International journal of clinical pharmacology and therapeutics最新文献

Obesity is a global health issue that impacts millions of people worldwide. Semaglutide is a glucagon-like peptide-1 receptor agonist that was initially developed as a treatment for type 2 diabetes mellitus under the brand name Ozempic. Additional studies showed semaglutide at larger doses (marketed as Wegovy) to be an effective medication for weight management. Wegovy for managing obesity is typically well tolerated; however, there have been reports of gastrointestinal adverse effects. Only 1 case of Wegovy-induced transient intestinal ischemia has been documented, making it extremely unusual. Here, we report the case of a 50-year-old man who experienced transient intestinal ischemia following his first Wegovy dosage.

Hematologic responses (< 1%) to piperacillin/tazobactam were uncommon, and mostly reported in non-pregnant adults. The use of piperacillin/tazobactam during pregnancy is considered to be moderately safe for the human embryo-fetus (pregnancy grade B). However, changes in pharmacokinetics during pregnancy (such as an increase in plasma volume and an increase in renal clearance rate) may alter the toxicity threshold of the drug. This is a case of a pregnant woman (26 weeks of gestation) treated with piperacillin/tazobactam for psoas abscess (Proteus mirabilis). After 22 days, the patient developed low-grade fever, leukopenia, neutropenia, and thrombocytopenia. Three days after discontinuation of piperacillin/tazobactam, the above adverse reactions were all reversed. The Naranjo scale yielded a score of 7, which indicates a definite result for this adverse drug reaction. This was the first report of piperacillin-tazobactam-induced pancytopenia in pregnancy.

Background: Linezolid is classified under the reserve group of antibiotics, and it exerts its antibacterial activity by disrupting protein synthesis. Clinically, linezolid is used for treatment of severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). It is eliminated through both renal and hepatic routes. Being a narrow therapeutic index drug, linezolid needs special dosing considerations for safe and effective treatment.

Materials and methods: A plasma concentration dataset of 94 patients with 347 samples was used for development of a population pharmacokinetic model on NONMEM software. The influence of significant covariates on pharmacokinetic parameters was analyzed by stepwise covariate modeling, and dosing simulations were performed on the basis of significant covariates.

Results: The data was best analyzed using a one-compartment model with first-order elimination. The clearance (CL) of linezolid was estimated as 3.38 L/h, while volume of distribution (Vd) was 36 L. The between-subject variability on linezolid CL was 29.8%, and that of Vd was 39.6%. Creatinine clearance (CrCl) and age of the patients were proven to be significant covariates on CL, while no significant covariate was observed for Vd during stepwise covariate modeling. The dosing simulations revealed that a different dose should be administered based on the CrCl of patients.

Conclusion: The renal status and age of the patients are significant covariates responsible for linezolid CL, and a dose of 200, 300, 400, and 600 mg is appropriate for patients with CrCl of 20, 40, 80, and 120 mL/min, respectively.

Objective: This study evaluated and compared the safety, pharmacokinetics, and pharmacodynamics of regadenoson injection (test) and regadenoson original injection (Lexiscan, reference) in healthy Chinese subjects.

Materials and methods: In a randomized, positive-control, single-center, single-dose study, 24 healthy Chinese subjects were divided into test and reference groups (12 subjects each). Subjects in the test group received a single bolus of test drug (0.4 mg/5 mL), while the reference group received the same dose of reference drug. Blood and urine samples were collected before and after drug administration, and regadenoson concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: No serious adverse events (AEs) occurred. There was no significant difference in the incidence of adverse reactions between the two preparations. The pharmacokinetic parameters, including maximum concentration (C_max), the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC_0-t), and the area under the concentration-time curve from time 0 to infinity (AUC_0-∞), were assessed to compare the pharmacokinetic of two regadenoson preparations. The test/reference geometric mean ratios of C_max, AUC_0-t, and AUC_0-∞ were 102.84, 99.16, and 99.77%, respectively. The 90% confidence intervals (CIs) of AUC_0-t and AUC_0-∞ fell within 0.8 - 1.25, but the 90% CIs of C_max did not. Blood pressure (BP) and heart rate (HR) were measured to compare the pharmacodynamics of the two preparations. The test and reference drugs had similar HR responses (63.22 ± 38.45% vs. 37.50 ± 16.96%), systolic BP response (4.81 ± 13.73% vs. -3.83 ± 12.29%), and diastolic BP response (-7.75 ± 12.84% vs. -16.13 ± 9.85%), p > 0.05. After adjusting the weight of males and females, there were significant differences in C_max, AUC_0-t, AUC_0-∞, T_1/2, V_ss, λ_z, Ae%, p < 0.05.

Conclusion: The test drug demonstrated similar pharmacokinetic and pharmacodynamic characteristics as the reference drug. Additionally, it was well-tolerated and safe in healthy Chinese participants. Sex may influence regadenoson pharmacokinetics.

Objective: The aim of this study was to analyze the cardiotoxicity associated with antifungal agents based on data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

Materials and methods: We extracted and evaluated cardiac adverse events (CAEs) linked to antifungals in the FAERS database (2004 - 2023). Signal strength for five antifungal classes was assessed using the reporting odds ratio (ROR) and information component (IC).

Results: Among 50,603 cases, triazoles, polyenes, and imidazoles showed significant associations with Torsade de Pointes (TdP)/QT prolongation (QTP), with fluconazole exhibiting the strongest link (ROR: 11.96, 95% CI: 10.62 - 13.46; IC: 2.19, 95% CI: 1.92 - 2.44). Triazoles were notably connected to arrhythmias, particularly itraconazole (ROR: 3.31, 95% CI: 2.88 - 3.79; IC: 1.67, 95% CI: 1.20 - 2.11). Fluconazole also demonstrated strong associations with conduction defects (ROR 6.44, 95% CI 5.60 - 7.39; IC 2.65, 95% CI 2.16 - 3.08) and ventricular tachyarrhythmias (ROR 9.09, 95% CI 7.84 - 10.54; IC 3.15, 95% CI 2.60 - 3.58). Notably, only itraconazole showed significant signals for cardiac failure (ROR 4.04, 95% CI 3.52 - 4.64; IC 1.96, 95% CI 1.48 - 2.40) and cardiomyopathy (ROR 6.34, 95% CI 5.04 - 7.96; IC 2.64, 95% CI 1.79 - 3.30). In contrast, echinocandins did not exhibit significant CAE signals.

Conclusion: These findings highlight that azoles and polyenes show substantial associations with CAEs, particularly for TdP/QTP and arrhythmias. Itraconazole showed a significant association with cardiac failure and cardiomyopathy, while the signal for isavuconazole was weaker than for other triazoles. No significant cardiotoxicity signals were detected for echinocandins.

Background: The misuse of antibiotics leads to antimicrobial resistance, particularly concerning infections related to orthopedic implants. The aim of this study was to determine the sensitivity pattern of bacterial isolates in patients with orthopedic implants having infections.

Materials and methods: A retrospective cross-sectional study was conducted at Ghurki Trust Teaching Hospital, Lahore. Culture sensitivity reports from 548 patients were collected between January 2020 and March 2023. Patient demographics, including age, sex, culture specimens (blood, wound, etc.), and antibiotic sensitivity were recorded.

Results: Seven types of implants were analyzed, with Ilizarov (25.5%) being the most infected external implant and nails (24.7%) the most infected internal implant. The study included 10 clinically significant bacteria, with Staphylococcus aureus (n = 195, 35.5%) being the most common Gram-positive pathogen, and Escherichia coli (n = 99, 18.0%) being the most prevalent Gram-negative pathogen. A total of 40 antibiotics were tested; amoxicillin was the least effective, whereas linezolid, vancomycin, and fosfomycin showed the highest efficacy against all implant-related infections included in this study.

Conclusion: The critical challenges of antimicrobial resistance in orthopedic implant-related infections have been highlighted. Urgent institutional and policy level interventions are required for implementation of stringent infection control protocols and robust antibiotic stewardship programs to prevent a post-antibiotic crisis.

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.

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.