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Although microbial contamination of ice machines has been reported, no previous study has addressed microbial contamination of ice produced by machines equipped with activated charcoal (AC) filters in hospitals. The aim of this study was to provide clinical data for evaluating AC filters to prevent microbial contamination of ice. We compared microbial contamination in ice samples produced by machines with (n = 20) and without an AC filter (n = 40) in Shunan City Shinnanyo Municipal Hospital. All samples from the ice machine equipped with an AC filter contained 10-116 CFUs/g of glucose nonfermenting gram-negative bacteria such as Pseudomonas aeruginosa and Chryseobacterium meningosepticum. No microorganisms were detected in samples from ice machines without AC filters. After the AC filter was removed from the ice machine that tested positive for Gram-negative bacteria, the ice was resampled (n = 20). Analysis found no contaminants. Ice machines equipped with AC filters pose a serious risk factor for ice contamination. New filter-use guidelines and regulations on bacterial detection limits to prevent contamination of ice in healthcare facilities are necessary.

We previously encountered a patient with epilepsy who exhibited rapid elimination of sustained-release valproic acid (VPA) administered at the dose of 2.8 g/d as a sodium salt. The purpose of this study was to clarify the relationship between the VPA elimination rate and the proportion of the dose excreted in urine as its glucuronide conjugate (VPA-G) in epileptic patients. Twenty-four-hour urine was collected from four epileptic patients who had taken VPA orally (age: 16-39 y, weight: 50-63 kg, dose: 1.0-2.8 g/d). VPA and its metabolites were detected by gas chromatography-mass spectrometry. The amounts of VPA, VPA-G, 3-keto VPA, and 3-OH VPA excreted in the 24-h urine were 1.8-13.2, 178-2158, 125-320, and 8.6-18.7 mg (converted into VPA), respectively, and 0.2-0.5, 20.5-88.7, 5.8-18.7, and 0.6-1.0% of the dose administered, respectively. The dose of VPA correlated well with the proportion of the dose excreted in urine as VPA-G in each patient, and the patients administered a high dose excreted a large amount of VPA-G in the urine. Thus, differences in the VPA-G production rate may be one of the major variable factors affecting the elimination of administered VPA. We also present a dynamic model of VPA in the kidney which may explain the VPA elimination phenomena in humans on the basis of the data obtained here regarding the concentrations of VPA and its metabolites in plasma and their urinary excretion levels.

The urinary excretion of valproic acid (VPA) and its metabolites (3-keto VPA, 3-OH VPA, and VPA-glucuronide) in 6 epileptic patients was studied using gas chromatography-mass spectrometry. The amount of VPA and 3-OH VPA excreted in the urine was low (0.1-0.5% of the dose of VPA and 0.6-1.5% of the dose of 3-OH administered). The amount of 3-keto VPA and glucuronide (VPA-Glu) excreted was marked (5.8-26.2% and 13.1-88.7% of the dose of VPA administered, respectively). The urinary excretion of VPA and its metabolites by patients who have taken a normal amount of a VPA preparation was almost the same as that of healthy volunteers. Two epileptic patients who took a large amount of the VPA preparation showed a high excretion of VPA-Glu without an increase in their plasma VPA-Glu.

In a previous study, we determined the in vivo binding parameters of valproic acid (VPA) to serum proteins in seven healthy young adults at steady state by using the Scatchard equation. To evaluate the ability of the Scatchard binding equation to predict steady-state unbound serum VPA concentrations (Cf), 39 adult patients receiving VPA monotherapy and ranging in age from 16 to 68 years were studied. The correlation between predicted and observed Cf was high (r = 0.865). Mean prediction error, mean absolute error (MAE), and root mean squared error (RMSE) were calculated, and served as a measure of prediction bias and precision. The MAE and RMSE were low (MAE = 12.9 mumol/L, RMSE = 17.7 mumol/L). It is feasible to use the Scatchard binding equation to predict Cf in patients receiving VPA monotherapy.

Two hundred milligrams of valproic acid (VPA) was administered orally to seven healthy adults at 9:00 and 21:00 h for 5 consecutive days, including the morning dose on day 6. On the sixth day, blood samples were drawn at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 3, and 6 h after the morning dose. Binding of VPA to serum protein was evaluated by ultrafiltration, and total and unbound VPA concentrations were determined by fluorescence polarization immunoassay. Binding parameters of VPA to serum protein were calculated for each subject by the Scatchard analysis. The binding parameters obtained from seven subjects showed that the mean association constant (K) was 2.72 x 10(4) L/mol while the total number of binding sites (nPt) was 789 mumol/L. There were marked interindividual variations and the coefficient of variation was 42% for K and 28% for nPt. These results show that endogenous free fatty acids (FFAs) significantly reduce the binding affinity of VPA to serum albumin (p less than 0.05). In addition, they suggest the possibility that the primary binding sites for VPA can be strongly reduced by FFAs. Therefore, we consider that interindividual differences in binding parameters may be clinically important.

The interindividual relationship between unbound fraction of valproic acid and some factors such as total drug concentration, level of albumin, free fatty acids (FFA) and total bilirubin was investigated after repeated oral doses in 7 healthy adults. All serum samples (n=63) were collected just prior to the last dose and the following times there-after.The correlation between unbound fraction and both corresponding each variable value and ratio of FFA/albumin and total bilirubin/albumin was determined in all samples (method (1)). Secondly, the correlation between individual average unbound fraction and both average values for each variable and ratio of FFA/albumin and total bilirubin/albumin of individual was also determined (method (2)).For applied method (1), there was significant positive correlation between unbound fraction and both total drug concentration (P

Valproic acid is highly bound to serum protein, mainly albumin. Valproic acid exhibits concentration-dependent protein binding, which partly accounts for considerable variability in the unbound fraction, even within the therapeutic range. Therefore, valproic acidprotein interaction and determination of the corresponding binding parameters should be considered. In the present study, we investigated the binding characteristics in epileptic adults and children under valproic acid chronic monotherapy, and determined the binding parameters of valproic acid to serum protein.There was a curvilinear relationship between total and unbound concentrations orunbound fraction, using a second-degree polynomial equation. The unbound fraction increased curvilinearly in proportion to the increase in total concentration . Averages of unbound fraction obtained from adults and children were not significantly different from each other (P>0.05). The unbound fraction ranged from 4.1 to 16 .7% (adults), and from 5.6 to 16.7% (children). There were marked about three-fold variations of unbound fraction in both adults and children.On the other hand, as the Scatchard plot was shown to be linear in both adults and children, valproic acid was bound to only one class of binding sites on the protein molecule. The binding parameters calculated by Scatchard plot were as follows: association constants (Ka) were 1. 14×104l/mol (adults) and 1.44×104l/mol (children), total number of binding sites (n (Pt)) was 1.36×10-3mol/l (adults) and 1. 20×10-3mol/l (children). There was no significant difference in the two parameters between adults and children (P>0 .05). Therefore, we determined the binding parameters from all samples (n=96) by using Langmuir plot. These results showed that dissociation constant (Kd) was 3 .89×10-5mol/l, total number of binding sites (n (Pt)) was 8.46×10-4 mol/l.These results suggested that valproic acid had the same binding characteristics in both adults and children. The molecular interaction between valproic acid and serum albumin involved one class of binding sites within the investigated range.

200mg of valproic acid (VPA) was orally administered to 7 healthy adults at 9 a.m. and 9 p.m. for 5 days. On the 6th day, blood samples were collected at 0, 10, 20, 30, 45, 60, 90, 180 and 360 min and the obtained 63 sera were prepared for analysis. There was a significant relationship between VPA dose and total VPA concentration in the serum, the regression curve was y=0.330x2+22.051 (r=0.469, p

Quality tests such as weight, hardness, disintegration, content, content uniformity and dissolution were made on 6 brands of pentoxifylline enteric-coated tablets, consisting of 1 original product and 5 me-too products.There were significant differences in the results of the tests among these products which were, however, confirmed to have fairly good qualities except in the dissolution properties of 2 me-too products. On the 2 products, the dissolution of pentoxifylline in the 1st fluid (pH 1.2) in JP X Disintegration Test was studied under a mild condition using rotating basket apparatus. Thus, both products were found to be unqualified. In this study, the original product was proved to have satisfactory qualitiy.

A new method of staining histamine in rat mast cell granules in formalin fixed paraffin section was developed. Mast cells of several organs of formalin fixed paraffin sections were stained well in red with orcein-water blue as well as in purple with toluidine blue. But only mast cells in dermis showed a different appearance in orcein-water blue stain and toluidine blue stain. The results of an electrophoretic study, diamine oxidase treatment and compound 48/80 treatment of rat lead to the conclusion that the substance stained in red with orcein may be histamine. It was shown that histamine in rat mast cell granule is fixed even by formalin, a finding contrary to previous studies.