Effect of tea beverages on aldehyde oxidase activity.

Aldehyde oxidase (AO) plays an important role in metabolizing antitumor and antiviral drugs, including methotrexate, cyclophosphamide and acyclovir. Green tea and its catechins have been shown to modulate the activities of various xenobiotic-metabolizing cytochrome P450 species, both in vivo and in vitro, but their effect on AO has not been studied. Therefore, we evaluated the effect of tea beverages on AO activity in rat and human liver cytosol. We also investigated the influence of several catechins on AO activity in rat liver cytosol. AO activity was evaluated in terms of oxidation of N-1-methylnicotinamide to N-1-methyl-2-pyridone-5-carboxamide and N-1-methyl-4-pyridone-3-carboxamide. Bottled green tea beverages at 10% (vol/vol) inhibited AO activity by 90.0-93.5%, while at 1.0% (vol/vol), they reduced AO activity by 73.9-90.0%. At 0.1% (vol/vol), green tea II and III, which have high contents of catechins and their derivatives, inhibited AO activity by 24.3% and 38.8%, respectively. Bottled mineral water had no effect. AO activity was inhibited potently by epicatechin and epicatechin gallate. These results indicate that the AO-inhibitory activity of tea beverages is predominantly due to catechins and their derivatives. Thus, consumption of tea beverages may cause a decrease of AO activity, which may result in reduced clearance of drugs that are AO substrates.

Factorial invariance of a questionnaire assessing medication beliefs in Japanese non-adherent groups.

OBJECTIVE: The aim of our study was to verify invariance of latent factors derived from the BMQ (Belief about Medicines Questionnaire) among Japanese adherent and non-adherent groups (adherent to medication and intentionally, unintentionally, and overlapping non-adherent groups) and to estimate mean differences of the latent factors among the groups. SETTING: A Japanese university hospital. METHODS: After administration of a cross-sectional survey, covariance structure analyses of the two-factor model were conducted. Groups that exhibited factorial invariance were identified, and structured mean analyses estimated the differences of the latent means of the factors between groups using the bootstrap method without relying on theoretical assumptions for sampling distributions. Effect size was employed as an indicator of these differences. MAIN OUTCOME MEASURE: The differences in the latent means of the two factors (the necessity and concerns factors for prescribed medications) across the groups exhibiting factorial invariance, which reflect true differences between them. RESULTS: Factorial invariance was demonstrated only across adherent and unintentionally non-adherent groups. Unintentionally non-adherent patients had significantly lower latent means for the necessity factor than adherent patients, with a very close to medium effect size (-0.49; 95% CI -0.84, -0.14; bootstrap method). CONCLUSION: A meaningful comparison of BMQ scale scores can be made between adherent and unintentionally non-adherent groups of Japanese patients.

Current situation of drug information in the kindergarten and nursery teacher: a pilot study.

Because children cannot be expected to take medications correctly by themselves, parents are responsible for administering drugs based on the information provided by pharmacists. It has been reported that 90% of children aged 3-5 years in Japan attend kindergarten or nursery school, where teachers are responsible for the administration of some drugs to children. This study evaluated the types of information that teachers receive from parents. We conducted a questionnaire-based survey on drug information imparted to 144 teachers working in kindergarten or nursery schools in Hiroshima and Kure. The teachers reported that drug information from parents mainly comprised dosage and usage. However, little information was provided concerning the drug name, adverse drug reactions, and interaction with food items. To administer drugs to children safely, kindergarten and nursery teachers considered the information regarding adverse drug reactions (111/123 teachers), interaction with foods (106/123 teachers), and effective means of administering drugs (117/123 teachers) as important. The pharmacists' prescription notes have information on dosage, usage, drug name, adverse drug reactions, and interaction with food items. However, the teachers receive drug information from parents in the order of oral communication, a written note, and via the pharmacists' prescription note. Seventy-two percent of teachers (89/123 teachers) insisted on needing the pharmacists' prescription note. These results suggest that teachers are uncomfortable administering medications to children primarily due to inadequate information. Pharmacists should instruct parents to provide teachers with prescription notes to prevent grave medication errors.

Dose adjustment of phenytoin for comedication in Japanese patients with epilepsy.

This study sought a suitable physiological parameter related to daily phenytoin (PHT) dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of coadministered antiepileptic drugs on Ct quantitatively to adjust PHT dose. Data were derived from a total of 368 patients with epilepsy treated with multiple oral administrations of PHT. Phenobarbital, carbamazepine, valproic acid, zonisamide, clonazepam, and ethosuximide were coadministered. For the administration of PHT alone, 4 types of parameter, that is, total body weight, total body water volume, body surface area, and extracellular water volume (VECW) were examined. Then, a Michaelis-Menten kinetic model was postulated including VECW, which was assumed to detect the effect of the coadministered drug quantitatively. Adopting VECW as a transforming factor, the concentration to dose (L:D) ratio [Ct/(D/VECW)] was independent of the patient's age and gender in relation to Ct and expressed as Ct/(D/VECW) = 0.0245 x Ct + 0.076. Analysis clarified that ratios were estimated as 0.90, 0.91, 0.89, and 0.84 for phenobarbital, carbamazepine, valproic acid, and zonisamide, respectively, to maintain the same Ct concentration of PHT. Influences were not detected as the number (> or =2) of coadministered drugs increased, regardless of factor type. PHT clearance changed in an age-dependent manner and was usually poorly correlated with weight-based doses. VECW was more closely correlated with age-dependent changes in physiological parameters such as clearance. VECW was considered to remove the influence of age on clearance, and estimated ratios could be used for all age groups. In the case of the addition or removal of concomitant treatment with antiepileptic drugs in the same patient, the daily PHT dose was calculated using the value of each ratio or its reciprocal. Our results could be helpful in determining PHT dosing.

[Effect of the admixture of tetracycline and nadifloxacin ointments on their stability and their antibacterial activity].

Impetigo contagiosa staphylogenes is commonly treated by administering a combination of nadifloxacin and tetracycline ointments. However, it is not clear whether nadifloxacin and tetracycline are stable after mixing. The purpose of this study was to evaluate the stability of these agents in combination. We also evaluated changes in antibacterial activity after mixing. Mixing the two ointments caused tetracycline to change from yellow to brown in the admixture. Furthermore, the tetracycline content in the ointment decreased in a time-dependent manner, to about 40% at 288 h after mixing. In addition, the nadifloxacin content in the ointment did not change 288 h after mixing. In an alkaline environment (pH 9.0 and 11.0), the tetracycline content decreased and the color of tetracycline changed to brown. These results suggest that sodium hydroxide, which is an additive in nadifloxacin ointment, influences the content of tetracycline. We evaluated the chemical sensitivity of Staphylococcus aureus using disk tests. Nadifloxacin and tetracycline ointment showed the largest radius of inhibition circle, followed by the admixture 0 h after mixing and the admixture 72 h after mixing. These results suggest that the antibacterial activity is inhibited by the admixture. We propose that pharmacists should avoid mixing nadifloxacin with tetracycline ointment in the treatment of impetigo contagiosa staphylogenes and should take care to avoid interactions caused by additives in the ointments.

Comparison of individual perceptions of medication costs and benefits between intentional and unintentional medication non-adherence among Japanese patients.

OBJECTIVE: To identify Japanese patients' perceptions of the costs and benefits of their medications by administering a questionnaire validated in Western patients and to compare the association between the perception levels and non-adherence to medication in the two non-adherent patient types, intentional, and unintentional. METHODS: Japanese patients with chronic diseases were given a questionnaire and interviewed, and the validity and reliability of the scales generated were assessed. Logistic regression was used to analyse the association between individual perception levels and non-adherence to the medication regimen. RESULTS: From 151 responses, two kinds of scales were generated following a report of Western patients; the necessity scale showed satisfactory reliability (Cronbach's alpha 0.79) but the concerns scale did not. Individual levels of perception of the necessity of medications were associated with unintentional non-adherence (the higher the level, the lower the odds ratio 1.0, 0.56, 0.40, and 0.15), while they were not associated with intentional non-adherence. CONCLUSION: Japanese patients' perceptions of the benefits of medications, but not the costs were similar to those of Western patients, and these perceptions were likely to be different between intentionally and unintentionally non-adherent patients. PRACTICE IMPLICATIONS: Strategies to improve non-adherence should be designed according to the non-adherent type.

Changes in attitudes among Japanese patients after Pharmacist Law revision.

OBJECTIVE: To assess changes in patients' perception of their medications and their adherence to regimens after enactment of the Japanese Pharmacist Law revision of 1997, which stipulated provision of drug information to patients as one of the principal duties of pharmacists. Setting A university hospital in Japan. METHOD: Comparison of cross sectional analyses between two time periods: shortly after enactment of the Pharmacist Law revision and about a half-decade later. MAIN OUTCOME MEASURE: Patient's knowledge of the medications, anxiety level, individual beliefs regarding taking medications without anxiety, and adherence to the medication regimens. RESULTS: There were 141 and 151 patients who participated during each period, respectively. The proportion of non-adherent patients significantly decreased from 68.8 to 53.6% (P = 0.008). Multiple logistic regression analysis indicated that the features of the intentionally non-adherent patients have changed; they have switched from persons who lack general comprehension about the medications (P = 0.01), ones who place an importance on knowing the side effects (P = 0.04), or who place no value on mutual reliance on their doctors (P = 0.03) into persons who place no value on understanding the purpose of taking their medications (P = 0.04) or who place value on multiple items to take medications without anxiety (P = 0.03), i.e., supposedly people who prefer thinking about their drug therapy from their own point of view based on comprehension of their disease and medications. CONCLUSIONS: The rapid progression of drug information disclosure after enactment of the Pharmacist Law revision has likely resulted in drastic changes in patients' perception of their medications and led to improvements in medication adherence.

[Influence of tacrolimus and ciprofloxacin on glucose metabolism].

Tacrolimus is an immunosuppressive drug that causes glucose intolerance. On the other hand, ciprofloxacin, which is widely used in the treatment of infectious diseases, is known to cause hypoglycemia as a side effect. We investigated the effects of tacrolimus and ciprofloxacin on serum glucose and insulin levels in rats, as well as on insulin secretion and the viability of HIT-T15 cells. The rats received intraperitoneal injections of tacrolimus and/or ciprofloxacin for 1 week, and their arterial blood was sampled after the administration of glucose. HIT-T15 cells were cultured in the presence of tacrolimus and/or ciprofloxacin, and the insulin level in the supernatant was measured. Ciprofloxacin did not show a significant effect on serum glucose and insulin levels after multiple administrations in the rats. In contrast, rats in the tacrolimus treatment group showed low serum insulin and high serum glucose levels. Moreover, the coadministration of ciprofloxacin and tacrolimus resulted in higher glucose levels compared with tacrolimus alone 0.5 h after glucose stimulation. In addition, we observed that the rats administered tacrolimus and/or ciprofloxacin had low body weight and food intake. Tacrolimus caused a dose-dependent decrease in the viability of the HIT-T15 cells. Furthermore, both drugs were highly toxic to HIT-T15 cells. In contrast, tacrolimus alone and coadministration of the drugs resulted in no significant difference in insulin secretion. These results suggest that the cytotoxic effects of ciprofloxacin and tacrolimus cause a decrease in insulin secretion, leading to glucose intolerance.

[Monitoring sheet covering long-term chemotherapy to predict individual adverse reaction patterns for patients with gynecologic chemotherapy].

Monitoring the adverse reaction patterns specific to individual patients is important to avoid subsequent reactions. Gynecologic cancer chemotherapy is often implemented repeatedly with an altered protocol during prolonged terms. The purpose of this study was to develop and assess the efficacy of a worksheet that pharmacists can use to analyze adverse reaction patterns in individual patients with gynecologic chemotherapy. The worksheet which we developed consisted of multiple sections. One section is for necessary drug information for the proper use of antineoplastic agents. Another section is for the following items recorded by the pharmacists: a) patients' basic information such as stage of disease and protocol, b) state of implementation and break of chemotherapy and supportive therapy on calendar, and c) laboratory data and symptoms. We arranged the last item below the calendar and enabled pharmacists to easily assess individual adverse reactions coupled with the treatment course. Reviews of the developed worksheet indicated that the worksheet led to the convenient detection of individual adverse reaction patterns and effective prevention of additional adverse reactions. This monitoring sheet covering long-term chemotherapy which was designed to predict individual adverse reaction patterns will improve the individualization and safety of gynecologic chemotherapy.

Impact of prescription-term deregulation with revised medical service fees on drug therapy management.

The proclamation of April 2002 of a Ministry of Health, Labor and Welfare ordinance has enabled doctors to prescribe drugs for an outpatient without a limit on the length of prescription terms except for a few drugs. There is a concern that the prescription-term deregulation could cause careless drug therapy management in order to extend the interval between patient hospital visits. The purpose of this study is to make pre- and post-deregulation comparisons of two items, prescription terms and implementation of clinical examination that complied with package-insert precautions, and to discuss the approaches to increase safety. Prescription terms have lengthened progressively. In the pre-regulation period of January to March 2002, the mean prescription term was 19.9 days; in the post-regulation period of July to September 2002, it was 24.9 days; and in July to September 2003, 28.6 days. Even for anti-tumor agents, there were prescriptions over 90 days after deregulation. There was no significant difference between the pre- and post-deregulation compliance ratios for the package-insert precautions in eight drugs of investigated nine. However, one case had a delay in detection of liver dysfunction, which was caused by deviation from the once-a-month testing indicated in the package-insert precautions for prolonged prescription terms. The evidence suggested that the deregulation led to negligent drug therapy management. To assure safe therapy, the following should be addressed: first, sufficient function of a computerized prescriber order entry system and second, creation of a new framework with pharmacists' active involvement such as collaborative therapy management with physicians.

Influence of coadministered antiepileptic drugs on serum phenobarbital concentrations in epileptic patients: quantitative analysis based on a suitable transforming factor.

This study investigated most suitable transforming factor related to the daily Phenobarbital dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of concomitant antiepileptic drugs on Ct quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 326 epileptic patients treated with multiple oral administrations of phenobarbital (PB) as a powder, were used for the analysis. A total of 156 patients were administered PB alone, and 92, 57, and 21 patients were coadministered one, two, and three different antiepileptic drugs, respectively. Valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), zonisamide (ZNS), clonazepam, and ethosuximide were coadministered with PB. For administration of PB alone, four types of transforming factor corresponding to clearance, i.e., total body weight, total body water volume, body surface area and extracellular water volume (VECW) were proposed. With VECW as a transforming factor, the level/dose (L/D) ratio (:Ct/(D/VECW)) was independent of the patient's age and gender. Ct was dependent on only one variable regarding D/VECW and expressed as Ct=0.989 x (D/VECW). The coadministration of one drug caused a difference in the gradient of the regression line of PB alone, and the influence of each drug was detected by dividing each mean L/D ratio of PB plus one other drug by that of PB alone. VPA, CBZ, and PHT significantly increased (p<0.01) the L/D ratio to 1.48, 1.35, and 1.23 of the value for PB alone, respectively. With coadministration of multiple drugs, the L/D ratio rose significantly (p<0.05) as the number (< or =2) of drugs coadministered increased regardless of the type, and also increased with the concomitant use of 3 drugs compared with 2 drugs. For a more detailed analysis, we defined the parameter eta(i) (i=1, 2, ..., 6) and an alteration ratio Ri, representing the influence of each antiepileptic drug on the L/D ratio of PB alone. A model based on the assumption that each coadministered drug competitively inhibited PB-metabolizing enzyme, was adopted. The analysis clarified that VPA, CBZ, and PHT significantly increased (p<0.05) the L/D ratio of PB to 1.466, 1.177, and 1.186, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each Ri and compared with the measured value. The mean of prediction error was calculated as 23.1%. Our results appear valid and Ri should be available for clinical use.

Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia.

OBJECTIVE: To define the pharmacokinetics of midazolam, a probe for monitoring cytochrome (CYP) 3A 4 activity, during moderate hypothermic therapy. DESIGN: A prospective randomized study. SETTING: The intensive care unit of a medical university hospital. PATIENTS AND INTERVENTIONS: In 15 consecutive brain-injured patients, midazolam concentrations were measured serially using high-performance liquid chromatography (HPLC). Under continuous administration of the agent, eight patients underwent moderate hypothermia of 32-34 degrees C (hypothermia group) and seven received normothermic therapy (normothermia group). A one-compartment model was selected for pharmacokinetic analyses for the continuous administration. Data represent +/-S.D. Statistical analysis was performed using ANOVA followed by Scheffe's F-test or the Mann-Whitney U-test ( P<0.05 ). MEASUREMENT AND MAIN RESULTS: Serum midazolam concentrations in the hypothermia group increased linearly until the body temperature (BT) reached 35 degrees C without plateauing, even during continuous administration, after which the levels decreased remarkably when BT rose to 36 degrees C. However, the concentrations in the normothermia group remained on a plateau, which lasted until the end of the study. In the hypothermia group, elimination rate constant (k(e)) and clearance (CL) in the phase below 35 degrees C BT were much lesser than those above 35 degrees C BT, whereas distribution volume (V(d)) during the hypothermic phase was greater than that during the period above 35 degrees C BT. CONCLUSION: This study has demonstrated for the first time that midazolum concentration changes biphasically even during continuous infusion in hypothermic therapy. The mechanisms for the change are unclear. Thus, further studies including confirmation of cytochrome 3A 4 activity are required, while monitoring for the development of undesirable effects from over-dosing is also needed.

Influence of coadministered antiepileptic drugs on serum zonisamide concentrations in epileptic patients: quantitative analysis based on suitable transforming factor.

We conducted a study to clarify the most suitable transforming factor related to the daily zonisamide dose (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 175 epileptic patients treated with the multiple oral administrations of zonisamide (ZNS) as a powder/tablets, were used for the analysis. Employing the extracellular water volume (V(ECW)) as a transforming factor, led the level/dose (L/D) ratio (:C(t)/(D/V(ECW))) to be independent of the patient's age and sex for the administration of ZNS alone. C(t) was revealed to be dependent on only one variable regarding D/V(ECW) and expressed as C(t)=0.604x(D/V(ECW)). Phenytoin (PHT) significantly lowered (p<0.01) the L/D ratio to 0.76 of the value for ZNS alone. For a more detailed analysis, we defined the parameter R(i) (i=1, 2, em leader, 6) as an alteration ratio, representing the influence of each antiepileptic drug on the L/D ratio of ZNS alone. A model based on the assumption that each R(i) value was independent from one another and multiplicative, was adopted. The analysis clarified that phenobarbital, valproic acid, carbamazepine, and PHT significantly lowered (p<0.05) the L/D ratio of ZNS to 0.849, 0.865, 0.846, and 0.804, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each R(i) and compared with the measured ones. The mean of prediction error was calculated as 22.9%. Our results appear valid and R(i) should be available for clinical use.

A novel type of DNA curvature present in a Clostridium perfringens ferredoxin gene: characterization and role in gene expression.

This study has revealed that a Clostridium perfringens ferredoxin gene (per-fdx) possesses a novel type of DNA curvature, which is formed by five phased A-tracts extending from upstream to downstream of the -35 region. The three A-tracts upstream of the promoter and the two within the promoter are located at the positions corresponding to A-tracts present in a C. perfringens phospholipase C gene (plc) and a Clostridium pasteurianum ferredoxin gene (pas-fdx), respectively. DNA fragments of the per-fdx, pas-fdx and plc genes (nucleotide positions -69 to +1 relative to the transcription initiation site) were fused to a chloramphenicol acetyltransferase reporter gene on a plasmid, pPSV, and their in vivo promoter activities were examined by assaying the chloramphenicol acetyltransferase activity of each C. perfringens transformant. Comparison of the three constructs showed that the order of promoter activity is, in descending order, per-fdx, pas-fdx and plc. Deletion of the three upstream A-tracts of the per-fdx gene drastically decreased the promoter activity, as demonstrated previously for the plc promoter. Substitution of the most downstream A-tract decreased the promoter activities of the per-fdx and pas-fdx genes. These results indicate that not only the phased A-tracts upstream of the promoter but also those within the promoter stimulate the promoter activity, and suggest that the high activity of the per-fdx promoter is due to the combined effects of these two types of A-tracts.

Effects of concomitant antiepileptic drugs on serum carbamazepine concentration in epileptic patients: quantitative analysis based on extracellular water volume as a transforming factor.

The effects of concomitant antiepileptic drugs on the serum carbamazepine concentration (C1) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBZ fine granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four different antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, Ct could be expressed approximately as a function of the daily dose per extracellular water volume (D/VECW) as Ct = A(D/VECW)B (A, B: parameter). By comparing the regression line on log Ct vs. log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was thus found to be affected at each definite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that Ct is affected by each concomitant antiepileptic drug i at each definite ratio. We defined the parameter Ri(i = 1, 2, ..., 7) representing the effect of each concomitant antiepileptic drug on Ct. A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not affect Ct. The number of patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the effect on Ct based on a test of significance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated Ct values were calculated using the value of each Ri and compared with the measured Ct values. Both values were in good agreement, and thus our results appear valid.

[Status of achievement of the aseptic preparation method for total parenteral nutrition expected by physicians and nurses].

In most medical institutions, although total parenteral nutrition (TPN) should be prepared by pharmacists in sterile condition, nurses actually perform this procedure in hospital wards. The currently growing belief is that pharmacists should prepare all preparations for injection using aseptic technique. Therefore, we conducted a survey on how physicians and nurses feel about methods of preparation of TPN and other agents for injection. The results demonstrated that physicians and nurses desired pharmacists to prepare all agents for injection according to prescriptions using aseptic technique, under pharmacological control and on a 24-hours basis. Based on these results, we examined a method to realize this expectation to the extent possible in our hospital and applied it when aseptic TPN preparations were extended to include relatively stable patients requiring TPN in all hospital wards. The number of TPN preparations increased steadily. The mean number of aseptic TPN preparations after stabilization of this method was 1214 a month. A total of 48% of all TPN solutions required were prepared in aseptic condition, with an average of 4.4 vials of agents mixed per prescription. For TPN base solution, 71% of a double--bag preparation consisting of electrolytes, saccharides, and amino acids was used. It was prepared in the wards most often for the reason, "described as an unscheduled prescription". The cost of consumables required for aseptic preparations was approximately 1.7 times the insurance coverage for addition of aseptic preparations. The physicians and nurses supported the method used by the pharmacists. To ensure complete aseptic preparation of injections by pharmacists, additional pharmacists, a review on their working system, more insurance points, and a broader range of insurance coverage may be required.

[Appropriate administration schedule of D-penicillamine for pediatric Wilson's disease patients based on urinary copper excretion].

The purpose of this study was to increase the amount of copper excreted resulting from the administration of D-penicillamine(DP) in pediatric Wilson's disease(WD) patients. By measuring the urinary copper excretion after adjusting the administration schedules, the appropriate timing for DP administration was investigated. The subjects were three brothers with pediatric WD. The initial daily dose of DP was 5 mg/kg/day, and gradually increased to the maintenance dose of 20 mg/kg/day. Until the maintenance daily dose was reached, DP was administered 2 h after the morning and evening meal. After reaching the maintenance daily dose of DP, the appropriate timing for taking DP was investigated in both the morning and evening. Three schedules of DP administration were compared: 2 h after meals; 30 min before meals (with fasting); and 1 h before the morning and 1.5 before the evening meal (direction 1). The resulting urinary copper excretion on each dosing schedule was compared. Little difference was found in urinary copper excretion on the first two schedules, i.e., 2 h after meals and 30 min before meals. When DP was administered 30 min before meals, urinary copper excretion [microgram/day] was 1173 in the first brother, 918 in the second, and 875 in the third. When DP was administered according to direction 1, however, urinary copper excretion was increased significantly to 1701 in the first brother, 2701 in the second, and 3808 in the third. It is known that the efficiency of urinary copper excretion with DP administration depends on the maintenance of chelating ability after absorption from the gastrointestinal tract. Our results indicate that the excretion was lower when DP was administered 2 h after or 30 min before meals (with fasting), as recommended in the package insert. Thus to achieve better copper excretion efficiency, direction 1 is recommended for WD patients.

[Surveillance of reasonable period of antibiotic administration to compromised hosts].

For the purpose of prevention of hospital-acquired infection caused by antibiotic-resistant bacteria, we examined a method to establish an appropriate time period for the administration of antibiotics to compromised hosts. Using these antibiotics we monitored patients who received instruction about the drug regimen in the Blood and Respiratory Diseases Department ward. We monitored a) third-generation cephalospolins, b) Imipenem/Cilastatin, and c) antibiotics used against methicillin-resistant Staphylococcus aureus. When the antibiotics were administered over 14 days, pharmacists notified physicians of the current duration of administration using a confirmation form, and confirmed their future administration schedule. We examined the antibiotic usage regimen of all the patients in this ward before and after the confirmation form was adopted. Patients given the same antibiotics within 14 days significantly increased in percentage from 82% to 91% after the confirmation form was adopted (p < 0.05). The median duration of antibiotic administration decreased from 7 days to 5 days. The case with antibiotic administration for the longest duration was a patient with leukemia who received vancomycin for 116 days after adoption of the confirmation form. This patient died 4 days after his antibiotic was changed. Only 16% of the patients administered antibiotics in this ward were monitored for the duration of antibiotic administration after adoption of the confirmation form. When the pharmacists positively provided physicians with information on some patients concerning the prolongation of antibiotics administration, the number of patients administered antibiotics for less than 14 days significantly increased throughout this ward without interfering with the treatment of patients who required long-term administration of antibiotics.