the night before surgery.

Results: The incidence of POD was significantly lower in the dexmedetomidine group than in the placebo group (18.4% vs 32.8%, RR:0.56, 95% CI:0.38-0.82, P=0.002). Preoperative dexmedetomidine also improved sleep quality on the night before surgery, including total sleep time (6.2±1.5 hours vs 5.3±1.7 hours, mean difference:0.89, 95% CI:0.56-1.23, P<0.001), sleep efficiency (77.3%±16.0% vs 66.3%±19.1%, mean difference:11.01%, 95% CI:7.3%-14.7%, P<0.001), and subjective sleep quality as assessed by the Richards-Campbell Sleep Questionnaire (68 ± 13 vs 59 ± 15, mean difference:9.31, 95% CI:6.35-12.27, P<0.001). There was no between-group difference in dNCR at day 7 or day 30 (both P > 0.05). Dexmedetomidine was associated with a higher incidence of bradycardia during the preoperative night (37.9% vs 16.7%; RR:2.28, 95% CI:1.55-3.34, P < 0.001), while the incidence of other adverse events was similar between groups (all P >0.05).

Conclusion: Preoperative intranasal dexmedetomidine reduced the incidence of POD and enhanced preoperative sleep quality in elderly patients with sleep disorders undergoing major noncardiac surgery. Given the increased risk of bradycardia, these benefits should be weighed against the need for perioperative monitoring.

Objective: We conducted a retrospective study to investigate the prevalence, clinical characteristics, and risk factors for leukopenia in patients receiving piperacillin-tazobactam (TZP) therapy.

Methods: This observational study was conducted from January to December 2022 at a tertiary general hospital in China. All patients over 18 years old who received TZP for more than 48 hours were included. Patients were stratified into adverse drug reactions (ADR) (n=41, TZP-induced leukopenia or neutropenia) and Control (n=8014, no ADR) groups. To balance covariates, 1:2 propensity score matching (PSM) was applied using age, infection type, gender, and comorbidity index, resulting in 82 matched controls for comparative analysis. We employed least absolute shrinkage and selection operator (LASSO) regression to identify risk factors for TZP-induced leukopenia.

Results: A total of 123 patients were analyzed. The average duration of treatment was 10 days (IQR: 7, 19). In 41 patients with TZP-induced leukopenia, the mean onset time was 17.7 ± 6.6 days. Among these, 29 (70.7%) developed neutropenia (including 1 severe case), and 3 (7.3%) had drug-induced fever. Therapy duration (odds ratio (OR) = 1.53, 95% confidence interval (CI) 1.32-1.76) was identified as a significant influencing factor for leukopenia caused by TZP through the LASSO regression screening process.

Conclusion: Clinicians should recognize the potential association between TZP administration and leukopenia. Routine hematologic monitoring should emphasize leukocyte trends to assess both therapeutic response and drug safety.

Objective: This study aims to investigate and discuss the effect of pericapsular nerve group (PENG) block with liposomal bupivacaine (LB) on postoperative rebound pain following hip fracture in older adults.

Patients and methods: Ninety patients scheduled for hip fracture surgery were randomized into three groups: LB (liposomal bupivacaine, 30 mL), R (0.375% ropivacaine, 30 mL), and C (saline, 30 mL). MAP and HR were recorded at T1 (pre-induction), T2 (post-intervention), and T3 (skin incision). NRS scores were evaluated at 12-72 h postoperatively, along with rebound pain, quadriceps function, analgesic consumption, and adverse reactions.

Results: The incidence of rebound pain was significantly lower in the LB and R groups than in the C group (p < 0.05). The AUC of NRS scores over 72 hours was significantly lower in the LB group (2.053 ± 1.258) than in the R (3.600 ± 2.087) and C (4.880 ± 2.739) groups (p < 0.0001). Hemodynamic analysis revealed significant differences in HR between T2 and T3 in all groups (LB: 77.10 ± 11.28 vs 73.77 ± 8.47; R: 79.57 ± 8.05 vs 74.00 ± 8.13; C: 80.50 ± 8.71 vs 84.13 ± 8.07; p < 0.05). MAP in the LB group differed significantly from Group C across the three time points (p < 0.05). There were no significant differences between the groups in adverse events.

Conclusion: LB PENG blockade reduces rebound pain incidence post-nerve block in elderly hip fracture patients, decreases PCA demand, preserves quadriceps function, and enhances satisfaction.

UDCA is a natural steroid in bear bile, which has important medicinal value. It is used to treat hepatobiliary diseases in clinic. Due to its unique molecular skeleton, UDCA has a wide range of biological activities, special target and low toxicity, and is considered to be a powerful structural mother nucleus, which has attracted more and more researchers' attention and become the focus of attention again. So far, UDCA derivatives with diverse structures have been designed and their biological activities have been extensively studied. In this paper, the pharmacological activities, biosynthesis and structural modification of UDCA were systematically discussed. It is believed that with the deepening of research, more UDCA derivatives with better medicinal properties will become drugs and better serve human health.

Purpose: The aim was to investigate the effect of esketamine-dexmedetomidine (ESK-DEX) combination on immediate postprocedural oxygenation index (OI) in severe pneumonia patients undergoing bedside fiberoptic bronchoscopic (FOB) sputum aspiration, and provide clinical reference.

Methods: A total of 90 patients diagnosed with severe pneumonia receiving non-invasive mechanical ventilation (NIV) who underwent bedside FOB were randomly and evenly divided into three groups: Group C (local anesthesia alone), Group D (DEX alone), Group ED (ESK-DEX). The primary outcome was the OI immediately after procedure (T1). The secondary outcomes: the OI was calculated at 6 h (T2), 12 h (T3), and 24 h (T4) after procedure; the mean arterial pressure (MAP) and heart rate (HR) were assessed at the following time points: FOB tip passage through nostril (t1), glottis (t2), 5 minutes after procedure (t3), and upon procedure completion (t4); Additionally, perioperative adverse events were also documented.

Results: The Group ED demonstrated significantly higher OI compared to Group C at T1 (mean difference, -8.1; 95% CI, -13.48, -2.64; P=0.001). Similarly, the Group ED demonstrated significantly higher OI compared to Group C at each time point from T2 to T4, respectively (all P<0.05). Regarding hemodynamic parameters, both Group ED and Group D exhibited significantly lower MAP and HR values compared to Group C from t1 to t4 time points, respectively (all P<0.05). The total incidence of adverse events in Group ED was significantly reduced compared to Groups C (P=0.033).

Conclusion: Compared with conventional sedation protocols, the ESK-DEX combined regimen demonstrated superior OI preservation immediately after procedure, enhanced OI within 24 hours postoperatively, improved hemodynamic stability, and enhanced safety profile in severe pneumonia patients undergoing bedside FOB-guided suction therapy. This pharmacodynamic synergy addresses critical gaps in FOB sedation-simultaneously preventing hypoxemia, maintaining respiratory drive, and minimizing adverse events.