Akihiro Tanaka

Estimation of the Initial Dose Setting of Vancomycin Therapy With Use of Cystatin C as a New Marker of Renal Function

In recent years, it has been suggested that the glomerular filtration rate (GFR) can be predicted on the basis of serum cystatin C concentrations and that this measurement is more sensitive than serum creatinine concentration as a marker of renal function. In this study, to investigate the clinical utility of the initial dose setting of vancomycin by the population mean method with use of serum cystatin C as a marker of renal function, we compared the correlations between measured vancomycin concentrations and predicted vancomycin concentrations based on serum cystatin C or serum creatinine concentrations in elderly (≥65 years old) and nonelderly (<65 years old) patients. An analysis of prediction accuracy (bias) and precision was evaluated by calculating the mean prediction error (ME), the mean absolute error (MAE), and the root mean squared prediction error (RMSE). For nonelderly patients (n = 50), there was no significant difference in the MAE based on the use of serum creatinine or serum cystatin C concentration. However, for elderly patients (n = 105), the MAE based on serum cystatin C concentration was significantly better than that based on serum creatinine level. These results suggest that serum cystatin C is a good marker of renal function in comparison with serum creatinine for dose setting of vancomycin, especially in an elderly population.

Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

ABSTRACT We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoeks formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem

Background The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime). Objective The maximum dose of cefepime in the USA (6xa0g per day) is higher than that in Japan (4xa0g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem. Methods A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2xa0years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem. Results The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders. Conclusion Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

Hoek's formula, a cystatin C-based prediction formula for determining the glomerular filtration rate, is the most effective method for original adjusting the dosage of vancomycin.

OBJECTIVEnSome formulas using the serum cystatin C level to estimate the GFR have recently been reported. However, there has been no report of a serum cystatin C-based formula for adjusting the dosage of the drugs cleared by the kidney. In this study, we compared the predictive performance of the serum vancomycin trough concentration predicted using serum cystatin C-based formulas.nnnMETHODnThe data were collected from 158 hospitalized patients. Five formulas have been published to predict the GFR using serum cystatin C. The cystatin C-based formulas were divided into two groups, formulas with or without anthropometric data. We predicted the serum vancomycin trough concentrations using VCM-TDM S_edition ver. 1.00 software.nnnRESULTSnIn formulas with anthropometric data, the mean absolute error (MAE) using Hoeks formula was 2.38, the MAE using Grubbs 1 formula was 4.13, the MAE using Sjöströms formula was 2.90, and the MAE using Cockcroft and Gault formula based on creatinine was 4.42. On the other hand, in formulas without an anthropometric data group, the MAE using Larssons formula was 3.07, and the MAE using Grubbs 2 formula was 3.63.nnnCONCLUSIONnThese results suggested that Hoeks formula is the most useful formula for determining the initial dosage settings for vancomycin.

Quantitative evaluation of central-type benzodiazepine receptors with [125I]Iomazenil in experimental epileptogenesis: II. The rat cortical dysplasia model

[(123)I]Iomazenil (IMZ) is a specific ligand for central-type benzodiazepine receptors (BZRs) and is available for single photon emission computed tomography (SPECT) to detect epileptogenic foci. We have recently demonstrated time-dependent alterations of [(125)I]IMZ binding in the rat kainate model of temporal lobe epilepsy. Quantitative evaluation of central-type benzodiazepine receptors with [(125)I]Iomazenil in experimental epileptogenesis. I. The rat kainate model of temporal lobe epilepsy. In the present study, we investigated regional changes in central-type BZRs in the cortical dysplasia (CD) model of epilepsy in rats. Pregnant rats were irradiated at day 17 of gestation with 1.2 Gy to produce CD in their pups, and in vitro autoradiography with [(125)I]IMZ was performed at 8 weeks after birth. Intact rats at the same age were used as controls. [(125)I]IMZ binding was significantly decreased in various cortical regions of the in utero irradiated rats, including the bilateral frontal cortex (down to 92-93% of control), cingulate cortex (91-92%), hippocampal areas CA1 (95%), CA2 (94-95%) and CA4 (95-96%), and caudate/putamen (90-94%). In addition, amygdala-kindling was significantly facilitated in the CD model, especially during the late phase of kindling, suggesting seizure susceptibility of this model. These results may replicate the clinical usefulness of central-type BZRs neuroimaging for detection of human epileptogenic CD and indicate dysfunction of GABA-A/BZR-mediated inhibition responsible for the seizure susceptibility.

Quantitative evaluation of central-type benzodiazepine receptors with [125I] Iomazenil in experimental epileptogenesis: I. The rat kainate model of temporal lobe epilepsy

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [(125)I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 microg/0.5 microl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [(125)I] IMZ and cell counts were performed in the hippocampal CA1-4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1-4. Compared with the control group, progressive reduction of [(125)I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [(125)I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3-6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.

Involvement of stimulation of α7 nicotinic acetylcholine receptors in the suppressive effect of tropisetron on dextran sulfate sodium-induced colitis in mice

Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC.

Evaluation of edaravone against radiation-induced oral mucositis in mice

Oral mucositis induced by radiotherapy for cancers of the head and neck reduce the quality of life of patients. However, effective therapeutic agents are lacking. Symptomatic treatment involves local anesthesia and analgesia. We focused on the antioxidant effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut(®)). Oral mucositis was induced on the tongue tips of mice using a single dose of X-rays (20xa0Gy). To evaluate the protective effect of edaravone (30 and 300xa0mg/kg), administration was carried out 30xa0min before irradiation. Survival, oral mucositis score, myeloperoxidase activity, and levels of 2-Thiobarbituric acid reactive substances were measured, and all were improved compared with those of control mice. A significant difference was not found in terms of survival due to edaravone. Histopathologic findings also highlighted the beneficial features of edaravone. Edaravone reduced the production of reactive oxygen species. These findings suggest that the protective effect of edaravone against radiation-induced oral mucositis is through an antioxidant effect.

Assessment of the hamster cheek pouch as a model for radiation-induced oral mucositis, and evaluation of the protective effects of keratinocyte growth factor using this model

Abstract Purpose: Oral mucositis induced by radiotherapy impacts quality of life. Previous studies have reported on the use of the hamster as a model for radiation-induced oral mucositis; however, details regarding factors such as radiation dose response, effects on myeloperoxidase (MPO) activity and related histopathological changes remain unclear. In the present study using the hamster, we evaluated the dose dependency of radiation-induced oral mucositis and the effects of keratinocyte growth factor (palifermin). Methods: Oral mucositis was induced in the cheek pouch by X-irradiation using single doses in the range 20–50 Gy. To evaluate the protective effect of palifermin, administration was carried out (5 mg/kg) on days 1, 2 and 3 or on days 9, 10 and 11 after single irradiation at a dose of 40 Gy. Results: The oral mucositis score, MPO activity and histopathological findings of inflammation increased in a dose dependent manner. Palifermin treatment stimulated the proliferation of mucosal epithelial cells. Additionally, palifermin when administered on days 1, 2 and 3 after irradiation (40 Gy) reduced the severity of oral mucositis. Conclusions: The hamster was found to be a suitable model for radiation-induced oral mucositis, with excellent results regarding the evaluation of radiation dose response and drug reactivity.

Evaluation of the clinical application of cystatin C, a new marker of the glomerular filtration rate, for the initial dose-setting of arbekacin

Objective: Recent studies have shown that serum cystatin C is a better marker for measuring the glomerular filtration rate (GFR) than the conventional method, using serum creatinine concentration. The purpose of this study is to evaluate the clinical application of serum cystatin C as a marker of GFR to determine the initial dosage of arbekacin, an antibiotic primarily excreted via the kidneys. In this study, the predictability of serum arbekacin peak and trough concentrations were assessed using estimated population mean GFR values calculated from either serum creatinine (Cockcroft–Gault equation) or cystatin C (Sjöström equation) concentrations.