Comparison of Incidence of Hyponatremia between Linezolid and Vancomycin by Propensity Score Matching Analysis.

Several cases of severe hyponatremia induced by linezolid (LZD) were reported. However, severe infections could also cause hyponatremia by increasing vasopressin secretion. To prove that hyponatremia is associated with LZD rather than infection, we compared the incidence and risk of developing hyponatremia between patients receiving LZD and those receiving vancomycin (VCM). A retrospective, single-center, observational cohort study was conducted in patients aged 18 years or older who received intravenous LZD or VCM for 7 d or longer. Hyponatremia was defined as serum sodium level lower than 134 mEq/L and more than 5% decrease from baseline after treatment initiation. The incidence and risk of developing hyponatremia were analyzed between LZD and VCM groups using chi-square test. Four hundred and fifty patients who satisfied the selection criteria were divided into LZD (n = 97) and VCM groups (n = 353). Significant differences in patient characteristics between LZD and VCM groups were observed before propensity score matching, but no significant differences were found after matching. LZD group showed a significantly higher incidence and risk of developing hyponatremia compared to VCM group both before (LZD: 16.5%, VCM: 5.4%; p < 0.001, odds ratio 3.472 [95% confidence interval (CI) 1.711-7.048]) and after (LZD: 17.8%, VCM: 5.5%; p = 0.020, odds ratio 3.738 [95% CI 1.157-12.076]) propensity score matching. In conclusion, propensity score analyses suggest that the risk of hyponatremia associated with LZD is approximately 3.7-fold higher than that associated with VCM, regardless of patient background.

A case of improvement of clozapine-induced low leukocyte counts by adenine, cepharanthin and ninjin-yoei-to in a patient with treatment-resistant schizophrenia.

BACKGROUND: Although clozapine is the optimal drug for patients with treatment-resistant schizophrenia, the drug has harmful adverse effects such as leukopenia. Adenine and cepharanthine are known to be effective for radiation- or drug-induced leukopenia. Furthermore, ninjin-yoei-to, a Chinese herbal medicine, augments the production of granulocyte-macrophage colony-stimulating factor. Thus, these drugs may be useful for clozapine-induced leukopenia. CASE PRESENTATION: A 21 years-old woman with schizophrenia was hospitalized for initiation of clozapine treatment. Despite concomitant use of adenine, cepharanthine, and lithium carbonate having activities of increasing leukocytes, a decrease in leukocyte counts occurred after the initiation of clozapine. Additional administration of ninjin-yoei-to increased leukocyte counts, which prevented the development of leukopenia. CONCLUSIONS: This is the first case that concomitant use of adenine, cepharanthin, and ninjin-yoei-to exhibited the effectiveness of reversing the decrease in leukocytes caused by clozapine. Monitoring leukocyte counts and preventing leukopenia are essential for successful treatment with clozapine for refractory schizophrenia. These medicines may be a potential option for preventing clozapine-induced leukopenia.

Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control.

Response to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r = - 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.

Simultaneous quantification method for 5-FU, uracil, and tegafur using UPLC-MS/MS and clinical application in monitoring UFT/LV combination therapy after hepatectomy.

Combination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2-500 ng/mL for 5-FU, 20-5000 ng/mL for uracil, and 200-50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.

Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study.

We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.

A retrospective test for a possible relationship between linezolid-induced thrombocytopenia and hyponatraemia.

WHAT IS KNOWN AND OBJECTIVE: Thrombocytopenia is one of the typical adverse events caused by linezolid (LZD). Recently, some cases of severe hyponatraemia occurring while receiving LZD have been reported. This study investigated a possible relationship between LZD-induced hyponatraemia and thrombocytopenia and identified the risk factors for hyponatraemia and/or thrombocytopenia. METHODS: In this retrospective, single-centre, observational cohort study, 63 hospitalized patients aged over 18 years who received intravenous injection of LZD for more than seven consecutive days in Oita University Hospital between April 2015 and March 2018 were analysed. RESULTS: Thrombocytopenia occurred in 25 (39.7%) patients and hyponatraemia in 11 (17.5%) patients. Seven of 11 patients with hyponatraemia had concurrent thrombocytopenia. Although both serum sodium level and platelet count declined in most patients who developed hyponatraemia, no significant association between thrombocytopenia and hyponatraemia was found. Creatinine clearance level (Ccr) was significantly lower not only in the thrombocytopenia (vs no-thrombocytopenia) but also in the hyponatraemia group (vs no-hyponatraemia group). Univariate and multivariate logistic regression analyses identified different risk factors for thrombocytopenia and/or hyponatraemia (thrombocytopenia: Ccr and administration period; hyponatraemia: serum albumin; thrombocytopenia and hyponatraemia: administration period and serum albumin). WHAT IS NEW AND CONCLUSION: In conclusion, this study found no significant relationship between LZD-induced thrombocytopenia and hyponatraemia and identified some possible risk factors associated with onset of the two adverse events. These require further validation.

A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis.

Genetic polymorphism exists for CYP2C19, a dominant metabolic enzyme of voriconazole (VRCZ), and VRCZ pharmacokinetics has been shown to fluctuate according to the CYP2C19 phenotype. Although dosages for different phenotypes have been recommended in various retrospective studies, few reports have adjusted the initial VRCZ dose based on CYP2C19 phenotype determined prior to administration. In this study, we prospectively evaluated the usefulness of CYP2C19 polymorphism analysis in adjusting the initial VRCZ maintenance dose. The study enrolled 19 patients who underwent analysis of CYP2C19 polymorphism prior to VRCZ administration. Subjects were classified into 3 phenotype subgroups: extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). The initial VRCZ maintenance doses given twice daily were proposed as follows: approximately 8, 6, and 4 mg/kg/day for EM, IM and PM, respectively, according to previous reports. In EM, the initial maintenance dose was 8.0 ± 0.5 mg/kg/day, and trough level was 6.6 ± 2.4 µg/mL. By contrast, the initial maintenance doses in IM and PM were 5.5 ± 0.7 and 4.1 ± 0.3 mg/kg/day, and the initial trough concentrations were 2.9 ± 1.2 and 2.6 ± 0.4 µg/mL, respectively. The attainment rate of target trough concentration of 1-6 µg/mL was 50% in EM, and was 100% in IM and PM. Determining the initial dose of VRCZ only by phenotype based on CYP2C19 gene polymorphism was found to be challenging. However, decreasing the initial maintenance dose in IM and PM may be important for adjusting the initial trough level to target range.

Sensitive and selective quantification of mid-regional proadrenomedullin in human plasma using ultra-performance liquid chromatography coupled with tandem mass spectrometry.

Mid-regional pro-adrenomedullin (MR-proADM) is suggested to be a prognostic indicator for various diseases. Plasma MR-proADM concentration is commonly measured using immunoassays based on its immunochemical characteristics. However, some immunological interactions affect the measured concentration. We developed and validated a sensitive and selective method for measuring plasma MR-proADM concentration using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) and evaluated its clinical applicability. Plasma samples were prepared by protein precipitation and solid-phase extraction. Samples obtained from healthy volunteers (n = 38), patients with chronic kidney disease (CKD) stages 3 and 4-5 (non-dialysis; n = 20 and 17, respectively), and CKD stage 5D (dialysis; n = 34) were analyzed. Within-batch and batch-to-batch accuracy of the UPLC-MS/MS assay for quality control samples ranged from -0.69 % to 8.05 % and from 1.72 % to 5.76 %, respectively. The lower limit of quantification was 0.4 ng mL-1. The MR-proADM concentration determined using the UPLC-MS/MS assay correlated strongly with that determined using the immunoassay (Pearson's product-moment correlation coefficient [r] = 0.7875, p < 0.001). Median (range) plasma MR-proADM concentrations of healthy volunteers, patients with CKD stages 3 and 4-5, and patients with CKD stage 5D were 0.67 (0.43-1.27), 1.89 (0.65-6.68), 3.86 (1.60-8.75) and 3.97 (0.66-9.20) ng mL-1, respectively, and a significant difference among four groups was confirmed. We established a sensitive and selective method for determining plasma MR-proADM concentration using UPLC-MS/MS. Our novel UPLC-MS/MS assay for determining plasma MR-proADM concentration can be used in the clinical setting and may have better selectivity than the immunoassay method.

A Retrospective Analysis of Risk Factors for Linezolid-Associated Hyponatremia in Japanese Patients.

Linezolid is an oxazolidinone antibiotic against Gram-positive bacteria. Although thrombocytopenia is a major adverse effect of linezolid, hyponatremia also often develops after linezolid administration. This study examined the frequency of hyponatremia that developed during linezolid treatment and identified its risk factors. In this retrospective, single-center, observational cohort study, 61 hospitalized patients treated with linezolid between January 2013 and January 2015 were analyzed. Hyponatremia was defined as a sodium level of ≤134 mEq/L for the duration of linezolid treatment. Its risk factors were identified via a logistic regression analysis. Hyponatremia occurred in 11 (18.0%) patients, and it was severe in a case (a sodium level of ≤128 mEq/L). Univariate and multiple logistic regression analyses identified the plasma C-reactive protein (CRP) level before the initial administration of linezolid and the concomitant use of a potassium-sparing diuretic as the independent variables associated with the development of hyponatremia. The odds ratios were 1.081 (95% confidence interval [CI]; 1.008-1.158) (p=0.028) and 11.017 (95% CI; 1.869-64.939) (p=0.008), respectively. Before linezolid treatment, the CRP levels of the hyponatremia group were significantly higher than those of the no-hyponatremia group (p<0.001). The frequency of hyponatremia development was significantly higher in the patients who received both the potassium-sparing diuretic and linezolid (p=0.016). These results suggest that the plasma sodium levels of patients with severe inflammation who are treated with linezolid and those of linezolid-treated patients co-administered a potassium-sparing diuretic should be continuously monitored.