International journal of clinical pharmacology and therapeutics最新文献

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: 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: 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.

Aims: To assess the renoprotective effects of dulaglutide and identify mechanisms of action in patients with type 2 diabetes and diabetic kidney disease (DKD).

Materials and methods: Outpatients/ambulant patients at the Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University between October 2021 and July 2023, with type 2 diabetes and DKD, a urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol and who were receiving hypoglycemic agents were prescribed dulaglutide at a dose rate of 0.75 - 1.5 mg once weekly (intervention group; n = 70). Patients receiving hypoglycemic agents other than glucagon-like peptide-1 (GLP-1) receptor agonists and who were not prescribed dulaglutide constituted the control group (n = 65). Observations/outcomes: The primary outcome was a change in the UACR and biomarkers of epithelial-mesenchymal transition (EMT) determined after 12 months of intervention treatment. Adverse events (estimates of tolerability and safety) were recorded during treatment and a follow-up period of 12 months.

Results: UACR changes in the intervention group compared to the control group were significantly lower (p < 0.01 at 6 months and p < 0.05 at 12 months). The frequency of gastrointestinal adverse events in the two groups were not significantly different, and there were no significant increases in the number of hypoglycemic events. Dulaglutide significantly increased the epithelial marker E-cadherin and inhibited the mesenchymal marker periostin.

Conclusion: It is concluded that dulaglutide causes significant reductions in urinary albumin and modulates EMT-related proteins thereby ameliorating the decline in kidney function in patients with type 2 diabetes and DKD.

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.

Introduction: Sunitinib is an oral drug approved for the treatment of metastatic renal cell carcinoma. Serious cutaneous adverse reactions to sunitinib are rare, and when they occur, discontinuation of the treatment may be needed.

Case report: A 70-year-old male patient was diagnosed with stage IV clear cell renal carcinoma and received treatment with sunitinib. After a second cycle with a 25% dose reduction, the patient was admitted with a diagnosis of grade 3 genital erythema. After ruling out other common causes, sunitinib was considered the cause of genital erythema and was stopped. Treatment with corticosteroids, topical applications, and morphine was started, with resolution after 18 days of evolution.

Discussion: There are only a few published reports that describe erythema and scaling of the genital skin. As in those few cases, for our patient, the first clinical signs appeared on day 28 of sunitinib treatment, and the lesions disappeared after 2 weeks without the use of the drug. Erythema and scaling reappeared when the drug was reintroduced, with greater severity than what was described in some of the other cases, which even included cases for which the lesions did not reappear.

Conclusion: Rare instances of severe and limiting skin toxicity may necessitate treatment suspension and compromise survival, as observed in our case. It is crucial to recognize these skin toxicities and understand their appropriate management strategies to initiate treatment as early as possible, thereby avoiding hospitalizations and enabling the resumption of sunitinib therapy.

Objective: The purpose of this study is to evaluate the pharmacokinetics (PK) parameters of an ezetimibe 10 mg (test drug) and assess its bioequivalence to the branded reference product in healthy Chinese subjects under fasting and fed conditions.

Materials and methods: A single-center, randomized, open-label, four-period, two-sequence, full replicate crossover study was conducted in 88 healthy Chinese subjects under fasting or fed conditions. Subjects received a single oral dose of 10 mg ezetimibe tablet as test or reference formulation. There was a minimum 14-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of free ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) was determined by a validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Pharmacokinetik and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded.

Results: 40 and 48 eligible healthy subjects were enrolled in the fasted and fed study. Under fasting state, total ezetimibe with 90% confidence intervals (CIs) of C_max, AUC_0-t, and AUC_0-∞ were 87.17% (81.99 - 92.66%), 95.98% (92.38-99.72%), and 96.04% (91.37 - 100.95%), respectively. Under fed state, total ezetimibe with 90% confidence intervals (CIs) of C_max, AUC_0-t, and AUC_0-∞ were 98.71% (90.11 - 108.13%), 98.32% (94.71 - 102.06%), and 97.90% (92.68 - 103.42%), respectively. The 90% CIs of the ratio of geometric means (GMRs) of C_max, AUC_0-t, AUC_0-∞ of the test and reference formulation in both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80 - 1.25. No severe adverse events were observed.

Conclusion: The test and reference 10-mg ezetimibe tablets were bioequivalent under fasting and fed conditions in Chinese subjects. Both preparations showed good safety and tolerability.

Objective: Previous findings on predictors of vancomycin-induced acute kidney injury (AKI) are inconsistent. We aimed to identify the predictors of vancomycin-induced AKI using the Observational Medical Outcome Partnership Common Data Model.

Materials and methods: We analyzed data from patients treated with vancomycin between January 1, 2012, and May 31, 2022, who were positive for Staphylococcus aureus and had undergone oxacillin susceptibility tests. After excluding patients without data for vancomycin or baseline serum creatinine levels, 116 patients were included in the final dataset. Data up to the third measured vancomycin concentration were collected for each patient. Logistic regression models were used to estimate the odds ratio and 95% confidence interval for each variable associated with vancomycin-induced AKI.

Results: High baseline serum creatinine levels, intensive care unit admission, and concurrent renal disorders were significantly associated with vancomycin-induced AKI. Although high trough levels or area under the curve values were not significantly associated with vancomycin-induced AKI, both were significantly higher in patients with AKI than in those without AKI at the second vancomycin concentration measurement. The proportion with trough levels > 20 mg/L was higher in patients with AKI than in those without AKI at the third measurement.

Conclusion: Our findings revealed that underlying renal disease and intensive care unit admission are more significantly associated with vancomycin-induced AKI than vancomycin pharmacokinetic parameters or dosage, likely due to vancomycin concentration-based dosage adjustment in clinical settings. Our findings may help develop strategies for reducing the incidence of vancomycin-induced AKI; however, further prospective studies are essential.

Objectives: To evaluate the indications and dosing regimens for oral metronidazole monotherapy (OMM) for the management of oral anaerobic infections (OAIs) other than periodontitis.

Materials and methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in literature of PubMed/Medline, Scopus, and Cochrane databases. Data were retrieved from reports published in English in the period January 1, 1980 - August 30, 2023. Joanna Briggs Institute Critical Appraisal Tools were used to assess study risk of bias.

Results: A total of 228 articles were retrieved from the databases of which 16 met the inclusion criteria necessary for achieving the aims of the study. OAIs in which OMM was used or recommended included pericoronitis; necrotizing ulcerative gingivitis/periodontitis/stomatitis, osteomyelitis, acute periapical infection, and cellulitis. OMM was prescribed in dosages ranging from 200 to 500 mg t.i.d. for periods ranging from 2 to 7 days. Osteomyelitis of the jaw was the only infection for which the dosage regimen of metronidazole was not clearly described.

Conclusion: Evidence from the databases searched support the view that OMM has clinical efficacy in the treatment of specific OAIs namely pericoronitis and necrotizing oral infections in immune-competent and immune-compromised patients. The evidence does not support the use of OMM in "deep tissue" infections such as osteomyelitis, and odontogenic infections such as acute apical infection and cellulitis. Clinical trials are warranted to determine the efficacy of OMM in comparison with other antibiotic regimens.