International journal of clinical pharmacology and therapeutics最新文献

Objective: In this study, we aimed to develop a method for predicting the response of patients to three commonly used anti-epileptic drugs (AEDs), namely, carbamazepine, phenytoin, and valproate, using machine learning models, based on the patients' peripheral blood RNA profiles.

Materials and methods: A data set from the Gene Expression Omnibus Series database (GSE143272) was utilized that included the peripheral blood RNA information and some clinical features (age, weight, sex, epilepsy type, drug response) of 57 epilepsy patients. 22 classification models were constructed and trained, in which the peripheral blood RNA information, age, weight, sex, and epilepsy type served as predictors, and the patient' response to anti-epileptic drug as the outcome. The predicting capacity was evaluated by utilizing the sensitivity, the specificity, and the receiver operating characteristic curve of the models.

Results: Among the 22 trained models, the model of a quadratic support vector machine with a pretreatment of principal component analysis displayed the highest accuracy at 0.75, and the highest value of area under ROC curve at 0.81.

Conclusion: The model of a quadratic support vector machine with a pretreatment of principal component analysis is a potential tool for predicting the response of patients with epilepsy to drug treatment.

Objective: To characterize tofacitinib pharmacokinetics (PK) in patients with active ankylosing spondylitis (AS) and estimate the effects of covariates on variability of PK parameters.

Materials and methods: Pooled data from two studies in patients with AS who received tofacitinib were analyzed using nonlinear mixed-effects modeling. Tofacitinib PK was described by a one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution (V/F), and a first-order absorption rate constant (k_a). Covariates evaluated: baseline age, sex, race, creatinine clearance (BCCL), and C-reactive protein for CL/F; baseline age/body weight for V/F.

Results: Analysis included 279 patients. The point estimates for CL/F, V/F, and k_a were 27.1 L/hour, 126 L, and 3.07 hour^-1, respectively, in a reference patient. Excluding BCCL, point estimates of area under the concentration-time curve (AUC) over a dosing interval at steady-state and maximum steady-state tofacitinib concentration (C_max) change vs. the reference patient ranged from 98 - 112% and 89 - 115%, respectively. Estimated AUC was 24% higher in a patient with BCCL = 50 mL/min vs. the reference patient (BCCL = 126 mL/min). Point estimates and 90% confidence intervals of the AUC and C_max ratios indicated no major differences in tofacitinib exposure over the range of baseline age/body weight studied, and sex/race.

Conclusion: Tofacitinib does not require dose adjustment/restriction for age, body weight, sex, or race based on the differences (< 20%) in exposure relative to a reference patient with AS. The tofacitinib CL/F and BCCL relationship was consistent with known contribution of renal excretion to total tofacitinib clearance.

Objective: This study aimed to characterize adverse drug reactions (ADRs) associated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in cancer immunotherapy, identifying demographic, pharmacological, and clinical determinants of toxicity severity using real-world pharmacovigilance data.

Materials and methods: We analyzed 93,925 ADR reports from the FDA Adverse Event Reporting System (FAERS, 2023-2024). Data preprocessing included deduplication, terminology standardization, and severity classification. Multivariate logistic regression and machine learning models were employed to assess predictors of serious ADRs, integrating demographic variables (age, sex), drug agents, and organ-specific toxicities.

Results: Pembrolizumab (38.4%), atezolizumab (26.5%), and nivolumab (25.0%) accounted for 89.9% of ADR cases. Frequent ADRs included death (7.9%), off-label use (7.5%), and malignant progression (6.9%). Immune-related toxicities (diarrhea, hypothyroidism, pneumonitis) comprised 6.1 - 2.4% of cases. Severe ADRs (grade 3 - 4) predominantly affected hepatic (68%), cardiac (65%), and neurological systems (62%). Octogenarians exhibited a 42% increased risk of serious ADRs (p < 0.001), with males representing 51.1% of severe cases (p < 0.001).

Conclusion: Age, sex, and drug-specific profiles critically influence PD-1/PD-L1 inhibitor toxicity. The findings support personalized risk stratification and time-dependent monitoring protocols to mitigate immune-related adverse events, particularly in elderly and male patients. These insights enhance evidence-based management strategies for optimizing immunotherapy safety.

Background: Septic shock is a critical condition requiring vasopressor support and mechanical ventilation. The sequence of vasopressor weaning may affect clinical outcomes, such as mechanical ventilation duration and patient survival.

Objectives: This study assesses how vasopressor weaning order affects hemodynamic stability, clinical outcomes, and the length of mechanical ventilation in critically ill septic shock patients.

Materials and methods: A retrospective cohort study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, from January 2022 to December 2023. Critically ill adult patients receiving intravenous norepinephrine and vasopressin for septic shock and requiring mechanical ventilation were included. Patients were classified into two groups: vasopressin weaned first or norepinephrine weaned first. The duration of mechanical ventilation was the main outcome. These were secondary outcomes: mean arterial pressure (MAP) stability, 30-day and in-hospital mortality, length of stay (LOS) in the intensive care unit and hospital, and rates of reintubation.

Results: Among 100 patients (mean age: 65.1 ± 19.7 years; 58% male), vasopressin was weaned first in 47 patients (47%) and norepinephrine first in 53 (53%). Patients extubated while on vasopressors (vasopressin weaned first) had a shorter median duration of mechanical ventilation (4 days) and lower odds of mortality (adjusted OR = 0.30, 95% CI: 0.09 - 0.98; p = 0.046) compared to those weaned off norepinephrine first. No significant differences were observed in reintubation rates or LOS.

Conclusion: Weaning vasopressin before norepinephrine may be associated with improved survival and reduced mechanical ventilation duration in septic shock patients, although further research is needed to validate these findings and optimize vasopressor weaning strategies.

Objective: We aimed to evaluate the effect of extracorporeal anticoagulation with nafamostat mesilate (NM) and continuous renal replacement therapy (CRRT) on sepsis complicated with acute kidney injury (AKI).

Materials and methods: The clinical data of 106 sepsis patients complicated with AKI admitted from January 2023 to December 2024 were retrospectively analyzed. According to different treatment protocols, the patients were assigned into a control group (n = 53, regional citrate anticoagulation (RCA) plus CRRT) and a study group (n = 53, NM extracorporeal anticoagulation plus CRRT). The use of extracorporeal circulation circuit was compared.

Results: After 3 days of treatment, the levels of procalcitonin, interleukin-6, and tumor necrosis factor-α decreased in the two groups compared to those before treatment (p < 0.05), and they were lower in the study group than in the control group (p < 0.05). After 3 days of treatment, both groups had lowered levels of serum creatinine (Scr), cystatin C (Cys-C), and blood urea nitrogen (BUN), together with increased mean transit time (MTT), peak intensity (PI), and area under the curve (AUC) compared with those before treatment. In the study group, the levels of Scr, Cys-C, and BUN declined, while MTT, PI, and AUC rose compared with those in the control group (p < 0.05). The incidence of adverse reactions in the study group was lower than that in the control group (3.77 vs. 16.98%) (p < 0.05).

Conclusion: NM outperforms RCA in prolonging the hemofilter lifespan, reducing hemofilter replacement frequency, improving renal perfusion and renal function, and eliminating inflammatory mediators.

Objective: To investigate the colonization rate of group B Streptococcus (GBS) during the second trimester of pregnancy, the correlation between GBS infection and miscarriage as well as the impact of intervention on pregnancy outcomes.

Materials and methods: 228 GBS-positive pregnant women at 14 - 28 weeks of gestation were divided into 3 groups according to their preferences to receive medical intervention: group A (antibiotic group, n = 54) received oral antibiotic, group B (probiotic group, n = 96) received oral probiotic, and group C (non-intervention group, n = 78) received no drug treatment. 300 GBS-negative pregnant women were selected voluntarily and randomly as the control group (group D). The incidence of miscarriage-related conditions, negative conversion rate of GBS were compared between the 4 groups. Perinatal outcomes were compared between the GBS persistent positive and negative groups.

Results: GBS colonization rate was 14.7%. The incidence of threatened miscarriage and miscarriage in group A were 1.85 and 1.85%, both of which were lower than those in group B at 21.9 and 6.3%, and group C at 33.3 and 7.7%, with all differences being statistically significant (p < 0.05). The incidence of threatened miscarriage and miscarriage in group B and group C were significantly higher than those in group D at 3.3 and 2.7% (p < 0.05). The negative conversion rate of GBS in group A was significantly higher than that in group C (14.8 vs. 2.7%, p < 0.05). There was a difference in the incidence of fetal distress, premature delivery, premature rupture of the fetal membrane, chorioamnionitis, and neonatal infection between the continuously positive and negative pregnant women (p < 0.05).

Conclusion: GBS colonization rate was 14.7% in the second trimester of pregnancy. GBS infection can increase the risk of threatened miscarriage and miscarriage as well as the risk of adverse pregnancy outcomes. Early intervention with antibiotics can increase the negative conversion rate of GBS, reduce the incidence of threatened miscarriage and miscarriage, and ameliorate the adverse outcome of pregnancy. The effect of probiotic intervention on the negative conversion of GBS was insignificant.

Ocrelizumab is a recombinant humanized IgG1 monoclonal antibody that depletes B lymphocytes by binding their surface antigen CD20 and is approved for the relapsing forms of multiple sclerosis (MS). Several studies report that in utero exposure to ocrelizumab is not associated with an increased risk of malformations, and very few cases of neonatal B-cell count depletion are described after therapy ending shortly before conception or during early pregnancy. We report the first case of transient and complete neonatal B-cell depletion, while conception took place 3 months after the last administration.

Background: Acenocoumarol is a widely used vitamin K antagonist, particularly in European countries. While age and body metrics are known to influence dose requirements, the role of renal function in guiding acenocoumarol dosage remains underexplored.

Aims: The primary aim of this study was to investigate the relationship between renal function and the weekly dose of acenocoumarol required to maintain therapeutic international normalized ratio (INR) levels.

Materials and methods: We analyzed 425 INR measurements from 204 adult patients receiving acenocoumarol, stratified by target INR ranges of 2.00 - 3.00 and 2.50 - 3.50. Renal function was assessed using the body surface area (BSA)-adjusted chronic kidney disease-epidemiology (CKD-EPI) 2021 formula. Weekly acenocoumarol doses were evaluated in relation to age, sex, estimated glomerular filtration rate (eGFR), and body size.

Results: Patients with lower eGFR and older age required significantly lower weekly doses of acenocoumarol. In the INR 2.00 - 3.00 group, males required higher doses than females, correlating with both greater body size and higher eGFR. However, in the INR 2.50 - 3.50 group, males and females received the same median dose despite differing body metrics, mirroring their similar renal function. A positive correlation was found between BSA-adjusted eGFR and weekly dose, particularly when eGFR exceeded 90 mL/min (Spearman r = 0.48, p = 0.0001).

Conclusion: Renal function, as measured by BSA-adjusted eGFR, is a critical determinant of acenocoumarol dose requirements. These findings support the inclusion of renal function in future acenocoumarol dose calculators and emphasize the importance of individualized dosing strategies.

Objective: To investigate the analgesic effect of sufentanil plus dexmedetomidine following cesarean section and to determine its influence on placental hypoxia-inducible factors.

Materials and methods: A cohort of 150 puerperae who underwent prenatal examinations and cesarean section in our hospital were randomized into a control group (n = 75) and a study group (n = 75). Anesthesia and analgesia were carried out using sufentanil alone in the control group and sufentanil plus dexmedetomidine in the study group. Measurements were made before anesthesia (T0), 5 minutes (T1) and 10 minutes (T2) after anesthesia, and immediately after delivery (T3) and after the end of surgery (T4).

Results: Mean arterial pressure (MAP) and heart rate (HR) decreased in both groups at T1 - T4 compared with T0, but were higher in the study group compared to the control group (p < 0.05). The visual analogue scale (VAS) score, and levels of substance P (SP), neuropeptide Y (NPY) and malondialdehyde (MDA) in the study group were lower than those in the control group (p < 0.05). The beginning and duration of labor and the dose of analgesics within the 48-hour observation period were all lower in the study group compared to the control group (p < 0.05).

Conclusion: Sufentanil plus dexmedetomidine can effectively maintain hemodynamic stability during cesarean section without marked changes in placental hypoxia-inducible factors and oxidative stress responses and has a limiting effect on the secretion of pain mediators.

Background: Black patients experience a disproportionately high incidence of heart failure with reduced ejection fraction (HFrEF), where vasodilators serve as a key therapeutic strategy.

Materials and methods: A retrospective cohort study based on medical records of Black patients with HFrEF and an ex vivo analysis of mouse thoracic aorta stimulated with empagliflozin (empa) and hydralazine-isosorbide dinitrate (H-ISDN).

Results: The combination synergistically activated cyclic guanosine monophosphate (cGMP) production in the ex vivo thoracic aorta and improved kidney function, reduced brain natriuretic peptide (BNP), and lowered mortality compared to H-ISDN alone in HFrEF patients.

Conclusion: Empa + H-ISDN offered superior benefits in Black patients with HFrEF, possibly by reducing oxidative stress and enhancing nitric oxide (NO) bioavailability.