Drug Design, Development and Therapy最新文献

Background: Bacterial lysates are known for having immunomodulatory properties and have been used mainly for the prevention and treatment of respiratory tract infections (RTIs). However, rigorous studies are needed to confirm the clinical efficacy of bacterial lysates with various bacterial antigen components, preparation methods, administration routes and course of treatment. OM-85, an oral standardized lysate prepared by alkaline lysis of 21 strains from 8 species of common respiratory tract pathogens, is indicated as immunotherapy for prevention of recurrent RTIs and acute infectious exacerbations of chronic bronchitis. OM-85 acts on multiple innate and adaptive immune targets and can restore type 1 helper T (Th1)/Th2 balance. Sporadic studies have shown advances in pharmacology and therapeutics of OM-85, and thus an update review is necessary.

Methods: Literature was retrieved by searching PubMed, Web of science, Embase, CNKI, and Full Text Database of Chinese Medical Journals.

Results: New roles of OM-85 were discovered in prevention and treatment of lung cancer, pulmonary tuberculosis, SARS-CoV-2 infection, allergic rhinitis, pulmonary fibrosis, atopic dermatitis, and nephrotic syndrome. Pharmacoeconomic values of OM-85 were demonstrated in prophylaxis and treatment of RTIs, chronic obstructive pulmonary disease, asthma, chronic bronchitis, rhinosinusitis and allergic rhinitis. Two consecutive courses of OM-85 (6 or 12 months apart) could prevent recurrent RTIs in children. Maternal OM-85 treatment could offer benefits for offspring. Product-specific response was observed. The efficacy of OM-85 may be associated with patient's characteristics (eg, severity of the disease, age, immune response pattern, malignancy risk stratification).

Conclusion: OM-85 can improve effectiveness of standard care for some primary diseases, and carry significant pharmacoeconomic implications. The benefits shown by OM-85 in vitro and in vivo, when extrapolated to humans, are exciting but also require caution. Individualized treatment may need to be considered. It is necessary to compare the efficacy and safety of various bacterial lysate preparations.

Purpose: Previous research has demonstrated that real-time ultrasound-guided (UG) spinal anesthesia requires a higher minimum local anesthetic dose (MLAD) compared to traditional methods. However, the precise MLAD of ropivacaine for UG cesarean sections remains undetermined. In this study, we ascertained the MLAD of ropivacaine for cesarean section. We also investigated the mechanism underlying the diffusion of ropivacaine within the spinal canal using fluid simulation technology.

Patients and methods: We randomly placed 60 healthy parturients undergoing elective cesarean section with real-time UG spinal anesthesia into Groups I (26-gauge spinal needle) and II (24-gauge spinal needle). For the first parturient in both groups, 15 mg of ropivacaine was administered intrathecally. Based on the effective or ineffective response of the previous parturient, the dose for the subsequent parturient was increased or decreased by 1 mg. Spinal anesthesia characteristics and side effects were recorded. A computer-generated spinal canal model was developed. Leveraging fluid dynamics simulation technology, we documented the diffusion of ropivacaine in the spinal canal using 26-and 24-gauge spinal needles.

Results: The MLADs in Groups I and II were 12.728 mg (12.339-13.130 mg) and 9.795 mg (9.491-10.110 mg), respectively. No significant difference was observed in the onset times and durations of sensory or motor blocks, incidence of complications, or neonatal Apgar scores between both groups. Fluid simulation modeling indicated that the 26-gauge spinal needle achieved a higher distribution level more quickly; however, its peak drug concentration was lower compared to the 24-gauge spinal needle.

Conclusion: For cesarean section anesthetization, the required MLAD of ropivacaine when using a real-time UG 26-gauge spinal needle is significantly greater than that with a 24-gauge needle. The spinal needle diameter influences ropivacaine's MLAD by markedly affecting its diffusion rate within the spinal canal.

Purpose: We designed this trial to compare the recovery time of remimazolam and propofol in elderly patients undergoing painless gastrointestinal endoscopy.

Patients and methods: In this randomized, non-Inferiority trial, 360 patients aged 65 years or older, scheduled for elective outpatient gastrointestinal endoscopy, were randomly assigned to the remimazolam combined with fentanyl (RF) group or the propofol combined with fentanyl (PF) group. The primary outcome was the post-anesthesia care unit (PACU) stay time, defined as the time from the end of the examination to scoring 9 points using the Modified Post-Anesthetic Discharge Scoring System (MPADSS) criteria. Secondary outcomes included sedation-related adverse events, recall, injection pain, as well as postoperative Quality of Recovery-15 (QoR-15) scores and Pittsburgh Sleep Quality Index (PSQI) scores at 1 day, 1 week, and 1 month postoperatively.

Results: A total of 351 patients completed the study, with 174 receiving remimazolam and 177 receiving propofol. The PACU stay time in RF group was non-inferior to that in PF group [14 (11, 18) vs 13 (10, 17), mean difference 1 (95% confidence interval 0, 2), P=0.084 for noninferiority]. However, remimazolam was associated with lower rate of hypoxemia [4.7% (8/180) vs 12.4% (22/180), P=0.011], reduced use of vasoactive drugs [1 (0, 1) vs 1 (1, 2), P<0.001], less injection pain [2 (1.2%) vs 35 (21.3%), P<0.001], and lower recall [20 (11.8%) vs 36 (20.3%), P=0.034]. There were no differences in the QoR-15 scores and PSQI scores at postoperative 1 day, 1 week, and 1 month between groups.

Conclusion: This non-inferiority study revealed that in elderly outpatients undergoing gastrointestinal endoscopy, remimazolam achieved recovery times comparable to propofol, with fewer associated complications.

Background: Dauricine is an important natural organic compound in Menispermum dauricum, which often has significant biological activity.

Purpose: The purpose of this review is to systemically summarize and discuss the pharmacological activity and underlying mechanisms of dauricine in recent years.

Methods: Web of Science (121 articles) and PubMed databases (97 articles) were used to search for articles related to "dauricine" published from 2000 to 2024. Meanwhile, we classified the pharmacological activity of dauricine by screening these articles.

Results: Emerging evidence suggests that dauricine possesses numerous pharmacological activities, including neuroprotection, anti-cancer, anti-arrhythmia, anti-inflammatory and anti-diabetes.

Conclusion: Dauricine has a potential value in the treatment of many diseases. We hope that this review will contribute to therapeutic development and future studies of dauricine.

Purpose: We aimed to prepare a β-cyclodextrin (β-CD) polymer using radical polymerization with co-monomers, 6-deoxy-6-(2-methacryloyloxyethylsuccinamide)-β-cyclodextrin (CD-MSAm) and N,N,N-trimethyl-N-(2-hydroxy-3-metacryloyloxopropyl)-ammonium chloride (QA) to design cyclodextrins suitable for use in ophthalmology. In addition, we evaluated their solubility and inclusion properties with rebamipide (REB), a poorly soluble drug, and investigated the usefulness of the β-CD polymer and REB (REB@CDQA) combination in treating dry eye.

Methods: The β-CD polymer (CD-MSAm-co-QA, CDQA) based on CD-MSAm/QA was prepared via radical polymerization, and the usefulness of REB@CDQA in treating dry eye was evaluated using a rabbit treated with N-acetylcysteine (dry eye model).

Results: The solubility of the CDQA powder was higher than that of the β-CD powder, and 80 nm colloids were observed in the CDQA solution. No corneal toxicity was observed in human corneal epithelial cells or rat corneas treated with 0.2% CDQA solution. The levels of REB dissolved in the CDQA solution were higher than those of the β-CD solution. Moreover, the application of the CDQA solution enhanced REB retention in the cornea and attenuated the transcorneal penetration of REB. In addition, instillation of REB@CDQA enhanced the volume of the lacrimal fluid and normalized the reduced mucin levels in the dry eye model. The extent of tear film breakup was attenuated by REB@CDQA instillation.

Conclusion: The CDQA solution enhanced the solubility of REB, and the combination of CDQA and REB enhanced the drug content in the corneal tissue. Moreover, the therapeutic effect on dry eye was higher than that of REB suspensions without CDQA.

Purpose: The purpose of this study was to compare the efficacy of Follitropin alpha (Gonal-F) and Follitropin beta (Puregon) on cumulative live birth rate (CLBR), defined as the percentage of the number of patients who delivered for the first time in a single ovarian stimulation cycle and the number of patients in all oocyte retrieval cycles.

Methods: A retrospective cohort study including 2864 infertile patients who underwent ovarian stimulation with Puregon (group A, n=1313) and Gonal-F (group B, n=1551) was conducted between July 2015 and June 2021 at a university-affiliated reproductive medicine center. Reduce potential confounding factors between groups, propensity scores and multivariable logistic regression analyses were estimated to obtain unbiased estimates of outcomes. The primary outcome was the difference in CLBR between the two groups.

Results: Each group identified 1160 individuals after propensity score matching (PSM). Baseline characteristics were similar between groups after PSM. The total gonadotrophin (Gn) dose (2400 vs 2325), p=0.038) and cost of Gn usage (5327.9¥ vs 7547.2¥, p<0.001) between the Puregon and Gonal-F groups were statistically significant. Nevertheless, the pregnancy outcomes between the two groups were comparable after fresh embryo transfer and subsequent frozen-thawed embryo transfer. Additionally, there was also no difference observed in the primary outcome of CLBR (52.8% vs 55.7%, p=0.169). Multivariable regression analysis revealed that the type of Gn was not associated with CLBR (p = 0.912).

Conclusion: Gonal-F may be a reasonable option for infertile patients who are hesitant to receive more Gn dosage injections. Furthermore, Puregon can eliminate unneeded anxiety and expenses while also administering more flexibility. Taken together, these findings could well be utilized in everyday clinical practice to better inform patients when deciding on an ovarian stimulation strategy.

Background: EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct a bibliometric analysis to elucidate evolving research hotspots and trends in EGFR-TKI resistance, offering insights for clinical interventions and scientific inquiries.

Methods: Publications spanning from 1996 to 2024, focusing on EGFR-TKI resistance in NSCLC, were sourced from the Web of Science Core Collection. Utilizing VOSviewer 1.6.19, CiteSpace 6.2. R2, and Scimago Graphica 1.0.35, we analyzed these articles to identify countries/regions and institutions, Journals, publications, key contributors, collaborations, and emerging topics.

Results: An analysis of 8051 articles by 38,215 researchers from 86 countries shows growing interest in EGFR-TKI resistance mechanisms. Since 1996, publications have steadily increased, surpassing 500 per year after 2016, with a sharp rise in citations. Research articles make up 84% of publications, emphasizing scholarly focus. Global collaboration, especially among researchers in China, the US, and Japan, is strong. Leading institutions like Dana-Farber and Harvard, along with journals such as "Lung Cancer", are key in sharing findings. Professors Yi-Long Wu and William Pao are prominent contributors. Keyword analysis reveals core themes, including first-generation EGFR-TKIs, emerging agents like osimertinib, and research on the T790M mutation.

Conclusion: EGFR-TKI resistance remains a critical issue in NSCLC treatment, driving ongoing research efforts worldwide. Focusing future research on clear identification of resistance mechanisms will guide post-resistance treatment strategies, necessitating further exploration, alongside the validation of emerging drugs through clinical trials. Moreover, "chemo+" treatments following EGFR-TKI resistance require more clinical data and real-world evidence for assessing safety and patient outcomes. As research advances, a multidisciplinary approach will be key to overcoming these challenges. Continued innovation in treatment could greatly enhance patient survival and quality of life.

Background: Ischemia-reperfusion (I/R) injury to the testis can lead to organ damage, infertility, and subfertility. The goal of this study was to investigate the effects of fasudil on this devastating condition.

Methods: Thirty male Long-Evans rats were divided into five groups: a control group (no torsion), rats administered fasudil (30 mg/kg, no torsion), rats subject to ischemia with no treatment (I) (I/R injury), injured rats that received treatment 1 (T1) (I/R with 30 mg/kg fasudil before detorsion), and injured rats that received treatment 2 (T2) (I/R with 30 mg/kg fasudil after detorsion). Serum levels of TNF-ɑ and IL-6, along with tissue levels of glutathione (GSH), malondialdehyde (MDA), caspase-3, and Johnsen Tubular Biopsy Score (JTBS), were measured.

Results: Group I exhibited significantly higher levels of MDA and caspase-3 than all other groups except T2 (p ˂ 0.05). Although the difference was not statistically significant, Group T2 exhibited lower MDA and caspase-3 levels than Group I (p ˃ 0.05). Additionally, Group I displayed significantly higher TNF-ɑ and IL-6 levels, and lower GSH and JTBS values, than the other groups (p ˂ 0.05).

Conclusion: Our findings indicate that fasudil protects the testis from I/R injury, particularly when administered early.

Background: Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease that lacks effective treatments. Qingchang Wenzhong Decoction (QCWZD) is a clinically effective herbal prescription that has been proven to attenuate intestinal inflammation in IBD. However, its molecular mechanism of action has not been clearly elucidated.

Purpose: We aimed to probe the mechanism of QCWZD for the treatment of IBD.

Methods: The dextran sulfate sodium (DSS)-induced mouse model of IBD was used to identify the molecular targets involved in the mechanism of action of QCWZD. Metagenomics sequencing was utilized to analyze the differences in gut microbiota and the functional consequences of these changes. Network pharmacology combined with RNA sequencing (RNA-seq) were employed to predict the molecular targets and mechanism of action of QCWZD, and were validated through in vivo experiments.

Results: Our results demonstrated that QCWZD treatment alleviated intestinal inflammation and accelerated intestinal mucosal healing that involved restoration of microbial homeostasis. This hypothesis was supported by the results of bacterial metagenomics sequencing that showed attenuation of gut dysbiosis by QCWZD treatment, especially the depletion of the pathogenic bacterial genus Bacteroides, while increasing the beneficial microorganism Akkermansia muciniphila that led to altered bacterial gene functions, such as metabolic regulation. Network pharmacology and RNA-seq analyses showed that Th17 cell differentiation plays an important role in QCWZD-based treatment of IBD. This was confirmed by in vivo experiments showing a marked decrease in the percentage of CD3⁺CD4⁺IL-17⁺ (Th17) cells. Furthermore, our results also showed that the key factors associated with Th17 cell differentiation (IL-17, NF-κB, TNF-α and IL-6) in the colon were significantly reduced in QCWZD-treated colitis mice.

Conclusion: QCWZD exerted beneficial effects in the treatment of IBD by modulating microbial homeostasis while inhibiting Th17 cell differentiation and its associated pathways, providing a novel and promising therapeutic strategy for the treatment of IBD.