Drug Design, Development and Therapy最新文献

Purpose: The effects of sufentanil-ropivacaine combination on the parturient women and the course of labor have been well documented. However, there is little information regarding the time-dependent pharmacokinetic characteristics of sufentanil after epidural administration in laboring women. We aimed to develop a population PK model for epidural sufentanil in laboring women to evaluate the sufentanil placental transfer quantitatively.

Patients and methods: Forty-one participants who underwent epidural labor analgesia were recruited into this study. Patients received a continuous epidural infusion of sufentanil 0.3 µg/mL with ropivacaine 0.1%. Maternal venous blood samples and umbilical venous blood samples were collected for population PK analysis. The trends of sufentanil blood concentrations in the mothers and umbilical cord were predicted by the model.

Results: Sufentanil disposition after continuous epidural administration in laboring women followed a two-compartment pharmacokinetic model. The estimated sufentanil central clearance (CL), central volume of distribution (V1), clearance between central compartment and umbilical cord compartment (CL2), and umbilical cord volume of distribution (V2) were 176 L/h, 519 L, 0.0134 L/h, and 0.187 L. The absolute level of sufentanil in placental circulation is low after epidural administration. A slow decline in placental sufentanil concentration was predicted by the final PK model after epidural infusion was discontinued.

Conclusion: A slow decline in placental sufentanil concentration is predicted by the final two-compartment PK model after epidural infusion was discontinued. This suggests that very large doses of epidural sufentanil should be avoided during labor analgesia.

Trial registration: https://www.chictr.org.cn, No: ChiCTR1800018810.

Background: Aspirin is widely used to prevent and treat cardiovascular diseases. The most common side effect is gastrointestinal damage. In recent years, aspirin-associated enteropathy has received increasing attention. This study aimed to establish a chronic model of aspirin-associated enteropathy, investigate the effect of enteric-coated aspirin on the intestinal flora, and explore the specific molecular mechanism of small intestinal damage.

Methods: C57BL/6J mice were given aspirin for 45 days to induce chronic small intestinal injury. The intestinal mucosal injury was observed macroscopically and microscopically. Intestinal mucus levels were assessed by PAS staining. The intestinal permeability was measured by FD4. The oxidative stress levels of the small intestine were detected by immunofluorescence and immunohistochemistry. The mRNA and protein levels of inflammatory factors, tight junctions, and antioxidant defense-related genes were measured by qRT-PCR and Western Blot. The MPO activity, SOD activity and MDA content in serum were measured. The mitochondrial morphology and paracellular space were observed under transmission electron microscopy. The fecal samples were analyzed by high-throughput sequencing of 16S rRNA V3-V4 amplicons.

Results: Aspirin induced weight loss, reduced food intake and increased faecal occult blood in mice. Aspirin led to a shortened small intestine, macroscopic and microscopic damage to the intestinal mucosa, and local inflammation. Aspirin disrupted the intestinal barriers and increased the permeability of the small intestine. Aspirin destroyed mitochondrial structure and damaged antioxidant capacity, and aspirin may induce oxidative stress through Nrf2/Gpx4 signaling pathway. Intestinal flora analysis showed that aspirin could induce changes in the abundance of Akkermansia and Lactobacillus.

Conclusion: Long-term administration of enteric-coated aspirin successfully established a chronic small intestinal injury model in mice. It increased oxidative stress in the small intestine by disrupting mitochondrial structure and impairing antioxidant capacity. This damaged the intestinal mucosal barrier, increased intestinal permeability, and triggered gut microbial dysbiosis and inflammation.

Background: Perioperative shivering is a common adverse reaction to neuraxial anaesthesia. Intravenous oxycodone can be used to prevent shivering. However, few trials have been conducted on the use of oxycodone to prevent shivering, and the optimal dose is unknown. This study aimed to determine the optimal dose (90% minimum effective concentration [MEC90]) of intraoperative oxycodone to prevent shivering during caesarean section.

Methods: This study was designed by the biased-coin up-and-down method. We recruited pregnant women who underwent caesarean section under combined spinal-epidural anaesthesia. Oxycodone was administered intravenously after the delivery of the foetus. The initial dose was 80 µg/kg, and subsequent dose adjustments were determined by up-and-down sequential allocation using a biased-coin design based on the response of the previous patient. The primary outcome was the MEC90 for oxycodone injection based on the success or failure of the shivering-preventing dose.

Results: Fifty patients were enrolled in the study. The oxycodone dose ranged from 80 to 95 µg/kg. The estimated MEC90 (95% confidence interval [CI]) for preventing shivering was 88.1 µg/kg (81.5-92.5 µg/kg). The patient's postoperative temperature was 36.5 ± 0.2 °C. The incidence of intraoperative traction pain was 12%. The 5-min and 30-min Ramsay sedation scores were 3 (3-4) and 3 (3-3), respectively. The 2-h and 6-h postoperative VAS scores were 3 (2-3) and 4 (3-5), respectively. The patient's anaesthesia satisfaction score was 5 (4-5). The incidence of respiratory depression was 2%, and the incidence of nausea and vomiting was 16%.

Conclusion: The MEC90 of intraoperative intravenous oxycodone for the prevention of shivering in women undergoing caesarean section with neuraxial anaesthesia was 88.1 µg/kg (95% CI: 81.5-92.5 µg/kg).

Objective: This study compares postoperative recovery quality between Ciprofol and Propofol, providing a reference for the clinical application of anesthetics.

Methods: We randomized 112 patients undergoing ureteroscopic surgery into two groups: the Ciprofol group (Group C), with an induction dose of 0.4 mg/kg and a maintenance dose of 0.8-1.5 mg/(kg·h), and the Propofol group (Group P), with an induction dose of 2 mg/kg and a maintenance dose of 4-10 mg/(kg·h). Both groups received sevoflurane at a concentration of 1%. The Bispectral Index (BIS) was maintained between 40 and 60. The primary outcomes were the Quality of Recovery-15 (QoR-15) scores on postoperative day 1 (POD1). Secondary outcomes included hemodynamic parameters, vasopressor use, timing indicators, sedative consumption, BIS values, Riker Sedation-Agitation Scale (R-SAS) scores, urinary tract symptoms, patient satisfaction, and adverse events.

Results: No significant differences were observed in QoR-15 scores between the two groups. Although Group C had higher pain (P = 0.004) and comfort (P = 0.002) scores on POD1, these differences were not clinically significant. The incidence of hypotension and vasopressor use was lower in Group C, which had more stable hemodynamics. Additionally, the time from induction to BIS ≤ 60 was shorter in Group P (P = 0.001), while Group C had lower BIS values from drug discontinuation to full recovery of consciousness (P = 0.001). The incidence of urinary tract symptoms on POD1 was lower in Group C (P = 0.043). There were no significant differences in time to spontaneous breathing recovery, extubation, recovery room stay, time to first ambulation, hospital stay, patient satisfaction, or other adverse events.

Conclusion: Ciprofol provides comparable early postoperative recovery to Propofol during ureteroscopy and may be a preferable alternative for urological procedures, especially in patients with blood pressure concerns.

Trial registration: Chinese Clinical Trial Registry (ChiCTR2400082736).

Background: Proton pump inhibitors (PPIs) and potassium competitive acid blockers (P-CABs) are widely used to treat acid-related diseases (ARDs). Precisely quantifying their plasma levels is crucial for clinical pharmacokinetic assessments and therapeutic drug monitoring.

Aim: This study aimed to establish a generic and efficient ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the determination of five PPIs (esomeprazole, rabeprazole, ilaprazole, lansoprazole, and pantoprazole) and the P-CAB (vonoprazan) in human plasma.

Methods: The six analytes were extracted from human plasma via protein precipitation and a single dilution step. Detection was performed on a triple quadrupole tandem mass spectrometer with positive electrospray ionization. Chromatographic separation was achieved on the ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) using gradient elution. The mobile elution was composed of 0.2% formic acid in acetonitrile (mobile phase A), 0.1% ammonium hydroxide and 10 mmol/L ammonium formate in deionized water (mobile phase B). The flow rate was 0.4 mL/min, the run time was 4.5 minutes, and the injection volume was 20 µL.

Results & conclusions: The method exhibited excellent linearity across the ranges of 0.2-200 ng/mL for PPIs and 0.5-500 ng/mL for the P-CAB. Both intra- and inter-day precision and accuracy were within the acceptance criteria, with precision ranging from 1.1% to 14.6% and accuracy ranging from 0.0% to 14.7%. Extraction recoveries were consistent, ranging from 88.1% to 96.7%, with no significant matrix effects observed. The stability of the six analytes under diverse storage and processing conditions was also confirmed, with both precision and accuracy falling within the acceptable range of 15%. The UPLC-MS/MS assay provided an efficient and reliable approach for the simultaneous determination of six acid-suppressing medications in a single analytical run. It has been successfully applied to the pharmacokinetic studies of PPIs and P-CABs, offering a valuable tool for clinical research and therapeutic drug monitoring.

Purpose: The provision of comfortable and safe environment for painless gastroscopy in obese patients is an urgent clinical problem. This study aimed to determine the efficacy and safety of the novel Li anesthetic protocol for obesity (LAPO) which included remifentanil-propofol regimen, manual right hypochondrial compression (MRHC), easy-to-create mask, and jaw thrust at preoperative painless gastroscopy in obese patients.

Patients and methods: This prospective, single-center, single-arm trial recruited 106 participants underwent LAPO for gastroscopy. The primary outcome was the incidence of hypoxemia (peripheral oxygen saturation [SpO₂]: 75% ≤ SpO₂ <90%, for >10 s and ≤60 s). Second outcomes included severe hypoxemia, the lowest SpO₂ (L-SpO₂), duration of hypoxemia, and other events.

Results: The 98 obese patients under LAPO, the median body mass index (BMI) was 39.2 kg/m² and the incidence of hypoxemia was 27.5%, while the conventional anesthetic protocol for obesity (CAPO) in the reference was 40.4% with BMI 31.4 kg/m². With the increase of class of obesity, a significant rise in the incidence of hypoxemia was observed, from class I by 11.8%, to 15.1% in class II, and 41.7% in class III. Paired t test showed that the L-SpO₂ was significantly higher than L-SpO₂ in overnight polysomnography (Nadir SpO₂) (92% vs 76%, P<0.001). Moreover, severe obstructive sleep apnea (OSA) was associated with a 4.019-fold higher risk of hypoxemia (Odds ratios [OR], 4.019; 95% confidence interval [CI], 1.184 to 14.610; P=0.028); diabetes was associated with a 4.790-fold higher risk of hypoxemia (OR, 4.790; 95% CI, 1.288 to 23.600; P=0.030).

Conclusion: Compared with CAPO, LAPO reduced the incidence of hypoxemia from 40.4% to 27.5%, so, LAPO was safe and effective for painless gastroscopy. The finding might provide some new schedules for anesthetic management in the absence of advanced airway support instruments.

Clinical trial registration: ChiCTR2300077889.

Background: Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine prescription with a history of nearly 2000 years, originally widely used for gynecological diseases, and in recent years research has found that DSS also has a good therapeutic effect on Alzheimer's disease (AD).

Purpose: The objective is to investigate the metabolic components of the DSS in the blood and the potential mechanisms for AD.

Materials and methods: Liquid chromatography‒mass spectrometry (LC-MS) combined with gas chromatography‒mass spectrometry (GC-MS) based non-targeted metabolomics were used to conduct in-depth research. Serum Pharmacology was used to analyze potential mechanisms of DSS for AD. C57BL/6J mice and Hippocampal neuronal cell line (HT-22) were used to prepare the AD model. Enzyme linked immunosorbent assay (Elisa), quantitative polymerase chain reaction (q-PCR), Morris water maze,Western blot (WB), Immunohistochemical and Immunofluorescence were used to study the effect of DSS on AD. Flow cytometry and Cell Counting Kit-8 (CCK-8) reveal the effect of DSS serum on HT-22 proliferation and apoptosis.

Results: A total of 57 metabolic components were screened in DSS serum. Serum Pharmacology revealed that the calcium signaling pathway and cAMP/PKA/CREB pathway may be a potential mechanism through which DSS treated AD. DSS can reduce aberrant phosphorylation of Tau and modulates cAMP/PKA/CREB pathway to improve cognition and apoptosis in AD mice. DSS serum can increase the cell viability of HT-22 and reduce apoptosis mainly by alleviating mitochondrial calcium overloading.

Conclusion: DSS can modulate the calcium signaling pathway and enhance the cAMP/PKA/CREB signaling pathway to ameliorate Tau aberrant phosphorylation, cognitive deficits and neuronal apoptosis after AD.

Peptic ulcer disease (PUD) remains a significant global health issue, affecting millions despite a decrease in overall prevalence. However, complications continue to persist, with substantial mortality rates in regions like India and China. Current treatments, though effective, have limitations, driving interest in plant-derived therapy. Anthocyanins, including cyanidin and cyanidin-3-glucoside (C3G), are known for their antioxidant and anti-inflammatory properties. This study aims to explore the potential of cyanidin and C3G in alleviating PUD, focusing on their mechanisms of action and therapeutic efficacy in preclinical studies. Articles were searched in Scopus and PubMed databases and filtered for publication from 2014 to 2024, resulting in 89 articles from Scopus and 11 articles from PubMed. The articles were further screened by title, abstract, and full text, resulting in 6 articles. Cyanidin and C3G were described to be able to alleviate PUD by inhibiting the cytokine pro-inflammatory, reducing inflammation in gastric mucosa, and reducing lipid peroxidation in the gastric mucosa. These compounds have proven effective in managing other health problems, including peptic ulcers, but more in-depth exploration in clinical settings is required to confirm therapeutic potential in humans. It is necessary to validate the therapeutic efficacy and safety in human populations. This review provides an overview of preclinical studies of cyanidin and C3G, such as in vitro and in vivo, focusing on mechanism of action or their effectiveness in alleviating peptic ulcers.

Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). Recent research has therefore focused on the development of targeted therapies aimed at disrupting specific pathogenic signaling cascades within podocytes, resulting in noteworthy advancements. The role of mechanisms such as alterations in the actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy within the microenvironment of podocyte injury have garnered increasing attention. Corresponding targeted medications such as Abatacept, chemokine receptor (CCR) inhibitors, CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), adenosine monophosphate-activated protein kinase (AMPK) activators, and Adalimumab are currently under investigation. Notably, some medications such as Rituximab and Sparsentan, may simultaneously target multiple downstream mechanisms, Furthermore, exploring molecular strategies for established medications and developing novel treatments guided by biomarkers such as Anti-CD40 antibody, blood microRNA, urinary microRNA, and tumor necrosis factor-alpha (TNF-α) may provide additional therapeutic avenues for patients with FSGS.

Background: The neuropathic pain side induced by Vincristine severely limit its clinical application. However, the mechanism of neuropathic pain is not clear. This study aims to clarify the mechanism of C/EBP-β regulating TGF-β1 mediated spinal astrocyte A1/A2 polarization in the neuropathic pain caused by vincristine.

Methods: Neuropathic pain model was established in rats by intraperitoneal injection of Vincristine (VCR). In vitro experiment, the astrocyte model was constructed by Vincristine, and si-C/EBP-β was regulated before VCR administration. Pain threshold of rats was measured by thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT), Elisa was used to detect the expression level of inflammatory factors, qRT PCR and Western blotting were used to detect astrocyte polarization markers, C/EBP-β, TGF-β1, p-smad2 and p-smad3.

Results: Following Vincristine administration, the TWL and MWT of rats exhibited a decrease. Additionally, there was an increase in A1 polarization of astrocytes, while A2 polarization remained relatively unchanged. Furthermore, the expression levels of pro-inflammatory factors were elevated, whereas no significant alterations were observed in anti-inflammatory factors. Notably, Vincristine promoted the expression of C/EBP-β and TGF-β1. TGF-β1 inhibitor alleviated VCR induced astrocyte A1 polarization and release of proinflammatory factors, ameliorated abnormal pain. Moreover, silencing C/EBP-β reversed the enhanced expression of TGF-β1 induced by Vincristine, attenuated astrocyte A1 polarization and proinflammatory factor release.

Conclusion: Vincristine induced spinal cord inflammation by promoting A1 polarization of astrocytes via upregulating the C/EBP-β/TGF-β1 signal pathway, thus leading to neuropathic pain. It was different from the traditional signal pathway, this study shown a new signal pathway for astrocyte A1 polarization, which may provide a possibility for clinical treatment of neuropathic pain.