International journal of clinical pharmacology and therapeutics最新文献

Objectives: Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)).

Materials and methods: We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study.

Results: We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023).

Conclusion: A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Objectives: Estimated glomerular filtration rate (eGFR) using serum creatinine (Cr) is commonly used to evaluate renal function. However, it can be influenced by other factors, which can risk the overestimation of the true GFR. Impaired renal function prior to cardiovascular surgery reportedly increases mortality and the incidence of postoperative complications. Thus, overestimation of renal function may affect the assessment of postoperative complication risks. Therefore, we aimed to compare the eGFR calculated from serum Cr and cystatin C (Cys-C) levels to assess preoperative renal function and to investigate factors affecting renal function overestimation.

Materials and methods: 88 patients admitted for cardiovascular surgery who had preoperative serum Cr and Cys-C measurements were included in the study. Correlations between factors associated with eGFR calculated from serum Cr (eGFRcre) and Cys-C (eGFRcys) and their ratio (eGFRcre/eGFRcys) were examined using multiple regression analysis.

Results: Multiple regression analysis revealed that eGFRcre/eGFRcys was significantly negatively correlated with the Short Physical Performance Battery score (SPPB). A clinically significant difference in renal function overestimation was defined as GFRcre/eGFRcys > 1.2, with a cutoff value of 9 points for the SPPB score. The chair stand test, a component of the SPPB, had the same discriminative power as the SPPB for identification of renal function overestimation.

Conclusion: The SPPB can be used to identify likely GFR overestimation in patients. Additionally, the chair stand test may be used as an alternative to the SPPB for the identification of renal function overestimation when the SPPB is difficult to perform.

Background: Domperidone has long been used as a prokinetic agent in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new generic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition.

Materials and methods: This was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including C_max, t_max, AUC_0-t, AUC_0-∞, and T_1/2, were acquired based on the concentration vs. time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of C_max, AUC_0-t, and AUC_0-∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine.

Results: The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC_0-t, AUC_0-∞, and C_max were 101.48% (96.79 - 106.38%), 101.17% (96.66 - 105.90%), and 104.61% (96.73 - 113.14%), respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19 - 112.12%), 104.21% (98.19 - 110.61%), and 112.78% (103.64 - 122.73%), respectively, for AUC_0-t, AUC_0-∞, and C_max. All values fell within the accepted bioequivalence range of 80 - 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions.

Conclusion: Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in healthy Chinese subjects. Both products were safe and well tolerated.

Background: Medications are biologically plausible and potentially modifiable risk factors for delirium. Therapies for delirium might involve more specific strategies such as avoiding the use of delirium-inducing drugs to reduce the incidence of delirium. The association between opioid exposure within 24 hours prior to delirium assessment and the risk of delirium was studied.

Materials and methods: Using three large databases, the MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research, we performed a multicenter, observational cohort study with two cohorts to estimate the relative risks of outcomes among patients administered opioids within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1 : 1 matched cohort and to identify potential prognostic factors. The outcomes included mortality, length of intensive care unit (ICU) stay, length of hospitalization, and odds of being discharged home.

Results: Propensity matching successfully balanced the covariates for the 9,529 patients in each group. Opioid use was associated with a significantly higher risk for delirium than not using opioids (p < 0.001). Additionally, treatment with opioids was associated with higher mortality and a longer ICU stay (p < 0.001) than treatment without opioids. However, patients treated with opioids were more likely to be discharged home (p < 0.001).

Conclusion: Opioids may be an independent risk factor for delirium in critically ill patients.

Objective: To evaluate the possibility of deprescribing proton pump inhibitors in adult inpatients hospitalized in a teaching hospital in Slovenia.

Materials and methods: We conducted a prospective observational clinical study in 120 patients taking a proton pump inhibitor. Data were obtained from hospital medical records and patient interviews. First, treatment compliance with relevant guidelines was assessed, and then the possibility of deprescribing was considered.

Results: Treatment with a proton pump inhibitor was in accordance with guidelines in only 39% of the 120 patients. In 24% of patients, the indication for proton pump inhibitor use was invalid, and 22% and 15% of patients were taking a proton pump inhibitor at a higher dose or for a longer period than recommended, respectively. Deprescribing could be undertaken in 61% of patients, as discontinuation in 38%, and dose reduction in 23%. A deprescribing possibility was noted more frequently in patients prescribed proton pump inhibitors for peptic ulcer disease, Helicobacter pylori infection, or without a valid indication (p < 0.001), as well as in patients taking a double or higher dose of a proton pump inhibitor (p < 0.001).

Conclusion: Deprescribing of proton pump inhibitors could be undertaken in nearly 2/3 of our cohort of adult hospitalized patients. Hospitalization may serve as an opportunity to deprescribe proton pump inhibitors.

Objective: Recombinant human soluble thrombomodulin (rhsTM) is a therapeutic agent for sepsis-induced disseminated intravascular coagulation (DIC) and is associated with bleeding events. rhsTM is a renal excretion drug; however, information on the role of rhsTM in renal function is limited.

Materials and methods: In this retrospective observational study, we assessed rhsTM-associated bleeding events according to the renal function of patients with sepsis-induced DIC. We analyzed the data of 79 patients administered a standard-dose of rhsTM for sepsis-induced DIC, at a single center. Patients were classified based on estimated glomerular filtration rate (eGFR). We measured fresh bleeding events following rhsTM administration, DIC score efficacy, and 28-day mortality.

Results: Fresh bleeding events were observed in 15 patients, with a significant difference in the eGFR, platelet count, and DIC scores. Furthermore, fresh bleeding events tended to increase with the deterioration of renal function (p = 0.039). The DIC scores in all renal function groups decreased after -rhsTM administration. Additionally, the 28-day mortality was less than 30% in all groups.

Conclusion: Our results indicate that the effectiveness of the standard-dose of rhsTM is not related to renal function. However, standard-dose rhsTM therapy could potentially increase the risk of adverse bleeding events with severe renal function equivalent to G5.

Objective: To understand the effect of prolonged intravenous acetaminophen infusion on blood pressure.

Materials and methods: We retrospectively studied a cohort of intensive care patients receiving initial intravenous acetaminophen. We used propensity score matching to adjust for differences between patients who were classified into two groups: control (acetaminophen infusion for 15 minutes) and prolonged administration (acetaminophen infusion for > 15 minutes).

Results: After acetaminophen administration, diastolic blood pressure was unchanged in the control group, and was significantly lower at 30 and 60 minutes in the prolonged administration group.

Conclusion: Prolonged duration of acetaminophen infusion did not prevent acetaminophen-induced blood pressure reduction.

Objective: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy.

Materials and methods: In total, 138 patients with lung cancer who received ≥ 75 mg/m² CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis.

Results: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia.

Conclusion: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.