International journal of clinical pharmacology and therapeutics最新文献

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.

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: To investigate the epidemiological characteristics of severe cutaneous adverse reactions (cirAEs) induced by immune checkpoint inhibitors (ICIs) and to provide evidence for the rational clinical use of ICIs and pharmacovigilance for cutaneous toxicities.

Materials and methods: We systematically searched the PubMed, MEDLINE, EMBASE, CNKI, and Wanfang databases using keywords including "immune checkpoint inhibitors," "cutaneous adverse reactions," "cutaneous toxicity," "induced," and "case," and their combinations to identify detailed case reports on cirAEs. Data on patient demographics (sex and age), primary cancer type, ICI use, time to cirAE onset, cirAE severity grading, and reaction classification were extracted. Descriptive statistics, co-occurrence analysis of clinical manifestations, and the Apriori algorithm were employed to analyze cirAE patterns.

Results: The analysis included a total of 120 articles involving 126 patients (male: 80; female: 46) with a mean age of 63.05 ± 11.85 years. The highest incidence was observed in patients aged 60 - 69 years. The primary cancers were predominantly non-small cell lung cancer and melanoma. Programmed death 1 (PD-1) inhibitors were the most commonly used therapeutic agents. The median time to onset was 15 - 28 days. Most cases were classified as severe Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

Conclusion: Healthcare professionals must remain vigilant for severe cirAEs and ensure timely diagnosis and management to safeguard patient safety during ICI therapy.

Objective: Oral semaglutide contains salcaprozate sodium, which promotes the opening of epithelial tight junctions and increases gastric pH to prevent its degradation; these actions together improve absorption. Proton pump inhibitors (PPIs) increase gastric pH. However, it is unclear whether PPIs affect the absorption of semaglutide and may therefore enhance the blood glucose lowering effect of semaglutide or affect the reduction of hemoglobin A1c (HbA1c). Therefore, this study investigated differences in HbA1c changes and adverse events between those with and without PPI co-administration.

Materials and methods: This single-center retrospective study included patients with type 2 diabetes who received oral semaglutide. Patients were categorized into two groups: those on treatment with PPI (w/PPI) and those not on treatment with PPI (without PPI (w/o PPI)). The primary outcome was the change in HbA1c levels at 52 weeks, while the secondary outcomes included changes at 26 weeks and the incidence of adverse events.

Results: A total of 66 patients were included. HbA1c reduction at 52 weeks was significantly greater in the w/PPI group (-1.56 ± 0.37%) than in the w/o PPI group (-1.08 ± 0.76%, p = 0.024). The incidences of adverse events were 24.0% and 31.7% in the w/PPI and w/o PPI groups, respectively (p = 0.502).

Conclusion: HbA1c reduction at 52 weeks was significantly greater in the PPI co-administration group than in the group without PPI. Future research should include larger sample sizes and pharmacokinetic studies to clarify the clinical implications and interactions between oral semaglutide and PPIs.

Objective: To examine the effects of the oral uremic toxin absorbent AST-120 on the concentration of free and protein-bound indoxyl sulphate (IS) and to assess the effects of serum albumin in end-stage kidney disease (ESKD) patients undergoing hemodialysis.

Materials and methods: The study enrolled 37 ESKD patients who initiated hemodialysis at the Shirasagi Hospital. Serum free and bound IS concentrations were measured before the first of 4 hemodialysis sessions and after the last hemodialysis 7 days later. The cohort contained a subgroup of patients in whom AST-120 treatment (6 g/day) was discontinued immediately prior to the first hemodialysis and a subgroup not treated with AST-120. Clinical characteristics were obtained from electronic medical records.

Results: Discontinuation in AST-120 treatment prior to dialysis resulted in marked but highly variable increases in IS concentrations, measured 7 days later, where the efficiency of dialysis of IS was dependent on the serum albumin concentration.

Discussion: The observation that the percentage change in IS concentration was significantly higher after discontinuation of AST-120 compared to those not receiving AST-120 was unexpected as was the finding of a high inter-patient variability in IS concentrations before and after hemodialysis. The effects of a discontinuation in AST-120 administration can be interpreted as a rebound in the systemic absorption of indole precursors, but the source of variability in IS concentrations was unclear. Although there are important limitations in this investigation, the report presents valid and valuable data on free and albumin-bound IS concentrations during hemodialysis and AST-120 treatment as well as measurements of serum albumin concentrations in the group of largely elderly subjects.

Conclusion: AST-120 in ESKD patients has profound effects on the disposition of IS. There are important sources of variability having a possible marked effect on the concentration of IS in patients with chronic kidney disease. Discontinuing AST-120 treatment before hemodialysis, a practice in Japan to avoid the "off-label" administrations of the agent, will result in high and variable concentrations of uremic toxins such as IS. The consequences of this effect will include progression of the disease and the occurrence of cardiovascular and neurological degeneration.

Background: Extracorporeal membrane oxygenation (ECMO) provides life support for critically ill tuberculosis (TB) patients. However, during ECMO therapy, significant fluctuations in the plasma concentration of anti-TB drugs occur due to drug adsorption in the ECMO circuit, hemodilution, and metabolic disturbances.

Materials and methods: This single-case study monitored the plasma concentration of anti-TB drugs in a TB patient supported by ECMO.

Results: The differences in peak plasma concentrations (C_max) measured at the end of ECMO support vs. 7 days after ECMO withdrawal were as follows: isoniazid (66%), linezolid (63%), ethambutol (56%), and levofloxacin (12%).

Conclusion: We analyzed ECMO's impact on drug concentrations and implemented therapeutic drug monitoring to optimize therapy. However, this single-case study has inherent limitations; future multi-center studies are warranted to validate these findings.

Introduction: Asthma is a chronic disease that requires careful management, and its exacerbations can be life-threatening. The aim of this study was to ascertain whether inhaled corticosteroids (ICS)-containing inhaler in combination with oral montelukast and levocetirizine could lessen the exacerbation of asthma in comparison to inhaler alone.

Materials and methods: Among 437,915 asthma patients receiving ICS-containing inhaler, 91,122 participants were included. Treatment groups were categorized as (1) ICS-containing inhalers (ICS with or without long-acting β-2 agonist (LABA)), and (2) ICS-containing inhalers used in combination with both oral montelukast and levocetirizine, and (3) severe exacerbation of asthma (visit of emergency room or hospitalization). After 1 : 1 propensity score matching of treatment groups, survival analysis utilizing Cox regression was conducted for estimating the effect of treatment on asthma exacerbation.

Results: We found that the inhaler plus montelukast and levocetirizine group exhibited a lower crude incidence rate and was associated with a lower risk of all-cause death and moderate to severe exacerbation. Specifically, the adjusted hazard ratios (HRs) were 0.71 (p = 0.006) for all-cause death, 0.57 (p < 0.001) for moderate exacerbation. For severe exacerbations, the adjusted HRs were 0.59 for emergency room visits and 0.66 for hospitalizations (p = 0.018 and 0.011, respectively), compared to the ICS-only group, demonstrating a statistically significant reduction.

Conclusion: Treatment with ICS-containing inhaler plus oral montelukast and levocetirizine was significantly associated with a lower risk of exacerbations in asthma patients. Alongside the growing burden of healthcare utilization and costs in South Korea, consideration of the treatment of ICS with montelukast and levocetirizine may serve as an effective treatment option for patients with severe, uncontrolled asthma, potentially improving disease management and reducing healthcare costs.

Hand-foot syndrome (HFS) is a relatively common, dose-limiting dermatologic toxic reaction associated with multiple chemotherapeutic agents, including pegylated liposomal doxorubicin (PLD). Early symptoms of HFS include erythema, marked discomfort, swelling, and tingling on the palms and soles of the feet, which may progress to blistering and even ulceration in severe cases. We report a case of a breast cancer patient who developed HFS after receiving 3 cycles of PLD. The patient presented with redness, swelling, blistering, ulceration, and exudation in her palms, soles, axillae, groin, and waist. After symptomatic treatment, her HFS symptoms were significantly relieved. At the same time, we have also examined the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data for further reports of the relationship between different anthracyclines and risk of HFS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options for the prevention of progression. Relieving swallowing difficulties, reducing breathing difficulties, and alleviating muscle spasms are essential to improving the quality of life in patients with ALS. Many symptoms can be treated clinically with medication; however, the evidence level of related research is relatively low. Rehabilitation management can aid in improving various functional impairments and enhancing quality of life. This review introduces and describes the relevant evaluations of rehabilitation and nonpharmacological symptomatic treatment methods for functional disorders from the perspectives of motor and nonmotor symptoms. This review may promote the popularization of ALS rehabilitation management and provide an additional reference for ALS treatment.