International journal of clinical pharmacology and therapeutics最新文献

Objective: This study aims to utilize bioinformatics and network pharmacology to identify the active components of Bushen Tiansui decoction (BSTSD) and elucidate its molecular mechanisms and targets in promoting delayed fracture healing.

Materials and methods: Using various databases and tools, we identified 155 active compounds within BSTSD's herbal components. Key compounds such as eriodictyol and β-sitosterol were noted for their significant anti-inflammatory, antioxidant, and immunomodulatory effects, which are crucial for promoting fracture healing.

Results: Network analysis revealed compounds such as kaempferol and luteolin as having high centrality within the network, indicating their central role in the therapeutic effects of BSTSD. Gene ontology (GO) enrichment analysis highlighted that biological processes such as gland development and aging are vital for fracture healing. Cellular components like membrane rafts and microdomains are essential for maintaining cellular functions and signal transduction during bone repair. Molecular functions such as protein serine/threonine kinase activity play key roles in regulating bone cell proliferation, differentiation, and remodeling. KEGG pathway analysis identified critical pathways including prostate cancer, proteoglycans in cancer, lipid and atherosclerosis, EGFR tyrosine kinase inhibitor resistance, chemical carcinogenesis receptor activation, PI3K-Akt signaling pathway, hepatitis B, endocrine resistance, HIF-1 signaling pathway, and estrogen signaling pathway. Molecular docking results showed strong binding affinities between key compounds and target proteins, supporting the reliability of the network pharmacology predictions.

Conclusion: This study provides a comprehensive understanding of the molecular mechanisms by which BSTSD promotes fracture healing, identifying active compounds and pathways that offer scientific bases for the clinical application of BSTSD and paving the way for further experimental validation and therapeutic development.

Objective: Sodium-glucose cotransporter (SGLT) 2 inhibitors are expected to demonstrate secondary effects against malignancy. However, long-term and large-scale data are required to evaluate the effects of SGLT2 inhibitors on malignancy, which has not been sufficiently studied in clinical practice. This study aimed to evaluate the association between SGLT2 inhibitors and malignancy using the spontaneous adverse reaction database.

Materials and methods: The United States Food and Drug Administration Adverse Event Reporting System database between 1997 (4Q) and 2020 (2Q) was used in this study. Reporting odds ratio (ROR) was selected as the safety-signaling measure. An inverse signal suggesting potential alternative therapeutic opportunities was defined when the upper limit of 95% confidence interval (CI) was < 1. The association between SGLT2 inhibitors and malignancies was evaluated.

Results: The total number of reports in the database during the study period was 13,106,455. SGLT2 inhibitors showed significant associations with pancreatic cancer (ROR: 3.08. 95% CI: 2.68 - 3.55), and kidney cancer (ROR: 1.39. 95% CI: 1.13 - 1.72). SGLT2 inhibitors showed significant inverse associations with breast cancer (ROR: 0.32. 95% CI: 0.27 - 0.39), lung cancer (ROR: 0.47. 95% CI: 0.37 - 0.59), liver cancer (ROR: 0.68. 95% CI: 0.50 - 0.93), and malignant melanoma (ROR: 0.49. 95% CI: 0.34 - 0.70).

Conclusion: SGLT2 inhibitors may increase the incidence of pancreatic cancer and kidney cancer, and decrease the incidence of breast cancer, lung cancer, liver cancer, and malignant melanoma. These associations need to be further examined in other clinical studies and research in the future.

Objective: Current guidelines provide no clear recommendations for managing new-onset atrial fibrillation in critical illness, particularly with respect to anticoagulant use. This retrospective study aimed to evaluate the efficacy and safety of anticoagulants in such patients.

Materials and methods: Patients in the intensive care unit with new-onset atrial fibrillation were recruited during the period January 1, 2021, to June 30, 2022. Ischemic stroke and bleeding were considered primary outcomes, and in-hospital death was considered the secondary outcome. Hazard ratios for outcomes were determined using the Cox proportional hazard model.

Results: A total of 92 patients were included in the study of which 29 were anticoagulant users and 63 non-users. No significant differences were observed on the risk of ischemic stroke (HR, 3.46; 95% CI, 0.22 - 55.8, p = 0.38) and bleeding (HR, 1.07; 95% CI, 0.52 - 2.23, p = 0.85), but anticoagulant use was associated with a significantly decreased risk of in-hospital death (HR, 0.43; 95% CI, 0.19 - 0.97, p = 0.04).

Conclusion: Anticoagulant use in critically ill patients with new-onset atrial fibrillation did not increase the risk of bleeding and ischemic stroke but significantly reduced in-hospital deaths. These findings need confirmation in a randomized controlled trial.

Objective: Valproic acid, frequently prescribed for neurological and psychiatric disorders, can cause hyperammonemia (HA). This retrospective study aimed to investigate the association among the basic characteristics, comorbidities, co-medications, and risk of HA in patients receiving valproic acid.

Materials and methods: We compared groups with and without HA using data collected from the medical records of adults undergoing valproic acid monitoring between January 1, 2019, and December 31, 2021. We conducted a multivariable logistic regression analysis to explore the risk factors for HA and a comprehensive systematic literature review to identify factors significantly associated with valproic acid-related HA.

Results: In total, 247 patients were included, with 37 in the HA group (serum ammonia level > 150 mcg/dL); almost all of them eventually developed hyperammonemic encephalopathy (HE). Multivariable logistic regression analysis revealed that valproic acid levels (odds ratio (OR): 1.01, 95% confidence interval (CI): 0.99 - 1.03), epilepsy (OR: 3.82, 95% CI: 1.52 - 9.62), congestive heart failure (OR: 32.3, 95% CI: 4.09 - 255.4), and concomitant phenytoin use (OR: 6.4, 95% CI: 1.07 - 38.12) are independently associated with HA development during valproic acid therapy. Our data and those of previous studies demonstrate significant associations of valproic acid-related HA with concomitant phenytoin and topiramate use; serum valproic acid concentrations were also significantly positively correlated with serum ammonia levels.

Conclusion: The results suggest that serum ammonia and valproic acid levels should be monitored during valproic acid treatment, particularly with concurrent use of phenytoin or topiramate, to prevent further deterioration of HE.

Objective: To evaluate potential drug-drug interactions between polyethylene glycol loxenatide (PEX-168) and warfarin.

Materials and methods: This was an open-label, single-arm, two-treatment, sequential study. 16 healthy male subjects were administered warfarin (5 mg) alone on day 1 and received PEX-168 subcutaneously 200 µg once a week during days 14 - 42, with warfarin (5 mg) on day 44. Pharmacokinetics of R- and S-warfarin, as well as pharmacodynamics of warfarin, as measured by prothrombin time (PT) and international normalized ratio (INR), were assessed.

Results: The geometric mean ratios (GMRs) of area under the curve from time zero to the time of the last quantifiable concentration (AUC_0-t) for PEX-168 + warfarin vs. warfarin were 0.950 (90% CI: 0.898, 1.006) for R-warfarin and 0.989 (90% CI: 0.946, 1.033) for S-warfarin. The GMRs of maximum observed plasma concentration (C_max) values were 0.965 (90% CI: 0.893, 1.043) for R-warfarin and 0.983 (90% CI: 0.899, 1.075) for S-warfarin, both of which were contained in the interval 0.80 - 1.25. PEX-168 had no effect on the area under the effect-time curve from time 0 to 168 hours of INR and PT, as demonstrated by the GMRs of 0.987 (90% CI: 0.974, 1.000) and 0.990 (90% CI: 0.979, 1.002), respectively.

Conclusion: Concomitant administration of PEX-168 and single-dose warfarin was well tolerated. PEX-168 had no effect on the pharmacokinetics or pharmacodynamics of warfarin.

Objectives: To demonstrate adequate skin adhesion of a new once-daily rotigotine transdermal patch (ROT-TDS) compared to the originator product (reference) in patients with Parkinson's disease (PD).

Materials and methods: Pharmacokinetic bioequivalence (PK BE) was assessed with the 4 mg/24h patches in healthy adults in a single-/multiple-dose, crossover trial. The trial investigating skin adhesion in PD patients (stable dose ≥ 8 mg/day rotigotine) was performed with the 8 mg/24h patches as a multiple-dose, crossover trial (4 alternating once-daily patch applications). Skin status (seborrhea, sweating) was characterized at screening. Adhesion was assessed 5 minutes after application and 5 minutes before removal of each patch. Systemic safety and skin irritation/sensitization were monitored.

Results: ROT-TDS was bioequivalent to the reference product in the PK BE trial in 48 randomized healthy subjects. In the skin adhesion trial in 43 randomized PD patients, the cumulative mean percentage of adhesion (90% CI) at the end-of-dosing interval was 92.948% (90.156 - 95.740%) for ROT-TDS and 90.471% (87.574 - 93.367%) for the reference. For ROT-TDS, 80.23% of patches were ≥ 90% adhered at the end-of-dosing interval, while this was the case for 67.44% of the reference patches. Safety and skin tolerability of both products were comparable; the most frequent treatment-related adverse event was application-site pruritus for both treatments at comparable extent.

Conclusion: ROT-TDS - with shown BE to the originator reference product - displayed similar safety and local tolerability as the reference product in patients with PD. The results show a trend to improved skin adhesion of the new patch compared to the reference in the target population.

Objectives: We aimed to study sarcopenia for its significance in predicting the effect of hepatic artery intervention (HAI) plus lenvatinib on hepatitis B-related hepatocellular carcinoma (HCC) complicated with diabetes mellitus (DM).

Materials and methods: Hepatitis B-related HCC patients complicated with DM (n = 102) visiting during January 2021 and December 2023 were retrospectively selected. Computed tomography was performed to detect the third lumbar vertebra for its muscle cross-sectional area. A non-sarcopenia group (59 cases) plus a sarcopenia group (43 cases, men with a skeletal muscle index ≤ 40.8 cm²/m² and women with a skeletal muscle index ≤ 34.9 cm²/m²) were established according to different skeletal muscle indexes.

Results: Significant decline in body mass index (BMI) and albumin (ALB) level was observed in the sarcopenia group compared to the non-sarcopenia group (p < 0.05). The sarcopenia group, compared with the non-sarcopenia group, exhibited a significantly reduced objective response rate (53.49 vs. 74.58%) (p < 0.05), while no significant intergroup difference was discovered in the disease control rate (95.35 vs. 91.53%) (p < 0.05). Low BMI, alpha fetoprotein (AFP), low ALB, and pre-chemotherapy sarcopenia all influenced the overall clinical efficacy, as independent influencing factors (p < 0.05).

Conclusion: Sarcopenia may attenuate the efficacy of HAI plus lenvatinib on hepatitis B-related HCC with DM, and BMI, AFP and ALB are factors affecting the therapeutic effect.

Background: Patients discharged from intensive care units (ICUs) are at higher risk for medication discrepancies, which can harm patients, increase healthcare costs, and lead to readmission. This study aimed to describe the frequency and types of medication discrepancies among ICU patients upon discharge and identify the factors associated with medication discrepancies.

Materials and methods: This retrospective cohort study included patients ≥ 18 years old, admitted to medical or surgical ICUs, and discharged on one or more medications. This study was done at a tertiary university hospital in Riyadh, Saudi Arabia. Data were collected through chart review over a 3-month period in 2018. Medication discrepancy was defined as any difference identified between the documented home medication list and the medication list on ICU discharge without any clearly documented justification. χ², Fisher exact test, and logistic regression were used to analyze the data.

Results: Out of 204 screened patients, 121 were included. The mean age was 51 ± 15.7 years, 57 (47.1%) were female, and 91 (75.2%) were admitted to the surgical ICU. The median ICU length of stay was 3 (2 - 7) days. In total, 216 medication discrepancies were identified; only 23 (19%) patients were discharged without any medication discrepancies. The mean medication discrepancies identified per patient were 2 ± 1. The most common type of medication discrepancies identified were no indication of therapy (43.8%), drug omissions (33.7%), and discrepancies in the duration of therapy (11.2%). Mechanically ventilated patients were less likely to have medication discrepancies upon discharge (OR = 0.24, 95% CI = (0.07 - 0.90)).

Conclusion: This study demonstrated many medication discrepancies among patients discharged from ICUs at KSUMC University Hospital in Riyadh, Saudi Arabia. The lack of a systematic approach to medication reconciliation might contribute to the increased number of medication discrepancies in comparison to multiple studies in different countries exploring the medication discrepancies among ICU patients. Establishing a process that includes pharmacist-driven medication reconciliation is needed.

Background: Serratia marcescens has recently been categorized as low-risk for AmpC β-lactamase inducible production, but research on outcomes in Serratia bacteremia by antibiotic choice is limited.

Objectives: This study examined the clinical characteristics and outcomes of patients with ceftriaxone-susceptible Serratia bacteremia who received AmpC-directed β-lactam therapy vs. narrower spectrum therapies.

Materials and methods: Records of hospitalized adults with at least one positive blood culture for Serratia, over an 8-year period, across seven hospitals in an integrated health care system, were reviewed.

Results: Of the 73 identified patients, 17 (23.3%) received carbapenem-based therapy. More than half of cases were community-acquired, with urological and intravenous drug use being the most common sources. While there was a trend toward lower mortality in carbapenem-treated patients (14.8 vs. 0%; p = 0.10), this was not statistically significant. The composite outcome of clinical failure was also not significant. However, compared to non-carbapenem-treated patients, carbapenem-treated patients had longer treatment duration (13 vs. 15 days; p = 0.02), prolonged hospital stays (5 vs. 11 days; p < 0.001), and higher infection-related readmission rates (17.6 vs. 3.6%; p = 0.04). A subset analysis of the 56 non-carbapenem treated patients found no significant difference in 30-day mortality or clinical failure between cefepime and non-cefepime-containing subgroups.

Conclusion: Our study found that cefepime- or carbapenem-based therapy may have limited clinical relevance in the treatment of Serratia bacteremia when the strains are initially susceptible to ceftriaxone, highlighting the importance of antibiotic stewardship to prevent emergence of multidrug resistant organisms.