Drug Design, Development and Therapy最新文献

Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder associated with considerable morbidity and mortality. Currently, no therapeutic agents exist that can achieve a fundamental reversal or complete cure for this condition. Consequently, the identification of novel molecular targets and the development of innovative treatment modalities aimed at slowing progression and alleviating symptoms represent pressing priorities within AD clinical research. Ferroptosis, a regulated cell death process driven by intracellular iron dysregulation and excessive lipid peroxidation, is now recognized as a critical contributor to AD pathogenesis. Traditional Chinese medicine (TCM) has demonstrated beneficial outcomes in managing AD, and emerging evidence suggests its regulatory effects may extend to modulating ferroptotic pathways. This review summarizes and analyzes the therapeutic efficacy of various TCM strategies against AD, including herbal extracts, monomers (eg, alkaloids, terpenoids, glycosides, phenolic derivatives, quinones), compound formulas, and acupuncture. It highlights how these interventions target key ferroptosis-related axes-such as iron homeostasis, the system Xc-/GSH/GPX4 antioxidant system, and the Keap1/Nrf2/ARE pathway-to collectively address the pathological foundation of the disease. However, current evidence is predominantly preclinical, and the translational potential of TCM is constrained by challenges including blood-brain barrier penetration, pharmacokinetic profiles, standardization, and safety assessments. In conclusion, TCM exhibits substantial potential for both research and clinical application in AD by targeting and attenuating the ferroptosis pathway, offering promising avenues for disease modification and symptomatic relief.

Purpose: Intraoperative bradycardia is a recognized complication during radiofrequency (RF) rhizotomy for trigeminal neuralgia, primarily related to the trigeminal-cardiac reflex. Dexmedetomidine is commonly used for its sedative and analgesic properties during these procedures; however, its hemodynamic impact has not been well characterized. This study aimed to evaluate the association between dexmedetomidine use and intraoperative bradycardia and to identify relevant clinical risk factors.

Patients and methods: This retrospective observational study included 517 patients who underwent RF rhizotomy for trigeminal neuralgia under monitored anesthesia care between August 2020 and December 2022. Patients were categorized into dexmedetomidine (Dex) and non-dexmedetomidine (Non-Dex) groups. The primary outcome was intraoperative bradycardia, defined as a heart rate <60 beats per minute or the need for atropine. Secondary outcomes included atropine use, intraoperative heart rate distribution, and anesthetic drug requirements. Multivariable logistic regression and age-stratified subgroup analyses were performed.

Results: Dexmedetomidine was administered in 331 patients (64.0%). Intraoperative bradycardia occurred more frequently in the Dex group than in the Non-Dex group (59.8% vs 29.0%, p<0.001), with a higher incidence of atropine administration (18.1% vs 4.8%, p<0.001). Dexmedetomidine use was independently associated with bradycardia (odds ratio [OR] 5.16; 95% confidence interval [CI] 2.57-10.39; p<0.001). Notably, dexmedetomidine significantly reduced intraoperative requirements for midazolam (median 0.038 vs 0.044 mg/kg/h; p<0.001) and propofol (median 0.73 vs 1.25 mg/kg/h; p<0.001). Younger age (OR 0.97 per year; 95% CI, 0.96-0.99; p<0.001) and longer anesthesia duration (OR 1.04 per minute; 95% CI, 1.02-1.06; p<0.001) were additional predictors of bradycardia. Age-stratified analyses revealed a more pronounced reduction in heart rate among younger patients (< 45 years) receiving dexmedetomidine, suggesting an age-dependent modulation of the bradycardic response.

Conclusion: Although dexmedetomidine use was associated with a higher incidence of intraoperative bradycardia, it provided meaningful anesthetic benefits during RF rhizotomy, including significant sedative-sparing effects and reduced exposure to other hypnotic agents. With appropriate monitoring and individualized dosing, particularly in younger patients, dexmedetomidine remains a safe and valuable sedative option for trigeminal neuralgia procedures.

Perioperative EGFR-targeted therapy has transformed the management of resectable EGFR-mutated NSCLC. However, prolonged exposure introduces chronic toxicity and pain that may erode long-term benefit. This narrative review synthesizes evidence from pivotal perioperative EGFR-TKI trials, emerging fourth-generation EGFR-TKIs, and studies on pain, toxicity, adherence, and patient-reported outcomes, with a focus on minimal residual disease (MRD)-guided treatment adaptation. Current data show that adjuvant and neoadjuvant EGFR-TKIs substantially reduce recurrence and may improve survival, yet pain and related functional impairment remain under-recognized, under-measured, and inconsistently managed. Procedure-related and treatment-emergent pain, neuropathy, and musculoskeletal symptoms interact with psychological, comorbid, and social factors to undermine adherence, particularly during prolonged adjuvant therapy. Fourth-generation EGFR-TKIs and MRD-guided strategies create opportunities to optimize exposure and duration but demand structured monitoring of pain, standardized electronic patient-reported outcomes, and integrated oncology-anesthesiology-palliative care pathways. We propose an efficacy-safety-pain-adherence loop in which pain is treated as a core determinant of therapeutic success, aiming to maximise cure potential while preserving quality of life.

Purpose: Postoperative atelectasis remains a significant concern after video-assisted thoracoscopic surgery (VATS). This study aimed to evaluate the association between sugammadex use and postoperative atelectasis in patients who underwent VATS.

Patients and methods: From the TriNetX Global Collaborative Network (2016-2024), adults undergoing elective VATS who received rocuronium reversed with either sugammadex or neostigmine were identified. The primary outcome was atelectasis within 30 days, identified using the administrative ICD diagnostic codes recorded in the TriNetX database. The secondary outcomes included pneumonia, acute respiratory failure, pneumothorax, sepsis, and major adverse cardiovascular events (MACEs). Outcomes were additionally assessed at 7-day and 90-day intervals.

Results: After propensity score matching (1:1), 7345 patients were analyzed per group. Sugammadex exposure was associated with lower odds of atelectasis at 30 days (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.86; P < 0.001), corresponding to an absolute risk reduction of 3.3% (15.3% vs 18.6%). The association remained consistent at 7-day (OR, 0.75) and 90-day (OR, 0.81) follow-ups. Time-to-event analysis demonstrated a lower hazard of atelectasis (hazard ratio, 0.82; 95% CI, 0.76-0.88). Sugammadex was also associated with reduced pneumothorax (OR, 0.90) and MACEs (OR, 0.75), but not with pneumonia, respiratory failure, or sepsis. Subgroup analyses revealed significant interactions between sex (P = 0.003) and obesity status (P = 0.047), with more pronounced associations in males and non-obese patients.

Conclusion: Sugammadex use was associated with a reduced postoperative atelectasis risk in patients undergoing VATS. Prospective randomized trials are warranted to confirm these findings and establish causality.

Purpose: This study aims to explore the effect of preoperative esketamine nebulized inhalation on cough reflex during extubation for surgical patients who received general anesthesia.

Patients and methods: A total of 84 patients scheduled for thoracolumbar spine surgery were included in the study. All patients were randomly divided into two groups. Patients in the experimental group (Group K) received 5 mL of esketamine solution (50 mg esketamine + 3 mL of saline) by nebulized inhalation for 15 minutes. Patients in the control group (Group S) received an equal volume of saline as placebo. The incidence and intensity of the cough reflex were evaluated. The Riker Sedation-Agitation Scale score, Ramsay sedation score, and Monitoring of sore throat following surgery were performed at 0, 2, 4, 6, 12, and 24 hours post-surgery.

Results: The incidence of cough reflex was lower in Group K (31.0%) than in Group S (71.4%), and cough intensity was milder in Group K than in Group S (P<0.001). The Ramsay sedation scale score post-extubation was higher in Group K than in Group S (P=0.002). The incidence and severity of postoperative sore throat in Group K were lower than in Group S at 2, 4, 6, 12, and 24 hours following extubation (all P<0.05).

Conclusion: Preoperative esketamine nebulized inhalation has a potential inhibitory effect on the cough reflex during extubation for patients who received general anesthesia via tracheal intubation.

Purpose: This study is the first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of single ascending doses (SAD) and multiple ascending doses (MAD) of JMKX003142 injection in healthy Chinese subjects.

Patients and methods: In this Phase I, randomized, double-blind, placebo-controlled study, 48 subjects in the SAD (0.1-6 mg) study received intravenous injection of JMKX003142 or placebo in ascending dose. Thirty subjects in the MAD (1-4 mg) study received an intravenous injection of JMKX003142 or placebo once a day for five consecutive days. The primary endpoint was the safety and tolerability of JMKX003142 injection, with the secondary and exploratory endpoints focusing on its PK and PD profiles, respectively.

Results: The JMKX003142 injection exhibited favourable safety and tolerability, with all treatment-emergent adverse events (TEAEs) being mild. No serious adverse events, deaths or discontinuations due to TEAEs were observed. Following single and multiple intravenous injections of JMKX003142, the maximum concentration (C_max) and area under plasma concentration-time curve (AUC) of JMKX003142 and its metabolites increased with dose level, with increases in C_max being dose-proportional. In 1 mg or higher dose group of SAD study, the mean terminal half-life (t_1/2) of JMKX003142 was between 5.2 and 12.7 h. Following multiple intravenous injections of JMKX003142, the t_1/2 of JMKX003142 was determined to range from 11.1 and 11.8 h. Moreover, JMKX003142 demonstrated favourable PD profiles following both single and multiple intravenous injections. The evaluation of the daily cumulative urine volume indicated that the diuretic effect of the JMKX003142 injection was evident at doses of 1 mg and above, with effects intensifying at higher doses.

Conclusion: Overall, both single and multiple intravenous injections of JMKX003142 have been demonstrated to be safe, well tolerated, and to possess excellent PK characteristics as well as significant diuretic activity.

Trial registration: This study was registered with ClinicalTrials.gov (NCT06344533).

Diabetic kidney disease (DKD) represents the most severe microvascular complication of diabetes and is the leading cause of end-stage renal disease globally. Its pathogenesis is complex, and current treatments have limitations. Advanced glycation end products (AGEs) and AGEs receptor (RAGE), constitute a core mechanism driving DKD progression. AGEs accumulate abnormally in high-glucose environments. Upon activation, RAGE mediates oxidative stress, chronic inflammation, renal fibrosis, dysregulation of autophagy, and apoptosis through multiple signaling pathways, ultimately leading to damage to the glomerular filtration barrier and exacerbating renal injury from multiple dimensions. This paper aims to elucidate the role of the AGEs-RAGE pathway in DKD and systematically review therapeutic strategies targeting this pathway. These include AGEs antagonists, AGEs-RAGE axis modulators, RAGE ligand binding inhibitors, antibody-based therapeutics, and traditional Chinese medicine. Additionally, clinical studies of AGEs-RAGE axis-targeted drug therapies for DKD are analyzed. This paper provides theoretical foundations for developing novel therapeutic drugs in DKD.

Background: Preoperative sedation is critical to alleviate anxiety in children undergoing neurosurgery, but the role of remimazolam is still uncertain such as its unestablished dosing and safety. This study was aimed to determine the 90% effective dose (ED90) of remimazolam for moderate sedation in this pediatric population.

Methods: This dose-finding study enrolled children aged 3 months to 6 years scheduled for neurosurgery. The up-and-down method (k-in-a-row, k= 6) was employed to investigate the ED90 of remimazolam for moderate sedation. According to the k-in-a-row rule, one patient received a predefined dose of remimazolam and the dosing assignment of the next patient depended on whether the former patient reached moderate sedation or not. Moderate sedation was assessed using the modified Observer's Assessment of Alertness/Sedation (MOAA/S). Remimazolam doses ranged from 0.05mg/kg to 0.35mg/kg with a step gradient of 0.05mg/kg. The ED90 and 95% confidence interval (CI) were calculated by centered isotonic regression. Secondary outcomes included drug-related adverse events, the incidence of emergence delirium (ED), and changes in brain network connectivity which were monitored by functional near-infrared spectroscopy (fNIRS).

Results: Forty-eight children were enrolled with a median age of 20.5 (9.0, 35.0) months. The ED90 of remimazolam for moderate sedation was 0.28 (95% CI 0.24-0.42) mg/kg. The incidence of drug-related adverse events was about 12.5%, including respiratory depression and hiccup. The incidence of ED was 62.2%. fNIRS showed increased connectivity in right frontal lobe-right occipital lobe, right frontal lobe-left occipital lobe, and right frontal lobe-left parietal lobe (all P values < 0.05 after correction by false discovery rate).

Conclusion: This study reported the ED90 of remimazolam for moderate sedation in neurosurgical children. These results provided important information for the use of remimazolam in children with neurologic disease.

Introduction: Amiodarone (AMIO) is one of the most prescribed antiarrhythmic medications and is commonly used to treat atrial and ventricular fibrillations. A notable adverse effect of AMIO is pulmonary fibrosis. Cannabinoid (O-2545) has been shown to exert antioxidant, anti-inflammatory, and antifibrotic effects in both in vivo and in vitro experimental models. The present study aimed to investigate whether cannabinoid (O-2545) may attenuate amiodarone-induced pulmonary fibrosis in male Wistar rats.

Methods: A regimen of 50 mg/kg AMIO was administered via oral gavage daily for 10 consecutive days to induce acute pulmonary fibrosis. The experiment included 24 Wistar rats assigned to four groups. The control group received daily subcutaneous injections of normal saline for the same time period. The AMIO group received a daily oral gavage of AMIO (50 mg/kg) for 10 days. Concurrently, the O-2545 group received daily oral doses of cannabinoid. The combined treatment group received both AMIO and cannabinoid orally each day for 10 days.

Results: High-dose AMIO (50 mg/kg) administration resulted in a significant elevation of oxidative stress, followed by a decrease in antioxidant function, an increase in inflammatory cytokines, fibrosis markers, and apoptosis. Pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and adenosine (Adens), apoptotic markers tumor protein p53 (p53) and caspase 3 protein (caspase-3), oxidative stress malondialdehyde (MDA), fibrosis indicator hydroxyproline (HYDROX), and histone deacetylase (HDAC) activity, accompanied by a marked reduction in the antioxidant glutathione (GSH), compared to the control group. Histopathological examination of pulmonary tissues revealed that O-2545 significantly mitigated AMIO-induced pulmonary fibrosis. In conclusion, the results showed that cannabinoid (O-2545) may offer significant therapeutic potential in mitigating pulmonary toxicity induced by AMIO in rats.

Purpose: This study investigates the possible protective therapeutic effects of (O-2545) on AMIO-induced pulmonary fibrosis in Wistar rats.

Purpose: This study aimed to assess the physicochemical stability and compatibility of butorphanol tartrate, nicardipine hydrochloride, urapidil, and tirofiban hydrochloride to support safe infusion practices in the ICU.

Patients and methods: Compatibility systems involving four-, three-, and two-drug combinations were prepared in 0.9% sodium chloride injection under simulated clinical conditions at room temperature in the absence of light. Evaluations included appearance, pH, and insoluble particle counts at 0, 2, 4, 8, 12, and 24 hours. Quantitative analysis of drug concentrations was performed using high performance liquid chromatography (HPLC).

Results: All tested combinations retained physical stability within 24 hours, showing no measurable variation in appearance, pH, or particle. Nicardipine concentrations declined significantly, reaching 74.35% of baseline in the nicardipine-urapidil-tirofiban mixture at 24 hours, and decreasing to 76.29% at 12 hours and 71.46% at 24 hours in the nicardipine-tirofiban combination. The concentrations of active ingredients in the remaining mixtures remained stable, consistently exceeding 90% of initial values.

Conclusion: Butorphanol demonstrated compatibility with the other agents under the tested conditions. In clinical application, infusion of nicardipine combined with tirofiban should be restricted to less than 8 hours, and nicardipine combined with urapidil and tirofiban should not exceed 12 hours. Other mixtures can be administered for up to 24 hours with flexibility in infusion duration.