Frontiers in Pharmacology最新文献

Objective: There is a lack of studies investigating the safety of combination regimens specifically for cardiovascular and cerebrovascular diseases. This study aimed to evaluate the safety of combination drugs for cardiovascular and cerebrovascular diseases using real-world data.

Methods: We analyzed adverse drug reaction data received by the Hubei Adverse Drug Reaction Center from the first quarter of 2014 to the fourth quarter of 2022. The safety of combined drugs for cardiovascular and cerebrovascular diseases in different people was assessed using the association rule method and Ω shrinkage measurement.

Results: A total of 53,038 reports were included in this study, revealing 9 signals of adverse reactions caused by combination drugs. The strongest signal found in this study was jaundice caused by the combination of amlodipine and atorvastatin (Ω 0.025:3.08, lift: 1116.69, conviction: 1.75). Additionally, the combination of aspirin with other drugs was associated with hemorrhaging in various organs. Female patients showed a cold signal when taking vitamin C and vitamin B6 together compared to male patients (Ω 0.025:0.89, lift: 7.15, conviction: 1.12). Patients under 60 years old had a palpitations signal when combining eritrea bei sha Tanzania and felodipine (Ω 0.025:0.41, lift: 14.65, conviction: 3.8), and an erythema signal when combining nifedipine (Ω 0.025:0.23, lift: 8.17, conviction: 1.077).

Conclusion: Among the 9 signals identified in this study, 4 were off-label adverse drug reactions that require further clinical research for exploration and confirmation, in order to provide more scientifically informed drug labeling. Five adverse events associated with aspirin-induced bleeding were identified. Notably, different adverse drug reactions were observed in different populations, suggesting the need for future studies to expedite the development of personalized medicine.

Kleinia is a genus of over 50 species that are commonly used in primary care in several countries. This study seeks to inspire researchers to quickly discover and isolate the key active metabolites found in Kleinia taxa, thereby promoting the development of novel, safe, and effective therapies for a variety of illnesses. To this end, we performed a thorough search of English-language publications from PubMed, Scopus, ScienceDirect, Web of Science, Google Scholar, and ResearchGate. Our search utilized keywords such as "ethnobotany," "geographic distribution," "ethnomedicinal use," "phytochemistry," "pharmacological or bioactivities," and "toxicological activities" related to the genus Kleinia. Chemical structures were depicted using Chemdraw^® software. Literature highlights numerous Kleinia taxa used in traditional medicine for conditions like intestinal parasites, measles, smallpox, diabetes, edema, nerve disorders, sexual dysfunction, gastrointestinal issues, cancer and more. Phytochemical analysis identifies 77 secondary metabolites, mainly alkaloids, flavonoids, saponins, terpenes, and terpenoids and other miscellaneous metabolites. Among the Kleinia taxa, K. anteuphorbium, K. longiflora, K. grandiflora, K. odora, K. squarrosa, K. abyssinica, K. pendula, and K. azoides have been scientifically validated to exhibit various pharmacological activities. However, the existence of potentially harmful metabolites in Kleinia taxa, particularly pyrrolizidine alkaloids, emphasizes the significance of cautious application in traditional medicine and the need for rigorous toxicological assessments. In conclusion, this review highlights the promise of Kleinia taxa as significant medicinal resources and advocates for extensive bioprospecting. It encourages global pharmaceutical companies and academic institutions to conduct thorough investigations of the genus Kleinia to uncover new therapeutic possibilities.

Background: Postoperative visceral pain is a common complication after endoscopic retrograde cholangiopancreatography (ERCP). In this study, we compared the analgesic and anti-inflammatory effects of oxycodone and fentanyl in children undergoing ERCP.

Methods: A single-center, randomized, double-blind study was conducted at a tertiary care hospital affiliated with Shanghai Jiao Tong University. Eighty-two pediatric patients aged 2-18 years who were scheduled for elective ERCP were randomly assigned to receive either oxycodone (0.2 mg/kg) or fentanyl (2 μg/kg). The postoperative pain was evaluated after 10 min, 20 min, and 30 min in the post-anesthesia care unit (PACU) as well as 6 h and 24 h in the ward following ERCP. Additionally, inflammatory cytokines in the serum, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were examined by blood sampling at baseline, 6 h, and 24 h after ERCP.

Results: Compared to fentanyl, children receiving oxycodone had significantly lower pain scores at 30 min, 6 h, and 24 h after ERCP, while the scores at 10 and 20 min were similar in both groups. We also found that fewer patients had pain scores ≥3 at 6 h and 24 h after the procedure in the oxycodone group [36.6% (15/41) vs. 61.0% (25/41) at 6 h, 34.1% (14/41) vs. 58.5% (24/41) at 24 h, p = 0.027 for both cases]. Furthermore, fewer children in the oxycodone group had elevated inflammatory cytokines (IL-6 at 6 h and TNF-α at 24 h after ERCP) compared to the fentanyl group. The incidence of postoperative vomiting was also lower among children receiving oxycodone [14.1% (7/41) vs. 24.4% (10/41), p = 0.032].

Conclusion: Oxycodone (0.2 mg kg^-1) can provide effective analgesia and stable hemodynamics in children undergoing ERCP. This analgesic characteristic may be related to amelioration of inflammation after ERCP.

Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2300074473.

Background: Anticoagulants are the primary means for the treatment and prevention of venous thromboembolism (VTE), but their clinical standardized application still remains controversial. The present study intends to comprehensively compare the efficacy and safety of various anticoagulants in VTE.

Methods: Medline, Embase, and Cochrane Library from their inception up to August 2023 were searched to compare the efficacy and safety of various anticoagulants in VTE. We extracted data on study settings, baseline characteristics, interventions, and outcomes, applying the intention-to-treat principle. Two researchers assessed study bias using the Cochrane tool, resolving disagreements through discussion or third-party adjudication. Network meta-analyses were performed based on Bayesian generalized linear models, and a frequentist framework with multivariate random effects was used to fit the model.

Results: In terms of treatment, 58 trials with 119,417 patients proved eligible, while 125 trials with 225,414 patients were included in terms of prevention. All anticoagulants were found to reduce the recurrence or incidence of VTE compared with Placebo, of which high-level evidence indicated that direct thrombin inhibitors (TIs) and novel oral anticoagulants (NOACs) were the two most effective drugs. For treatment, low molecular weight heparin (LMWH), unfractionated heparin (UFH), and vitamin K antagonists (VKAs) significantly increased the risk of major bleeding in comparison to Placebo. For prevention, only UFH (OR 2.0, 95% CI 1.2-3.3) and NOACs (OR 1.8, 95% CI 1.2-2.6) showed significant increased risks in major bleeding. Additionally, after an exhaustive analysis of NOACs, analysis showed that apixaban (RR 0.5, 95%CI 0.17-1.46) had a superior performance in major bleeding compared to rivaroxaban (RR 3.87, 95%CI 1.48-10.09).

Conclusion: TIs and NOACs were superior in efficacy with minimal side effects, making them pivotal choices for both prevention and treatment of VTE. Clinical practitioners must carefully weigh drug characteristics, indications, and contraindications to optimize treatment outcomes.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=466775.

Background: Gynura procumbens (Lour.) Merr. is a plant used in traditional Chinese medicine that reduces hepatotoxicity, relieves kidney discomfort, and has anti-inflammatory and antioxidant properties.

Methods: We aimed to explore the mechanisms underlying the therapeutic effects of an ethanol extract from G. procumbens stems (EEGS) and selected metabolites on kidney injury and renal anemia associated with chronic kidney disease (CKD). An adenine-induced rat CKD model was used to elucidate the effective mechanism of EEGS and selected metabolites to correct renal anemia.

Results: The results showed that treatment with EEGS reversed abnormal changes in the blood indicators, including hemoglobin, red blood cells, serum erythropoietin (EPO), and creatinine levels. Moreover, EEGS inhibited xanthine oxidase (XOD) activity in vitro, significantly inhibited liver XOD activity, and reduced intrahepatic inflammatory infiltration. Analysis of the pathological changes revealed that EEGS treatments resulted in reduced renal tubular apoptosis, decreased a number of crystals, a narrowed tubular lumen, and attenuated tubular fibrosis. Immunohistochemical staining revealed that EEGS significantly ameliorated the adenine-induced abnormal changes in the expression of related proteins, including β-catenin, COX-2, HIF-2α, and EPO, in the rat kidney tissues. Among the selected EEGS metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was superior to that of either compound alone.

Conclusion: These results suggest that EEGS and selected metabolites can effectively correct renal anemia in CKD rats by inhibiting XOD activity, reducing inflammation, and alleviating renal injury.

Introduction: Tuberculosis (TB) poses a significant threat to global health, with millions of new infections and approximately one million deaths annually. Various modeling efforts have emerged, offering tailored data-driven and physiologically-based solutions for novel and historical compounds. However, this diverse modeling panorama may lack consistency, limiting result comparability. Drug-specific models are often tied to commercial software and developed on various platforms and languages, potentially hindering access and complicating the comparison of different compounds.

Methods: This work introduces stormTB: SimulaTOr of a muRine Minimal-pbpk model for anti-TB drugs. It is a web-based interface for our minimal physiologically based pharmacokinetic (mPBPK) platform, designed to simulate custom treatment scenarios for tuberculosis in murine models. The app facilitates visual comparisons of pharmacokinetic profiles, aiding in assessing drug-dose combinations.

Results: The mPBPK model, supporting 11 anti-TB drugs, offers a unified perspective, overcoming the potential inconsistencies arising from diverse modeling efforts. The app, publicly accessible, provides a user-friendly environment for researchers to conduct what-if analyses and contribute to collective TB eradication efforts. The tool generates comprehensive visualizations of drug concentration profiles and pharmacokinetic/pharmacodynamic indices for TB-relevant tissues, empowering researchers in the quest for more effective TB treatments. stormTB is freely available at the link: https://apps.cosbi.eu/stormTB.

Objective: Remimazolam besylate and Ciprofol are newer sedatives used in minor surgeries. Propofol is a classic drug mainly used for short surgeries. This trial was conducted to compare the efficacy and safety of remimazolam besylate, ciprofol, and propofol during hysteroscopic surgeries.

Methods: Patients undergoing hysteroscopy were randomly assigned to receive remimazolam besylate (Group R), ciprofol (Group C), or propofol (Group P). A total of 194 patients were assessed for eligibility. One patient in Group P was excluded because the operation had timed out of 60 min. Patients all in Group R、Group C and Group P received an induction dose of 0.2 mg/kg remimazolam besylate、0.4 mg/kg ciprofol、2.0 mg/kg propofol seperately over 30 s. A corresponding dosage of 1 mg/kg/h、0.6-1.2 mg/kg/h and 3.0-6.0 mg/kg/h was given by continuous intravenous infusion to maintain a BIS of 40-60 till the end of the surgery. The incidence rates of body movement, respiratory depression, and adverse effects were compared among the groups.

Results: The incidence of injection pain was much higher in Group P (64.1%) than that in Group R (3.4%) and Group C (3.2%, both P < 0.001). The onset time was significantly shorter in Group P than that in Group R and Group C (both P < 0.01). The awakening time (MOAA/S score = 3) was longest in Group R, followed by Groups C and Group P (P < 0.01). The time to complete recovery (MOAA/S score = 5) has no significantly difference between Group C and Group P, whereas the onset time was significantly shorter in Group R (P < 0.01). The number of body movements was significantly higher in Group R than that in Group C and Group P (P < 0.01). The incidence of hypotension was significantly lower in Group R than that in Group C and Group P (both P < 0.01). The rate of respiratory inhibition was significantly lower in Group R and Group C than that in Group P (both P < 0.05).

Conclusion: Considering jointly the safety and efficacy, ciprofol seems to be the best choice for sedation.

Oleuropein is a phenolic compound commonly found in cosmetic ingredients including olive leaves and jasmine flowers with various skin-beneficial effects. Here, we evaluated oleuropein's anti-inflammatory and antioxidant activities in human skin cells. In a cell-based inflammasome model with human monocytes (THP-1 cells), oleuropein (12-200 µM) reduced proinflammatory cytokine interleukin (IL)-6 by 38.8%-45.5%, respectively. Oleuropein (50 and 100 µM) also alleviated oxidative stress in keratinocytes (HaCaT cells) by reducing H₂O₂-induced cell death by 6.4% and 9.2%, respectively. Additionally, biological evaluations revealed that oleuropein's antioxidant effects were attributed to its mitigation of reactive oxygen species in HaCaT cells. Furthermore, a multiplexed gene assay identified IL-1β and thioredoxin-interacting proteins as potential molecular targets involved in oleuropein's protective effects in HaCaT cells. This was supported by findings from several cellular assays showing that oleuropein reduced the level of IL-1β and inhibited the activity of caspase-1/IL-1 converting enzyme, as well as ameliorated pyroptosis in HaCaT cells. Moreover, a bottom-up proteomics study was conducted to explore potential molecular targets and signaling pathways involved in oleuropein's antioxidant activities. Taken together, findings from this study expand the understanding of oleuropein's skin protective effects against oxidative and inflammatory stresses, which support that oleuropein is a promising natural cosmeceutical for skincare applications.

Objective: Minor ginsenosides have demonstrated promising anticancer effects in previous reports. Total minor ginsenosides (TMG) were obtained through the fermentation of major ginsenosides with Lactiplantibacillus plantarum, and potential anticancer effects of TMGs on the mouse colon cancer cell line CT26.WT, in vitro and in vivo, were investigated.

Materials and methods: We employed the Cell Counting Kit-8 (CCK-8), TdT-mediated dUTP nick end labeling (TUNEL), and Western blot analysis in vitro to explore the anti-proliferative and pro-apoptotic functions of TMG in CT26.WT cells. In vivo, a xenograft model was established by subcutaneously injecting mice with CT26.WT cells and administering a dose of 100 mg/kg/day TMG to the tumor-bearing mice. The level of apoptosis and expression of various proteins in the tumor tissues were detected by immunohistochemistry and Western blot. High-throughput 16S rRNA sequencing was used to determine the alterations in the gut microbiota.

Results: In vitro studies demonstrated that TMG significantly inhibited proliferation and promoted apoptosis in CT26.WT cells. Interestingly, TMG induced apoptosis in CT26.WT cells by affecting the Bax/Bcl-2/caspase-3 pathway. Furthermore, the result of the transplanted tumor model indicated that TMG substantially enhanced the activities of Bax and caspase-3, reduced the activity of Bcl-2, and suppressed the expression of Raf/MEK/ERK protein levels. Fecal analysis revealed that TMG reconstructed the gut microbiota in colorectal cancer-affected mice by augmenting the abundance of the advantageous bacterium Lactobacillus and decreasing the abundance of the harmful bacterium Proteus.

Conclusion: TMG can exhibit potent anti-colorectal cancer effects through diverse apoptotic mechanisms, with their mode of action closely related to the regulation of gut microbiota.

Natural pigments, or natural colorants, are frequently utilized in the food industry due to their diverse functional and nutritional attributes. Beyond their color properties, these pigments possess several biological activities, including antioxidant, anti-inflammatory, anticancer, antibacterial, and neuroprotective effects, as well as benefits for eye health. This review aims to provide a timely overview of the potential of natural pigments in the pharmaceutical, medical, and food industries. Special emphasis is placed on emerging technologies for natural pigment extraction (thermal technologies, non-thermal technologies, and supercritical fluid extraction), their pharmacological effects, and their potential application in intelligent food packaging and as food colorants. Natural pigments show several pharmaceutical prospects. For example, delphinidin (30 µM) significantly inhibited the growth of three cancer cell lines (B16-F10, EO771, and RM1) by at least 90% after 48 h. Furthermore, as an antioxidant agent, fucoxanthin at the highest concentration (50 μg/mL) significantly increased the ratio of glutathione to glutathione disulfide (p < 0.05). In the food industry, natural pigments have been used to improve the nutritional value of food without significantly altering the sensory experience. Moreover, the use of natural pH-sensitive pigments as food freshness indicators in intelligent food packaging is a cutting-edge technological advancement. This innovation could provide useful information to consumers, increase shelf life, and assist in evaluating the quality of packaged food by observing color variations over time. However, the use of natural pigments presents certain challenges, particularly regarding their stability and higher production costs compared to synthetic pigments. This situation underscores the need for further investigation into alternative pigment sources and improved stabilization methods. The instability of these natural pigments emphasizes their tendency to degrade and change color when exposed to various external conditions, including light, oxygen, temperature fluctuations, pH levels, and interactions with other substances in the food matrix.