Drug Design, Development and Therapy最新文献

Purpose: This study investigated fluoxetine (FLX) effects on chronic unpredictable mild stress (CUMS)-induced depression and constipation, and to explore the potential synergistic benefits of combining FLX with butyrate supplementation.

Methods: A mouse model of CUMS and functional constipation (FC) was established. Behavioral assessments, fecal parameters, colonic transit time, and histological analysis were performed. Serotonin signaling, gastrointestinal hormones, intestinal barrier function, and inflammatory markers were measured. Gut microbiota composition was assessed using 16S rRNA sequencing, and fecal short-chain fatty acid (SCFA) levels were quantified by gas chromatography-mass spectrometry.

Results: FLX significantly alleviated depressive-like behaviors (40% reduction in immobility time) and improved gastrointestinal motility (35% increase in fecal pellet output) in CUMS-FC mice. FLX restored serotonin signaling (2.5-fold increase in 5-HT levels), enhanced intestinal barrier integrity (60% upregulation of ZO-1/Occludin), and increased gut microbial diversity (Shannon index increased by 30%). FLX elevated butyrate-producing bacteria and fecal butyrate levels by 45%. Notably, the novel FLX-butyrate combination produced synergistic effects, achieving 65% improvement in gut motility, 70% reduction in pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), and 80% restoration of intestinal barrier function compared to FLX alone.

Conclusion: FLX alleviates CUMS-induced depression and constipation through restoring serotonin signaling, modulating gut microbiota toward SCFA production, and improving intestinal barrier function. The novel synergistic enhancement achieved by FLX-butyrate combination demonstrates superior therapeutic efficacy, highlighting its potential as an innovative dual-targeting strategy for gut-brain axis disorders.

Background: Establishing the minimum effective volume (MEV90) of liposomal bupivacaine for ultrasound‑guided interscalene brachial plexus block (ISB) is essential to optimize postoperative analgesia and minimize local anesthetic-related side effects in patients undergoing arthroscopic rotator cuff repair. Determining this optimal volume provides a clinically meaningful reference for achieving consistent nerve block success while reducing unnecessary drug exposure and the risk of systemic toxicity. Therefore, the present study aimed to identify the MEV90 of liposomal bupivacaine for ISB in patients undergoing arthroscopic shoulder surgery.

Patients and methods: This dose-finding study enrolled 51 patients scheduled for arthroscopic rotator cuff repair. Using a biased-coin up-and-down sequential design, patients received varying volumes of liposomal bupivacaine for ultrasound-guided ISB. The MEV90 was determined using centered isotonic regression. The occurrence of adverse events was systematically recorded for 72 hours.

Results: The MEV90 of liposomal bupivacaine for ISB was 10.0mL (90% CI, 9.3 to 12.5mL). A moderate positive correlation was identified between the time to first analgesic request and the volume of liposomal bupivacaine administered (r = 0.6, P < 0.001). Adverse events within 72 hours following the block included dizziness (7.8%), nausea and vomiting (9.8%), and chest discomfort (3.9%).

Conclusion: The MEV90 of liposomal bupivacaine for ultrasound-guided interscalene brachial plexus block in patients undergoing rotator cuff repair surgery was found to be 10.0 mL.

Objective: The objective of this study was to evaluate the developmental and hormonal safety profile of different doses of allylestrenol administered during gestation in SD rats, focusing on selected physiological and reproductive indices in the Parental (F0) and First-generation offspring (F1) generations.

Methods: In this study, 138 successfully mated Sprague-Dawley (SD) female rats were randomly divided into solvent control (Sol-C), progesterone injection control (PgI-C), progesterone soft-gel capsule control (PgSC-C), low-dose allylestrenol (Alt-LD, 5 mg kg^-1), medium-dose allylestrenol (Alt-MD, 10 mg kg^-1), and high-dose allylestrenol (Alt-HD, 20 mg kg^-1) groups, with 16 successfully mated female rats in each group. Satellite groups were also established, each consisting of 7 successfully mated female rats.

Results: Estradiol levels on gestation day 19 (GD₁₉) were reduced in the Alt-HD compared to the Sol-C (P < 0.05). Compared with the Sol-C, there was no significant change in the anogenital distance (AGD) on postnatal day 21 (PND₂₁) and PND₅₄ in both male and female littermates in each allylestrenol dose group (P > 0.05). Testosterone levels were significantly elevated in the Alt-MD and Alt-LD groups compared to the Sol-C (P < 0.05). On GD₁₉, the estradiol level was significantly reduced only in the Alt-HD group (9.981 ± 0.514 ng/mL) compared with the Sol-C group (18.725 ± 4.770 ng/mL; P < 0.05). The low-dose (Alt-LD: 17.575 ± 3.017 ng/mL) and medium-dose (Alt-MD: 11.927 ± 3.663 ng/mL) groups showed numerically lower values than Sol-C, but the difference was not statistically significant after adjustment. 95% CIs for Sol-C, Alt-MD, and Alt-HD were [17.1, 20.3], [10.2, 13.7], and [9.4, 10.5] ng/mL, respectively.

Conclusion: Allylestrenol at doses of 5, 10, and 20 mg kg^-1 did not result in overt developmental abnormalities in maternal or offspring rats across selected early endpoints. However, further long-term and functional evaluations across generations are needed to fully establish its safety profile.

Purpose: This study aims to ascertain the median effective time (ET50) and the 95% effective time (ET95) of EMLA cream and tetracaine hydrochloride gel for analgesia during non-coring needle insertion into totally implantable venous access devices (TIVADs).

Patients and methods: Participants were randomly assigned to either Group E, receiving 2g of EMLA cream, or Group T, receiving 1g of tetracaine hydrochloride gel. Prior to needle insertion, the topical anesthetic was uniformly applied to a 1 cm radius around the puncture site. The initial target application time was set at 60 minutes for Group E and 30 minutes for Group T. For each subsequent participant, the target time was adjusted using a 1:1.1-time gradient, based on the Numeric Rating Scale (NRS) score of the preceding participant. Baseline characteristics, NRS scores, and adverse reactions were documented by a researcher who was not involved in the needle insertion process. The probit analysis method was employed to determine the ET50 and ET95 values.

Results: The ET50 and ET95 of patients to achieve painless non-coring needle insertion with EMLA cream were 55.882 minutes (95% Confidence Interval [CI]: 51.369-59.935 minutes) and 63.587 minutes (95% CI: 59.684-92.592 minutes), respectively. In comparison, the ET50 and ET95 for tetracaine hydrochloride gel were 39.092 minutes (95% CI: 36.646-41.678 minutes) and 43.388 minutes (95% CI: 41.111-56.859 minutes), respectively. There was no statistically significant difference between the two groups regarding the incidence of mild and serious adverse reactions.

Conclusion: Application of EMLA cream for 64 minutes or tetracaine gel for 44 minutes at the site of TIVADs resulted in a safely conducted, painless non-coring needle puncture for 95% of patients.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally developed for glycemic control in type 2 diabetes, have shown potential therapeutic effects in cancer treatment. Studies suggest that SGLT2 inhibitors can suppress tumor growth and proliferation through the modulation of metabolic reprogramming in tumor cells, inhibition of tumor glucose uptake, and regulation of the tumor microenvironment. Recent studies have emphasized the potential benefits of combining SGLT2 inhibitors with conventional anticancer therapies, including chemotherapy (CT), immunotherapy, and targeted therapies. Several clinical trials are currently evaluating the safety and efficacy of these combinations. Both preclinical and clinical studies primarily explore the effectiveness of SGLT2 inhibitors in inhibiting tumor growth, reducing metastasis, and enhancing treatment outcomes. Identifying combination therapies with SGLT2 inhibitors could enable more personalized treatment selection and optimization. This review provides a comprehensive summary of the antitumor effects and underlying mechanisms of SGLT2 inhibitors when combined with conventional anticancer therapies, aiming to elucidate their emerging role in cancer treatment. Combination regimens involving SGLT2 inhibitors have the prospect to overcome certain limitations of monotherapy, offering promising clinical benefits and improving patient outcomes.

Objective: This study aimed to investigate the effective dose of oliceridine for suppressing hemodynamic responses to tracheal intubation during general anesthesia induction and to evaluate the influence of age on dosing requirements, thereby providing evidence for clinical medication protocols.

Methods: A prospective single-center sequential dosing trial was conducted using a modified Dixon's up-and-down method. Patients scheduled for elective surgery under general anesthesia with tracheal intubation were enrolled and divided into a young group (18-65 years) and an elderly group (≥65 years). The initial doses were 45 μg/kg for the young group and 39 μg/kg for the elderly, with 3 μg/kg adjustments based on intubation response until seven crossovers occurred. A positive cardiovascular response was defined as an increase in mean arterial pressure or heart rate exceeding 20% from baseline within 3 minutes after intubation initiation. ED50 and ED95 values were estimated using Probit regression. Secondary outcomes included the incidence of injection-related cough, sedation success rate (MOAA/S score ≤2), peri-intubation hemodynamic changes, and adverse events.

Results: Fifty-eight patients were enrolled (28 young, 30 elderly). The ED50 of oliceridine was 46.5 μg/kg (95% CI 42.0-51.19) and ED95 was 55.4 μg/kg (95% CI 43.58-86.56) in the young group. In the elderly group, ED50 was 39.73 μg/kg (95% CI 34.17-44.76) and ED95 was 50.11 μg/kg (95% CI 37.31-77.87). Probit models demonstrated good fit in both groups. No injection-related cough reactions were observed, and the sedation success rate was 100%. Heart rate and blood pressure decreased during induction and normalized after intubation, with no significant intergroup differences. Adverse event incidence was comparable between groups.

Conclusion: Under standardized general anesthesia induction, the ED95 of oliceridine for suppressing tracheal intubation-induced hemodynamic elevation shows age-related differences, being approximately 55 μg/kg in younger patients and 50 μg/kg in the elderly.

Clinical trial registration: ClinicalTrials.gov, NCT07134660.

Background: Methylene blue (MB) has been proposed as an adjunctive therapy in the early management of septic shock; however, its effects on microcirculatory function remain poorly understood. This study aimed to investigate whether MB infusion improves sublingual microcirculatory parameters in patients with septic shock.

Methods: In this single-center, randomized controlled trial, participants were allocated in a 1:1 ratio to either the MB group or the control group. The MB group received an intravenous bolus of 2 mg/kg MB over 15 minutes, followed by a continuous infusion of 1 mg/kg MB diluted in 500 mL of 0.9% saline via a central venous catheter for 12 hours. The control group received an equivalent volume of saline. The primary endpoint was the change in sublingual microcirculation parameters from baseline to 24 hours, assessed using a repeated-measures mixed-effects model. Secondary endpoints included 28-day organ support-free days and 28-day mortality.

Results: Among the 72 randomized participants, 70.8% (n=51) were male, with a mean age of 68.6±13.5 years. Following MB treatment, the mean microvascular flow index (MFI) in the MB group was 2.78, compared to 2.51 in the control group. MMRM analysis demonstrated that MB significantly improved MFI (least squares mean difference [95% CI]: 0.21 [0.09, 0.33], P=0.001), with significant increases observed as early as 1 hour post-intervention (T1: 0.24 [0.06, 0.42], P=0.009), and this effect persisted up to 24 hours (T24: P=0.005). However, no significant differences were observed between the groups in 28-day mortality (25.0% [9/36] vs 41.7% [15/36], P=0.200) or organ support-free days (20.0 [1.0-22.0] vs 16.0 [1.3-22.0], P=0.910).

Conclusions: Although MB improved sublingual microcirculatory parameters, these improvements did not translate into benefits in organ function or survival outcomes.

Trial registration: chictr.org.cn ChiCTR 2400081549.

Background: YK-4-279, a promising anticancer agent, has demonstrated therapeutic potential against various tumors. Osteosarcoma (OS), an aggressive bone cancer primarily affecting adolescents, lacks effective treatment options. Investigating YK-4-279's mechanisms in OS is critical for evaluating its clinical utility.

Methods: Using in vitro models, we examined YK-4-279's effects on OS cell viability, proliferation, apoptosis, cell cycle progression, and DNA damage. We also assessed its impact on MAPK signaling pathway activation. To clarify the pathway's role, we combined YK-4-279 treatment with a P38 inhibitor.

Results: YK-4-279 markedly suppressed OS cell viability and proliferation, triggered G2/M phase arrest, and enhanced apoptosis and DNA damage. Furthermore, it activated the MAPK pathway, elevating phosphorylation of ERK1/2, JNK, and P38 MAPK. Co-treatment with a P38 inhibitor partially reversed these effects, confirming MAPK's involvement in YK-4-279's antitumor action.

Conclusion: YK-4-279 inhibits OS cell growth, induces DNA damage and cell cycle arrest, and promotes apoptosis via MAPK pathway activation. These findings highlight its strong therapeutic potential for OS treatment.

Purpose: Oleanolic acid (OA), a naturally occurring pentacyclic triterpenoid, has been reported to possess anti-inflammatory and barrier-protective properties. However, its molecular mechanism in the context of ulcerative colitis (UC) remains unclear.

Methods: In this study, we evaluated the therapeutic potential of OA (25 and 50 mg/kg/day) in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL/6 mice.

Results: Oral administration of OA significantly alleviated clinical symptoms of colitis, including weight loss, colon shortening, increased disease activity index (DAI), and histopathological injury. Additionally, OA demonstrated potent anti-inflammatory effects by suppressing the production of pro-inflammatory cytokines and promoting anti-inflammatory cytokines. It also restored redox homeostasis by enhancing antioxidant defenses and reducing lipid peroxidation. OA also restored intestinal barrier integrity, as evidenced by increased tight junction protein expression and decreased intestinal permeability. Mechanistically, OA was found to inhibit the activation of the NF-κB signaling pathway, as evidenced by reduced phosphorylation of IKKα/β and p65, and decreased degradation of IκBα. A key finding was that OA restored the expression of PPARγ, a known negative regulator of NF-κB. OA promoted the accumulation of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor essential for maintaining intestinal epithelial homeostasis and anti-inflammatory signaling. OA inhibited the ubiquitin-mediated proteasomal degradation of PPARγ, thereby stabilizing its protein levels in colonic tissue. Pharmacological inhibition of PPARγ with GW9662 abolished the protective effects of OA on intestinal inflammation and epithelial barrier function, confirming that PPARγ activation is required for OA-mediated protection.

Conclusion: These findings identify a previously unrecognized mechanism whereby OA protects against colitis through post-translational stabilization of PPARγ. Our study not only highlights the therapeutic value of OA as a potential intervention for UC but also provides mechanistic insight into the regulation of nuclear receptor homeostasis during intestinal inflammation.

Monitored anesthesia care (MAC) is a widely used anesthetic technique designed to provide titratable sedation and effective analgesia during a variety of medical procedures, ensuring patient comfort and safety. MAC is not only applied in surgical interventions but is also extensively used in diagnostic examinations such as sedation gastrointestinal endoscopy and pediatric magnetic resonance imaging (MRI) scans. With ongoing advances in medical technology, the selection of drugs, optimization of combination strategies, and refinement of administration methods for MAC continue to evolve. This narrative review, based on a structured literature search, summarizes recent developments in MAC drug selection, combination therapy, and administration methods. We highlight the quality and limitations of the current evidence, provide scenario-based practical recommendations, and outline emerging agents and delivery technologies, alongside unresolved questions that warrant further investigation.Overall, the existing evidence indicates that refined drug combinations (eg, propofol or dexmedetomidine in combination with opioids) tailored to specific procedural contexts and individual patient needs, alongside target-controlled infusion technology, are significantly enhancing the safety, comfort, and efficiency of MAC. However, the optimal drug combinations and standardized administration pathways still require further high-quality research.