Introduction: Dental anxiety is a critical issue in dentistry. Buccal patches, a noninvasive drug delivery method, can potentially alleviate anxiety and pain during dental procedures. This study aimed to develop a three-layered buccal drug delivery system containing lidocaine or lidocaine–dexmedetomidine for improved pain management in dentistry.
Methods: Three-layered patches were made using ethyl cellulose, eudragit, and Carbopol, incorporating either lidocaine or a combination of lidocaine–dexmedetomidine. Forty participants were included: Both groups received placebo patches on one side of jaw and received their relevant drug patch of lidocaine or lidocaine–dexmedetomidine on the other side. Pain levels were assessed.
Results: The patches were 2-3 mm thick with a pH of 3.5–4.5. Lidocaine release efficiency was 41.69 ± 13.10%, and the combination patches showed 47.17 ± 5.10% for lidocaine and 74.71 ± 6.41% for dexmedetomidine. Release time for lidocaine and the combination patch was 25 and 15 min, respectively, with dexmedetomidine fully released within 3 min. The lidocaine–dexmedetomidine group reported significantly lower pain scores (2.1 ± 0.3) compared to the lidocaine group (4.3 ± 0.4) and placebo (6.8 ± 0.5). The onset and duration of analgesia was faster in the combination group versus the lidocaine group (5.2 ± 0.5 vs. 8.7 ± 0.6 min and 45 ± 5 vs. 30 ± 4 min, respectively).
Conclusion: Buccal patches, especially lidocaine–dexmedetomidine patches, significantly reduce pain and improve patient comfort. These patches offer a promising noninvasive alternative for pain management with enhanced efficacy and patient compliance. Further research is needed to optimize these patches for broader clinical applications.
Trial Registration: Iranian Clinical Trials Registration Center: IRCT20210118050067N2
Objective: The orally bioavailable glucokinase activator, globalagliatin, is used to improve glucose homeostasis. Its metabolism is primarily dependent on cytochrome P450 (CYP) 3A4. Here, the influence of rifampicin, a potent inducer of CYP3A4 and CYP2C19 inducer, moderate inducer of CYP1A2, CYP2B6, CYP2C8, and CYP2C9, and inhibitor of P-gp, on the pharmacokinetics of globalagliatin, were investigated in healthy Chinese subjects.
Methods: This single-center, open-label, one-sequence investigation was performed over 22 days in 24 healthy Chinese volunteers. The volunteers were given single oral doses of 80 mg of globalagliatin on Days 1 and 15 on an empty stomach, while rifampicin 600 mg was given orally once a day from Days 8–21 before breakfast. Blood samples were collected at 0 h (1 h before globalagliatin administration on Days 1 and 15) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after dosing to monitor the globalagliatin pharmacokinetic parameters. Blood samples on Day 8 were collected before rifampicin administration. The plasma levels of globalagliatin were assessed using LC-MS/MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin Version 8.3.3 and analyzed with SAS Version 9.4. Continuous monitoring was performed to assess drug safety and tolerance.
Results: Analysis of the effect of rifampicin on globalagliatin pharmacokinetics in 24 healthy participants showed that with rifampicin, the Cmax of globalagliatin decreased by 88.9%, while the AUC0–t and AUC0–∞ values were reduced by 97.0% and 96.4%, respectively. The geometric mean ratios of globalagliatin Cmax, AUC0–t, and AUC0–∞ and their 90% CI values were 11.09% (90% CI:9.40–13.10%), 2.96% (90% CI:2.59–3.39%), and 3.60% (90% CI:3.20–4.04%), respectively. The mean elimination half-life was reduced by 27.91 h, while Tmax was prolonged by 3.52 h. Six treatment-related adverse events were reported by five subjects (20.8%), with all being of Grade 1 severity.
Conclusions: Cotreatment with rifampicin significantly reduces the plasma levels of globalagliatin. The safety and tolerability of globalagliatin, both as monotherapy and in combination with rifampicin, were good in healthy Chinese volunteers.
Trial Registration: Chinese Clinical Trial Register: CTR20210959
Background: The optimal strategy for dosing and monitoring vancomycin continues to evolve. A vancomycin 24-h steady-state area under the concentration–time curve/minimum inhibitory concentration (AUC/MIC) of ≥ 400 has been associated with positive clinical outcomes, while an AUC/MIC > 600–700 has been associated with increased risk of nephrotoxicity. The 2009 vancomycin dosing guidelines recommended target trough concentrations between 10–20 mcg/mL depending on infection; however, recent pharmacokinetic data suggest that most patients can achieve target AUC/MIC with trough concentrations < 15 mcg/mL. While existing literature has demonstrated reduced nephrotoxicity with AUC-guided dosing (AGD), there are limited data evaluating efficacy and other clinical outcomes. Therefore, this study compared the clinical efficacy of vancomycin using trough-guided dosing (TGD) versus AGD in patients with confirmed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.
Methods: This was a retrospective, observational, quasiexperimental study of adult patients who received vancomycin for treatment of MRSA bacteremia. Patients with central nervous system infections, weighing > 200 kg, with acute kidney injury, or receiving hemodialysis/continuous renal replacement therapy were excluded. The primary outcome was microbiological success defined as negative blood cultures within 7 days of vancomycin initiation. Secondary outcomes included achievement of therapeutic target concentrations and incidence of nephrotoxicity.
Results: Microbiological success was achieved in 52/55 (95%) patients with TGD versus 50/51 (98%) patients with AGD (p = 0.619). In the TGD group, 24/55 (44%) patients achieved therapeutic target concentrations within 48 h of initiation of vancomycin compared to 24/51 (47%) patients in the AGD group (p = 0.723). The median hospital length of stay was longer in the TGD group compared to the AGD group (16 days, IQR 11–27 days versus 13 days, IQR 9–24 days, respectively, p = 0.260). Nephrotoxicity occurred in 7/55 (13%) TGD patients versus 5/51 (10%) AGD patients during vancomycin therapy (p = 0.763).
Conclusions: AGD was similar to TGD at achieving microbiological success in patients with MRSA bacteremia and may lead to shorter lengths of hospital stay and lower rates of nephrotoxicity.
What is Known and Objective: The use of multiple medications, or polypharmacy, is associated with an elevated risk of potential drug–drug interactions (pDDIs), consequently heightening the probability of adverse drug reactions. Currently, there is a dearth of data regarding pDDIs in Chinese patients with atrial fibrillation (AF) within real-world scenarios. This study is designed to investigate the existing state of polypharmacy and pDDIs in Chinese AF patients and to analyze the factors influencing pDDIs.
Methods: This was a single-center retrospective investigation conducted at a tertiary hospital in China. Polypharmacy and pDDIs were examined based on the medications prescribed at the time of discharge. The pDDIs were assessed using the Lexi-Interact database and classified into Types A, B, C, D, and X.
Results and Discussion: The study encompassed 802 AF patients. The median age was 73 years (ranging from 64 to 80). The most (72.7%) were 65 years or older, and 53.9% were male. The incidence rates of polypharmacy and excessive polypharmacy were 74.8% and 29.8%, respectively. At discharge, 69.0% of patients had at least one clinically relevant pDDI. There were 1820 (84.2%), 261 (12.1%), and 81 (3.7%) interactions categorized as Types C, D, and X, respectively. The most prevalent Type C interaction was the combined use of antihypertensive medications. Among Type D interactions, the most common was the combination of anticoagulants and antiplatelet drugs. The most frequent Type X interaction involved drugs that augmented the hyperkalemic effect. Through multivariate analysis, advanced age (p = 0.008) and a greater number of medications (p < 0.001) were significant predictors of pDDIs.
What is New and Conclusions: Polypharmacy and pDDIs are widespread among AF patients. Advanced age and an increased number of drugs were determined to be predictive factors for pDDIs. The risk of DDIs can be reduced by decreasing the number of medications or opting for alternative drugs.
Background: Wen-Jing-Zhi-Tong decoction (WJZTD) is a traditional Chinese medicine herbal decoction that has demonstrated clinical efficacy in treating primary dysmenorrhea (PDM) over decades. However, the underlying therapeutic mechanism of WJZTD requires further clarification.
Objective: This study aims to explore and elucidate the therapeutic mechanism of WJZTD in treating PDM through metabolomics, integrated network pharmacology, as well as in vitro and in vivo experiments.
Methods: A PDM rat model was established by estradiol benzoate and oxytocin for 3 consecutive estrous cycles, and then WJZTD treatment was administered for 3 consecutive estrous cycles. To evaluate the therapeutic effect of WJZTD on PDM, behavioral tests, histological analysis, and evaluation of serum prostaglandins (PGs) were performed. Moreover, immunofluorescence and Western blot analysis were carried out in dorsal root ganglion (DRG) tissues to explore the role of WJZTD in reducing pain sensitivity. Metabolomics and integrated pharmacology were utilized to identify potential bioactive targets, which were then validated through in vitro experiments.
Results: WJZTD significantly reduces pain sensitivity in PDM rats, treating the condition effectively by decreasing brain-derived neurotrophic factor (BDNF) protein expression, c-Fos-positive neurons in DRG, and serum prostaglandin PGF2α (PGF2α) levels. A nontargeted metabolic analysis identified 11 differential metabolites, suggesting ESR1 (estrogen receptor α, ERα) as a potential target. In vitro experiments confirmed WJZTD’s efficacy in treating PDM through regulating the ERα/BDNF signaling pathway.
Conclusion: WJZTD decreases the excitability of DRG neurons in rats with PDM through the ERα/BDNF pathway, which enhances pain sensitization and contributes to reducing dysmenorrhea.
Objective: Serum lactic acidosis has been reported as a serious adverse effect associated with linezolid. This study aims to explore the risk factors of linezolid-induced lactic acidosis.
Methods: Patients admitted to a 3600-bed university hospital, who received linezolid treatment and had at least one steady-state concentration of linezolid, were retrospectively reviewed to analyze the incidence of linezolid-induced lactic acidosis. Meanwhile, univariate and multivariate logistic regression analyses were conducted to determine the risk factors of lactic acidosis.
Results: A total of 95 adult patients were included in the study. 18.95% (18 out of 95) of patients developed lactic acidosis during linezolid treatment. Importantly, patients who concurrently used linezolid and metformin had a high risk of developing lactic acidosis (90.9%, 10 out of 11). After excluding these patients from the original database, 9.52% (8 out of the 84) of the patients developed lactic acidosis. In the population not receiving concurrent metformin treatment, univariate analysis showed that patients who developed lactic acidosis had higher linezolid Cmin and serum creatinine levels or lower creatinine clearance, and multivariate analysis showed that Cmin (OR: 1.114; 95% CI: 1.012–1.226; p = 0.027) was an independent risk factor for lactic acidosis.
Conclusion: The concurrent use of linezolid and metformin raises the risk of lactic acidosis. Therapeutic drug monitoring of linezolid based on Cmin is recommended for decreasing the risk of lactic acidosis during linezolid treatment.
Objective: Many biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/ts DMARDs) are used in the treatment of psoriatic arthritis (PsA) during recent years, but there are few head-to-head studies that directly compare these drugs to evaluate and compare the relative efficacy of these treatments at week 24. The aim of this study is to conduct a comprehensive comparison of all clinically used bDMARDs or tsDMARDs for PSA using a network meta-analysis to evaluate relative efficacy of these drugs, which is evaluated by ACR20, ACR50, ACR70, PASI75, and PASI90.
Methods: All randomized controlled trials of these treatments are searched in PubMed, Web of Science, and Embase, and data are extracted from the included articles, and network meta-analysis is performed using the Stata 13 software.
Results: secukinumab 300 mg is the top-ranked treatment for ACR20 and PASI90, infliximab 5 mg/kg is the top-ranked treatment for ACR50, and adalimumab 40 mg is the top-ranked treatment for ACR70 and PASI75.
Conclusions: Tumor necrosis factor-α inhibitors and interleukin 17A inhibitors are the top-ranked treatments for arthritis and skin responses of active PsA.
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.
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