International journal of clinical pharmacology and therapeutics最新文献

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.

Objective: Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities.

Materials and methods: Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n = 18) and validation (n = 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to determine total AUC (AUC_0-lNF) from intensive sampling. Coefficient of determination (r²) and bias and precision were assessed via relative percent mean prediction error (%MPE), relative percent mean absolute error (%MAE), and relative percent root mean square error (%RMSE).

Results: The geometric mean observed AUC_0-INF was 1,680 ng×h/mL. The 2-, 5-, and 2- plus 5-hour LSMs met backwards stepwise linear regression significance (p < 0.15) to remain in the model but had unacceptable %RMSE (17 - 29%). The majority of partial AUC LSMs had unacceptable r² (0.21 - 0.83), with all models having unacceptable %MAE (12 - 35%).

Conclusion: Fexofenadine limited sampling strategy using single-timepoint, 2-timepoint, and partial AUCs were unable to accurately estimate AUC_0-lNF and thus constitutive P-gp and OATB1B1/3 activities in healthy adults. Timepoints that were not measured or selected may have improved LSM performance.

Objective: To develop an immediate-release tablet preparation containing rebamipide (RBM) and perform the bioavailability assessment in the healthy human subjects.

Materials and methods: Raw RBM powder was characterized using differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy (SEM). RBM tablets were manufactured by the wet granulation method, and their dissolution behavior was compared with the reference tablet (Mucosta). A phase I study (n = 47; sequence-randomized, open-label, single-dose, and two-way cross-over design) was designed for oral administration of a test formulation (F4) and Mucosta to healthy human male subjects, and pharmacokinetic parameters including the maximum plasma concentration (C_max) and area under the curve from 0 to 12 hours (AUC_0-12h) were compared.

Results: RBM powder had a multimodal size distribution with typical crystallinity, and the needle-like and elongated morphologies of RBM were visualized using SEM. Various tablet formulations (F1 - F6) were successfully manufactured using wet granulation method. F4 formulation was selected based on the dissolution profile most equivalent to that of Mucosta. F4 was stable for 6 months under accelerated and long-term storage conditions. Based on one-way analysis of variance, the AUC_0-12h (F(1,92) = 2.40, p = 0.13) and t_max (F(1,92) = 0.04, p = 0.85) were not significantly different; however, the C_max (F(1,92) = 5.45, p = 0.022) showed significant difference between F4 and reference tablets.

Conclusion: Despite similar in vitro dissolution profiles, in vivo pharmacokinetic results revealed a partial difference between F4 and reference tablets. Thus, further study on formulation development is still needed.

Objectives: Pegfilgrastim is a long-acting, granulocyte colony-stimulating factor approved in Japan for the prevention of neutropenia caused by antineoplastic agents. Severe thrombocytopenia was reported with pegfilgrastim, however, the factors associated with thrombocytopenia are unclear. This study aimed to explore the factors associated with thrombocytopenia in patients with metastatic castration-resistant prostate cancer treated with pegfilgrastim for primary prophylaxis of febrile neutropenia (FN) with cabazitaxel.

Materials and methods: This study included metastatic castration-resistant prostate cancer patients who received pegfilgrastim for primary prophylaxis of FN with cabazitaxel. The timing and severity of thrombocytopenia and factors associated with the reduction rate of platelets were examined in patients who received pegfilgrastim for the primary prevention of FN during the first course of cabazitaxel and by multiple regression analysis.

Results: Thrombocytopenia was most common within 7 days of pegfilgrastim administration, with 32 cases of grade 1 and 6 cases of grade 2 as per the Common Terminology Criteria for Adverse Events version 5.0. Multiple regression analysis revealed that the reduction rate of platelets after pegfilgrastim administration was significantly positively correlated with monocytes. In contrast, the presence of liver metastases and neutrophils was significantly negatively correlated with the reduction rate of platelets.

Conclusion: Thrombocytopenia due to pegfilgrastim administered as primary prophylaxis for FN with cabazitaxel was most likely to occur within one week after pegfilgrastim administration, suggesting that monocytes, neutrophils, and liver metastases were associated with a reduction in platelets.

Objectives: The goal achievement rate of patients' low-density lipoprotein cholesterol (LDL-C) levels and prescribing pattern of statin potency should be continuously monitored in a real-world clinical setting. This study aimed to describe the comprehensive status of LDL-C management.

Materials and methods: Patients first diagnosed with cardiovascular diseases (CVDs) between 2009 and 2018 who were followed for 24 months. LDL-C levels, its changes from baseline, and intensity of statin prescribed were evaluated four times during follow-up. Potential factors associated with goal achievement were also identified.

Results: The study included 25,605 patients with CVDs. At diagnosis, the goal achievement rates of the LDL-C level were 58.4, 25.2, and 10.0% for targets of < 100, < 70, and < 55 mg/dL, respectively. The proportion of moderate- and high-intensity statin prescription significantly increased over time (all p < 0.01). Nevertheless, LDL-C levels significantly decreased at 6 months and increased at 12 and 24 months following therapy compared with baseline values. Glomerular filtration rate (GFR) (15 - 29 and < 15 mL/min/1.73m²) and accompanying diabetes mellitus were significantly associated with the goal achievement rate.

Conclusion: Despite the need for active LDL-C management, the goal achievement rate and prescribing pattern were insufficient after 6 months. In cases with severe comorbidities, the goal attainment rate significantly increased; however, a more aggressive statin prescription was needed even in patients without diabetes or with normal GFR. The prescription rate for high-intensity statins increased over time, but was still low. In conclusion, physicians should aggressively prescribe statins to increase the goal achievement rate in patients with CVDs.

Objective: We present a case of a patient who developed myasthenia gravis (MG)-like symptoms during erenumab treatment.

Case report: The patient had a years-long history of chronic migraine with visual and sensory aura. Two months after the beginning of erenumab therapy, she reported intermittent bilateral weakness of the eyelids, with ptosis. The eyelid ptosis was severe enough to block the patient's vision. The symptoms would usually last between 5 and 10 minutes and resolve completely spontaneously, but they repeated on a daily basis. Antibodies against acetylcholine receptors and muscle-specific kinase were all negative, and other work-up excluded the usual etiology of ptosis. Since the cause of symptoms was not detected, we suspected they were induced by erenumab. The treatment was discontinued, and after 7 weeks from the last dose of erenumab, ocular symptoms resolved completely. In the presented case, other possible causes of MG-like symptoms were excluded by diagnostic tests and clinical course of the disease. The temporal relationship between the administration of erenumab and occurrence of ptosis, with regression of the symptoms after the drug discontinuation supports the hypothesis of causal relationship with erenumab. According to the Naranjo's Adverse Drug Reaction Probability Scale, erenumab-related MG-like symptoms were rated 'probable'. Reviewing the literature, we identified no similar case reports.

Conclusion: Drug-induced MG-like symptoms might be life threatening. Therefore, clinicians should be aware of these adverse reactions during the use of erenumab.