Yuhki Sato

Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant staphylococcus aureus pneumonia.

Background: We analyzed the pharmacokinetic-pharmacodynamic relationship of vancomycin to determine the drug exposure parameters that correlate with the efficacy and nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus pneumonia and evaluated the need to use peak concentration in therapeutic drug monitoring (TDM). Methods: Serum drug concentrations of 31 hospitalized patients treated with vancomycin for methicillin-resistant S. aureus pneumonia were collected. Results: Significant differences in trough concentration (Cmin)/minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC0–24)/MIC were observed between the response and non-response groups. Significant differences in Cmin and AUC0–24 were observed between the nephrotoxicity and non-nephrotoxicity groups. Receiver operating characteristic curves revealed high predictive values of Cmin/MIC and AUC0–24/MIC for efficacy and of Cmin and AUC0–24 for safety of vancomycin. Conclusions: These results suggest little need to use peak concentration in vancomycin TDM because Cmin/MIC and Cmin are sufficient to predict the efficacy and safety of vancomycin.

Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity

BACKGROUND Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients. METHODS Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs: <4 μg/ml in the first TDM (group A, n=25), >4 μg/ml in the first and <4 μg/ml in the second TDM (group B, n=8), and >4 μg/ml in both first and second TDMs (group C, n=6). RESULTS Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity. CONCLUSIONS These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to <4 μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4β-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4β-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4β-hydroxycholesterol were 57.1 ± 11.2, 42.1 ± 11.8, and 34.5 ± 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4β-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4β-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure.

Effects of Itopride Hydrochloride on Plasma Gut-Regulatory Peptide and Stress-Related Hormone Levels in Healthy Human Subjects

Itopride hydrochloride (itopride), a gastrokinetic drug, has recently been evaluated for its clinical usefulness in functional dyspepsia. We investigated effects of itopride on human plasma gastrin-, somatostatin-, motilin-, and cholecystokinin (CCK)-like immunoreactive substances (IS); adrenocorticotropic hormone (ACTH)-immunoreactive substances (IS), and cortisol under stress conditions in healthy subjects. A single administration of itopride caused significant increases in plasma somatostatin- and motilin-IS levels compared to placebo. Itopride significantly decreased plasma CCK-IS, and suppressed the ACTH-IS level compared to placebo. We hypothesize that itopride may have an accelerating gastric emptying effect, and a modulatory effect on the hypothalamo-pituitary-adrenal axis and autonomic nervous functions. These effects might be beneficial in stress-related diseases, suggesting that itopride has clinicopharmacological activities.

Sodium alginate as an ideal submucosal injection material for endoscopic submucosal resection: preliminary experimental and clinical study.

BACKGROUND Sodium alginate is used clinically in the treatment of peptic ulcer disease. Because of its viscosity, sodium alginate could possibly become a new submucosal injection material for use in endoscopic resection. OBJECTIVE We evaluated the feasibility of endoscopic submucosal dissection (ESD) using sodium alginate. SETTING AND INTERVENTIONS The lesion-lifting properties of sodium alginate were examined in porcine stomachs and were compared with those of normal saline solution and sodium hyaluronate solution. After confirming the proper concentration of sodium alginate, ESD using sodium alginate was performed in 11 patients with gastric mucosal cancer or adenoma. MAIN OUTCOME MEASUREMENT The lesion-lifting properties of sodium alginate and clinical outcomes were assessed. RESULTS The thickness of the submucosal elevation created by 3% sodium alginate in porcine stomach was equivalent to that of sodium hyaluronate. ESD using sodium alginate was completed successfully in all patients without adverse effects except in 1 patient in whom transient shrinkage of the gastric wall disappeared spontaneously after approximately 30 minutes. The mean tumor size was 15.3 mm. En bloc resection and a negative resection margin were obtained in all. Histopathologic examination revealed that all tumors were confined to the mucosal layer except for 1 that was confined to the submucosal layer without lymphovascular invasion, and there were no adverse effects such as tissue damage. No patient required additional treatment, and none showed recurrence during a median follow-up period of 28 months. LIMITATIONS Small sample size. CONCLUSION This preliminary study suggests that sodium alginate might be a novel, safe submucosal injection material for use in endoscopic resection. Further investigation of the properties of sodium alginate is warranted.

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Several previous studies have shown that renal failure decreases not only renal elimination but also metabolic clearance of drugs, particularly those metabolized by CYP3A. However, whether recovery of renal function results in recovery of hepatic CYP3A activity remains unknown. In this study, we evaluated the effect of renal function on CYP3A activity after kidney transplantation in patients with end-stage renal disease (ESRD) by measuring the change in CYP3A activity using plasma concentration of 4β-hydroxycholesterol as a biomarker. The study enrolled 13 patients with ESRD who underwent the first kidney allograft transplantation. Morning blood samples were collected before and 3, 7, 10, 14, 21, 30, 60, 90, 120, 150 and 180 days after kidney transplantation. Plasma concentration of 4β-hydroxycholesterol was measured using GC-MS. Compared with before kidney transplantation, creatinine clearance increased significantly from day 3 after kidney transplantation and stabilized thereafter. Plasma concentration of 4β-hydroxycholesterol was elevated significantly on days 90 and 180 after kidney transplantation. In conclusion, this study suggests the recovery of CYP3A activity with improvement in renal function after kidney transplantation in patients with ESRD.

No effect of co‐administered antiepileptic drugs on in‐vivo protein binding parameters of valproic acid in patients with epilepsy

Objectives  The aim of this study was to establish the population protein binding parameters of valproic acid (VPA) in patients with epilepsy receiving VPA monotherapy and those receiving VPA combined with other antiepileptic drugs.

Ecabet sodium raises plasma levels of calcitonin gene‐related peptide and substance P in healthy humans

Ecabet sodium (ecabet), a cytoprotective drug, produces an increase in mucosal blood flow. One of the gastrointestinal motility regulatory factors has been assumed to be the induction of changes in the levels of peptides (gastrin, somatostatin and motilin) in plasma. On the other hand, recently, capsaicin‐sensitive afferent nerves were shown to play an important role in gastric mucosal defensive mechanism. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene‐related peptide (CGRP) and substance P in the stomach. We studied the effect of ecabet on human plasma gastrin‐, somatostatin‐, motilin‐, CGRP‐ and substance P‐like immunoreactive substance (IS) in healthy subjects. Ecabet sodium at a dose of 3.0 g, or placebo, was orally administered in five healthy males. The blood samples were taken before and at 20, 40, 60, 90, 120, 180 and 240 min after administration, subjected to extracting procedures, and submitted to a highly sensitive enzyme immunoassay system. Single administration of ecabet caused significant (P < 0.05) increases in plasma CGRP‐, substance P‐ and somatostatin‐IS concentration compared with placebo. Ecabet significantly decreased plasma gastrin‐IS levels compared with placebo. In this study, we hypothesized that ecabet might stimulate capsaicin‐sensitive afferent nerves indirectly and improve mucosal blood flow; this might be a key mechanism underlying its gastroprotective action.

A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy.

BACKGROUND The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy. METHODS In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed. RESULTS A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%). CONCLUSIONS These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy.

CYP3A5 polymorphism affects the increase in CYP3A activity after living kidney transplantation in patients with end stage renal disease

AIMS It has been reported that cytochrome P450 (CYP)3A activity increases significantly in patients with end stage renal disease (ESRD) after kidney transplantation, with wide interindividual variability in the degree of increase. The aim of this study was to evaluate the influence of CYP3A5 polymorphism on the increase in CYP3A activity after living kidney transplantation, by measuring the plasma concentration of 4β-hydroxycholesterol. METHODS This prospective study recruited 22 patients with ESRD who underwent a first living kidney allograft transplantation, comprising 12 patients with CYP3A5*1 allele (CYP3A5*1/*1 or *1/*3) and 10 patients without CYP3A5*1 allele (CYP3A5*3/*3). RESULTS No significant difference in estimated glomerular filtration rate over time was observed between patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele, suggesting that the degrees of recovery in renal function after living kidney transplantation were similar in the two groups. However, plasma concentrations of 4β-hydroxycholesterol on days 90 (57.1 ± 13.4 vs. 39.5 ± 10.8 ng ml(-1)) and 180 (55.0 ± 14.5 vs. 42.4 ± 12.6 ng ml(-1)) after living kidney transplantation were significantly higher in the presence of the CYP3A5*1 allele than in the absence of the CYP3A5*1 allele [P = 0.0034 (95% confidence interval of difference 6.55, 28.6) and P = 0.043 (95% confidence interval of difference 0.47, 24.8), respectively], suggesting that CYP3A activity may increase markedly associated with recovery of renal function in patients with the CYP3A5*1 allele. CONCLUSIONS These findings suggest that the presence of the CYP3A5*1 allele contributes to marked elevation of CYP3A activity associated with recovery of renal function after kidney transplantation.