Journal of Clinical Pharmacy and Therapeutics最新文献

Backgrounds: Quercetin has potentially beneficial therapeutic effects for several chronic, inflammatory disorders of the airways. Thus, we explore the therapeutic value and mechanism of quercetin in the treatment of asthma and pulmonary fibrosis overlap syndrome after COVID-19.

Methods: The potential targets and molecular mechanisms of quercetin for the treatment of overlap syndrome were predicted using a network pharmacology method. The binding mechanism between the core potential compounds and their targets was predicted using molecular docking with AutoDock Vina. An asthma model induced by ovalbumin was built to evaluate the effect of quercetin on asthma.

Results: 55 common targets and eight key genes between the overlap syndrome and quercetin were obtained for further study. Most of the interested target genes were mainly focused on inflammation-related signaling pathways. Via molecular docking, quercetin showed a high degree of affinity for TNF, IL-6, and MMP9. In addition, quercetin improved asthma symptoms, inflammatory response, and pulmonary fibrosis.

Conclusion: This study, which examined the use of quercetin for the treatment of the overlap syndrome of asthma and pulmonary fibrosis following COVID-19 from the aspect of network pharmacology, might serve as a useful guidepost for future studies and clinical applications.

Backgrounds: The Zao Ren An Shen (ZRAS) Capsule, stemming from a traditional Chinese herbal formula, is recognized as a safe and effective sleep-regulating medication. Asthma often worsens during the night and early morning due to its distinct day–night rhythm, suggesting the potential for the ZRAS Capsule to intervene in asthma attacks and prognosis. Since inflammation is a primary mechanism in asthma, exploring the anti-inflammatory effects of the ZRAS Capsule is essential.

Methods: This study identifies the intersection of ZRAS Capsule-related targets and anti-inflammatory targets to uncover potential anti-inflammatory mechanisms. Core compounds and relevant genes were identified using protein–protein and compound–protein interaction networks. KEGG pathway and Gene Ontology analyses were performed on the anti-inflammatory targets to validate their role in mitigating asthma inflammation. Binding activities between the compounds and anti-inflammatory targets were assessed using western blot, qRT-PCR, molecular docking, and immunohistochemistry (IHC).

Results: Key compounds, including luteolin, (S)-Coclaurine, and zizyphusine, along with targets IL6, TNF, and MMP9, were identified. Their biological processes were linked to the IL-17 signaling pathway and TNF signaling pathway. Notably, the identified compounds inhibited the mRNA and protein expression of IL6, TNF, and MMP9.

Conclusion: Regulation of the IL-17/TNF signaling pathway is likely crucial for the protective effects of the ZRAS Capsule in asthma treatment.

Objective: To explore the effect and mechanism of pirfenidone (PFD) on lung injuries in newborn rats caused by intrauterine inflammation.

Methods: In vivo, we established the intrauterine inflammation model with lipopolysaccharide (LPS) injection in pregnant rats. The administration of PFD in pregnant rats was performed to evaluate its beneficial effect against intrauterine inflammation-induced lung injuries in neonatal rats. Lung tissues of newborns from three groups of pregnant rats (Saline + DMSO, LPS + DMSO, and LPS + PFD) were collected. Immunohistochemistry (IHC) and Western blot were used to detect the fibrotic-related protein expressions. In vitro, LPS-induced mouse lung epithelial cells (MLE 12) were employed to explore the underlying mechanism of PFD against intrauterine inflammation-induced lung injury in neonates.

Results: In vivo, the radial alveolar count (RAC) was decreased, the mean linear intercept (MLI) was increased, and the lung injury score was high in intrauterine inflammation (LPS + DMSO-treated pregnant rats) induced lung injuries in newborns. The protein level of matrix metallopeptidase 9 (MMP-9), TGF-β1 (transforming growth factor beta 1), phospho-Smad2 (Sma- and mad-related protein 2), and phosphor-Smad3 (Sma- and mad-related protein 3) levels were upregulated in neonatal lungs with intrauterine infection. Lung injuries were alleviated in LPS + PFD groups, and the protein levels of TGF-β1, p-Smad2, p-Smad3, and MMP-9 were reduced. In vitro, PFD attenuated the LPS-induced inflammatory response and reduced the expressions of MMP-9, TIMP-1, and Collagen IV in lung epithelial cells through the TGF-β1/Smad2/3 signaling pathway.

Conclusions: PFD alleviates intrauterine infection-induced lung injuries in neonates by targeting transforming growth factor beta 1/Sma- and mad-related protein signaling pathway. The inhibition of TGF-β1 signaling by PFD prevents the neonatal lung injuries by reducing MMP-9 and Collagen IV protein levels. This study provides theoretical basis and insights for PFD-mediated intervention of lung injury in neonates with intrauterine infection.

Background: The rise of drug-resistant bacteria poses a significant challenge to global healthcare, underscoring the urgent need for new therapeutic interventions. In this study, ethanolic extracts of Datura stramonium and Prosopis farcta, sourced from Northern Iran, were examined for their antibacterial properties against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Methods: The antibacterial activities of the medicinal extracts were examined in this study using disc diffusion, microbroth dilution, and agar well diffusion methods against both Gram-positive and Gram-negative microorganisms. In addition, the extracts were assessed for toxicity using the MTT assay on HT29 cells. The biofilm-inhibitory effects of the extracts were also investigated.

Results: The results showed that the ethanolic extracts from D. stramonium and P. farcta have strong antibacterial activity against S. aureus. However, their activity against P. aeruginosa and A. baumannii is less pronounced. The extracts showed significant antibiofilm capabilities against the tested bacteria at both MIC and 2× MIC concentrations (p < 0.05). The MTT test showed HT29 cells were more sensitive to P. farcta extract than D. stramonium, especially at 200 μg/mL concentration.

Conclusion: The findings demonstrate that ethanolic extracts of P. farcta and D. stramonium exhibit significant antibacterial activity, particularly against S. aureus, while also effectively disrupting bacterial biofilms. These results suggest that these extracts possess considerable potential as alternative therapeutic agents against drug-resistant bacterial infections. Further investigation is warranted to elucidate the specific mechanisms of action and to explore their efficacy in clinical applications.

Background: Pharmacological sedation during neonatal magnetic resonance imaging (MRI) is crucial for procedure success and minimizing artifacts. Hence, it is vital to evaluate the effectiveness and safety of conventional sedatives in this population. In this study, we aim to evaluate the effectiveness of oral chloral hydrate combined with intranasal dexmedetomidine in neonatal MRI.

Methods: Neonates aged 0 to 28 days undergoing MRI were enrolled and received intranasal dexmedetomidine followed by oral chloral hydrate. Subsequently, sedation scores, onset time, and overall time of sedation, as well as any potential adverse reactions, were recorded.

Results: All neonates completed the MRI without notable adverse reactions. 128 neonates (90.1%) completed the MRI study with a single dose, while 14 neonates (9.9%) required additional medications. In the neonates with a single dose, no statistically significant differences in onset time were observed across postnatal days, gender, and weight. And no statistically significant differences in total time were observed across postnatal days and gender. However, the total time was significantly extended in the neonates with a weight under 3 kg. Furthermore, compared to the neonates with a single dose, the total time was significantly extended in the neonates with additional medications.

Conclusion: Oral chloral hydrate combined with intranasal dexmedetomidine is effective and safe for neonatal MRI, but extra attention is needed for neonates under 3 kg.

To overcome TRAIL resistance, we tested the antidepressant drug citalopram (CTL) in combination with TRAIL. The resistance of several types of cancer cells to TRAIL impedes TRAIL-induced cancer cell death. In this study, we investigated the role of, and molecular mechanism by which, the antidepressant CTL-induced cell death in TRAIL-resistant lung cancer cells. We found that CTL increased death receptor 5 (DR5) expression levels by impairing autophagic flux and protecting against lysosomal degradation, thereby increasing the TRAIL-induced apoptosis of TRAIL-resistant A549 lung cancer cells. We also found that CTL impaired autophagic flux and promoted the conversion of light chain 3 (LC3)-I to its lipid-conjugated form, LC3-II, thereby inducing autophagosome accumulation. Our hypothesis that impaired autophagic flux plays an important role in the upregulation of DR5 being confirmed when we determined that DR5 upregulation by CTL was markedly decreased in the presence of rapamycin, an autophagy inducer. Further verification of our theory was achieved through experiments pairing CTL with the early-stage autophagy inhibitor 3-methyladenine (3-MA) and the late-stage autophagy inhibitor chloroquine (CQ). CQ inhibits autophagy by impairing autophagosome–lysosome fusion. Both CTL and CQ markedly increased DR5 expression levels and increase TRAIL-induced apoptosis, whereas 3-MA marginally enhanced TRAIL-induced apoptosis and resulted in minimal DR5 expression. In summary, our findings indicate that CTL impairs autophagic flux, resulting in autophagosome accumulation and augmentation of DR5 to potentiate TRAIL-induced apoptosis, suggesting that CTL may act as a therapeutic agent that sensitizes TRAIL-resistant cancer cells to TRAIL-mediated cancer therapy.

What Is Known and Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve renal and cardiovascular outcomes and have been reported to have a positive impact on anemia, a common and challenging condition in patients with chronic kidney disease (CKD). The aim of this study is to evaluate the effects of SGLT2 inhibitors on anemia in patients with CKD.

Methods: We performed a systematic review and meta-analysis of randomized controlled trials. Changes in hemoglobin (Hb) and hematocrit (Hct) levels were assessed in participants treated with SGLT2 inhibitors—empagliflozin, dapagliflozin, or canagliflozin—and compared with those receiving control treatments. Statistical analyses were performed using a fixed-effects model or a random-effects model, depending on the heterogeneity. Sensitivity analyses were also conducted to evaluate the impact of each study on the meta-analysis. Publication bias was examined using Begg’s and Egger’s tests.

Results and Discussion: Five studies assessing Hb levels were included. SGLT2 inhibitors significantly increased Hb levels compared with controls (standard difference in means [SE] = −0.350; 95% confidence interval [CI] −0.401–−0.299). Similarly, in three studies evaluating Hct levels, SGLT2 inhibitors significantly increased Hct levels compared with controls (SE = −0.453; 95% CI −0.829–0.077).

What Is New and the Conclusions: This systematic review confirms that SGLT2 inhibitors effectively improve anemia in patients with CKD. We recommend considering SGLT2 inhibitors as a treatment option for CKD patients, not only for their renal and cardiovascular benefits but also for their reliability in addressing anemia.

Objective: The primary objective of this study revolves around the development of a population pharmacokinetic (PPK) model for vancomycin in neonatal subjects, with the objective of providing a theoretical basis for judicious therapeutic interventions.

Methods: In this study, a retrospective collection encompassed 75 neonatal patients, contributing to a total of 89 vancomycin blood concentration monitoring datasets. The establishment of the PPK model is carried out utilizing the nonlinear mixed effects model methodology. The PPK model was constructed employing a one-compartment model with proportional residual error, and the influence of covariates on pharmacokinetic parameters was systematically assessed through forward stepwise addition and backward elimination methods. The stability and predictive accuracy of the final model were assessed using goodness-of-fit plots, nonparametric bootstrap validation, visual predictive checks, and normalized prediction distribution errors. Furthermore, Monte Carlo simulations were employed to predict vancomycin concentrations in neonatal patients with typical characteristics.

Results: The final PPK model yielded population-typical values of 0.24 L/h for vancomycin clearance (CL). Noteworthy contributors to vancomycin CL were identified as body weight, gestational age, creatinine clearance rate (CLcr), and sex. Internal validation results of the model indicate that it possesses stability, efficacy, and demonstrates a favorable predictive capacity. Monte Carlo simulations indicate that for a male neonatal patient characterized by a gestational age of 37 weeks, a body weight of 2.5 kg, and a CLcr of 60 mL/min, the recommended dosing regimen is 25.5 to 41.5 mg every 8 h.

Conclusion: This investigation has successfully formulated a PPK model for vancomycin in neonatal patients, offering the capacity to estimate individual CL. The dosing regimen for neonates should take into account factors such as body weight, gestational age, CLcr, and sex.

Background: Asthma is a prevalent chronic respiratory condition marked by airway inflammation and hyperresponsiveness, significantly impacting quality of life. Emerging evidence suggests a potential association between proton pump inhibitor (PPI) use and an increased risk of asthma. This systematic review and meta-analysis assessed the relationship between PPI use and the development or exacerbation of asthma.

Methods: A systematic search of PubMed, Web of Science, and Embase databases was conducted, covering studies published from the inception of the database to July 12, 2024. Observational studies examining the association between PPI use and asthma risk were included. Two reviewers independently extracted data using Nested Knowledge software, with study quality assessed via the Newcastle–Ottawa Scale. A random-effects meta-analysis was performed, pooling odds ratios (ORs) and hazard ratios (HRs) to assess the association, with heterogeneity evaluated via the I² statistic.

Results: Fourteen studies, conducted between 2009 and 2024 and involving over 1.7 million participants, met the inclusion criteria. The pooled HR showed a 38% increased risk of asthma among PPI users compared to nonusers (HR, 1.38; 95% CI, 1.14–1.62). OR analysis indicated a 29% higher risk (OR, 1.29; 95% CI, 1.23–1.35). PPI users had an 81% higher risk compared to histamine H₂ receptor antagonist (H₂RA) users (HR, 1.81; 95% CI, 1.09–2.53), and asthma patients using PPIs were 61% more likely to experience exacerbations (OR, 1.61; 95% CI, 1.42–1.80).

Conclusion: PPI use is associated with an increased risk of asthma. These findings underscore the need for cautious prescribing and further investigation into underlying mechanisms.

Background: Remimazolam is a good option for anesthesia in elderly patients undergoing gastrointestinal (GI) endoscopy procedures because of its rapid onset, short metabolic duration, and extensively documented safety profile. However, the accurate clinical dosage of these agents has yet to be determined. The objective of this research was to examine the efficacy of the 90% effective dose (ED90) of remimazolam in suppressing the responses of elderly patients during the insertion phase of upper GI endoscopy.

Methods: We enrolled 53 individuals aged 65– 85 years who underwent upper GI endoscopy and were anesthetized with an intravenous bolus of remimazolam. After initiating an initial dose of 0.35 mg/kg remimazolam, subsequent adjustments were made on the basis of the patient’s response, employing an up-and-down sequential allocation using a biased coin design. The primary outcome was the ED90 of the remimazolam infusion for inhibiting the response to upper GI endoscope insertion. Adverse reactions during the perioperative period were observed and recorded.

Results: The ED90 of remimazolam for upper GI endoscope insertion in elderly patients was 0.400 mg/kg (95% CI = 0.348–0.524). Stable circulation was maintained in all patients, and no serious adverse events were observed during sedation. Satisfaction levels were high among the participants: Patients reported a satisfaction score of 4.98 ± 0.14 points, anesthesiologists rated their satisfaction at 4.91 ± 0.35 points, and endoscopists expressed a satisfaction level of 4.89 ± 0.38 points (based on a total score of 5 points, with a minimum of 1 point).

Conclusion: Administration of remimazolam for upper GI endoscopy in elderly patients was found to be both safe and effective. A single intravenous bolus at an ED90 dose of 0.556 mg/kg effectively suppressed the response to the procedure.

Trial Registration: Chinese Registry of Clinical Trials: ChiCTR2200062535