Although acetazolamide, a carbonic anhydrase inhibitor, has an effect of lowering the intraocular pressure, a number of side effects have been reported with its use.We therefore investigated the pharmacokinetics and pharmacodynamics of acetazolamide in patients with an intraocular pressure (IOP) elevation. The plasma acetazolamide concentration and IOP in 17 patients with a transient IOP elevation were simultaneously measured after the last acetazolamide administration, and the findings were analyzed by nonlinear mixed effect modeling using the NONMEM software program. The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption.The apparent oral clearance (L/hr) showed a correlation with the creatinine clearance (CCR, mL/min), as estimated by the Cockcroft and Gault equation, as follows : 0.0468·CCR. The estimated apparent oral volume of the distribution, first-order absorption rate constant, and absorption lag time were 0.231 L/kg, 0.821 hr^-1, and 0.497 hr, respectively. The intraocular pressure after oral acetazolamide administration was characterized by an E_max model. The maximal effect in lowering the IOP (E_max) was 7.2 mmHg, and the concentration corresponding to 50% of E_max (EC₅₀) was 1.64 μg/mL. We next investigated the relationship between the acetazolamide concentration and its side effects in 23 glaucomatous patients who received repeated doses of oral acetazolamide for one week or more. The serum concentration of chloride ion was found to be higher than the normal range, and also showed a significant correlation with the acetazolamide concentration in the erythrocytes. The patients with an erythrocyte acetazolamide concentration of more than 20μg/mL had higher incidents of the side effects. Based on these results, the recommended dosage of acetazolamide was calculated so that the minimum plasma concentration at steady-state exceeded 4μg/ mL. The dosage regimen desired in this study is expected to contribute to the safe and effective pharmacotherapeutic use of acetazolamide.

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Carvedilol demonstrates α_1-, β_1-, β_2- receptor blocking activity and has recently been used for the treatment of heart failure. The serum concentrations of carvedilol were measured by high performance liquid chromatography (HPLC) using the method of Hokama et al. and Louis et al. with slight modifications. To extract carvedilol from the serum, we employed solid-phase extraction. The retention times of carvedilol and the internal standard were 7.1 and 5.8 minute, respectively. The detection limit was 0.25ng/mL. These results suggest that this assay is a rapid, simple and sensitive method. On the other hand, the mean±SD clearance of carvedilol was 1.10 ±0.541L/hr/kg and 0.611±0.320L/hr/kg in 4 male volunteers who received 10mg carvedilol orally and in 21 inpatients who received carvedilol b.i.d. for at least a week, respectively. Our findings indicated that even though the carvedilol concentrations increased depending on the dose, the individual variations among individuals were large.

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In hematopoietic cell transplantation, amphotericin B (AMPH) syrup is widely used for the prevention of local fungal infections in the intraoral and gastrointestinal tracts. However, the dosage compliance tends to be poor due to its unpleasant taste. We therefore developed a candy preparation for AMPH in order to improve compliance. In this study, we examined the thermostability, stability under storage and the dissolution pattern of AMPH in this preparation. The oral contents of AMPH after administration in the candy preparation were also measured in healthy volunteers. A low calorie sweetener was heated to melt and cooled down to several temperatures (150-190°C). After cooling, AMPH syrup or powder grinding tablets were added (9 mg/ 3 g/piece : the final contents). The results of a thermostability examination show that AMPH was not affected at 150°C, however, it tended to be damaged at higher temperatures. When one piece of AMPH candy preparation was administered for 30 sec to healthy volunteers, the oral concentration of AMPH is higher than 100μg/mL for 10 min, which is more than the minimal inhibitory concentration (MIC) for Candida albicans. Furthermore, the results of a texture test using healthy volunteers indicate that the taste, i.e., flavor, feel on the tongue, etc of the candy preparation made from syrup was superior to that made from powder. These results suggest that a sufficient oral concentration of AMPH to prevent fungal infection was obtained in this candy preparation. As a result, this candy preparation may improve not only the dosage compliance but also the QOL of the patients.

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The preventive effect of allopurinol mouthwash (Alkox-mw), which consists of allopurinol, polyethylene (oxide) (Alkox^®) and t-carrageenan, regarding the problem of stomatitis induced by cancer chemotherapy and/or radiotherapy was investigated. The investigation was done on patients who were diagnosed with either esophageal or gastric cancer, and were treated by radiotherapy and/or chemotherapy using 5-FU. The preventative effect of Alkox-mw was evaluated based on the common toxicity criteria advocated by the Japan Clinical Oncology Group. Alkox-mw was effective in 70% of the patients investigated in this study. Regarding cases of grade 1 stomatitis, the stomatitis healed after the regular use of the mouthwash treatment with Alkox-mw. However, even when Alkox-mw was used, the prognosis of the grade 2 or higher grade cases was not consistent. In a comparison of the preventative effect against stomatitis between Alkox-mw and mouthwash consisting of sodium carboxymethylcellulose (CMC-Na-mw), Alkox-mw was found to be more effective than CMC-Na-mw. The results obtained in this study thus suggest that Alkox-mw appears to be a useful preventative treatment modality against stomatitis.

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In order to supplement our lectures on the community health care system and the role of community pharmacists, we created hypertexts linked to 300 or more Web sites related to community health care including such subject areas as community pharmacies, pharmaceutical associations and prefectural governments and then used these resources to teach undergraduate students and assessed the efficacy of this method.
The subjects consisted of undergraduate at our university (265 in 1999, 297 in 2000). Before and after reading the hypertexts, they performed a subjective self-estimation of the efficacy of learning about pharmacies and pharmacists using a questionnaire graded from -2 to + 2 points. In the analysis, the subjects were separated into two groups, those who had experienced an externship at a community pharmacy and those without any externship experience. The scores before and after reading the hypertext material were compared in each group and interindividually, and significance was assessed using the Wilcoxon signed-ranks test (P<0.05).
The scores for the question of “Do you know the function of community pharmacies ?” increased significantly (shifted to “Yes”) after reading the hypertext material in the non-experienced group. The reason for this high information reception was considered to be that hypertexts are responsive tools (responsive environments) that promote effective learning, as well because the information in the hypertexts was new and interesting for the non-experienced group. The scores for the question of “Do you want to be a community pharmacist ?” also increased significantly (shifted to “Yes”) after reading the hypertext material in the non-experienced group, and we therefore suggest that the information in the hypertexts aroused curiosity about community pharmacists (diversive curiosity). On the other hand, scores for the question of “Do you want to go on to graduate school ?”, increased significantly (shifted to “Yes”) after reading the material in the experienced group. The reason that enthusiasm for learning (intrinsic motivation) appeared to be stimulated is considered to be as follows : We set students a task of choosing their favorite community pharmacy sites, as a result, they probably accessed a number of community pharmacy sites. We therefore suggest that the image formed from the information on the sites was incongruous with that formed through their externship and that this incongruity aroused their curiosity (specific curiosity) thus resulting in an increased enthusiasm for learning.
In conclusion, we consider that our hypertext educational materials were helpful in the training of undergraduate students before an externship at a community pharmacy while these materials also helped to stimulate the intrinsic motivation for learning in students who had already experienced an externship.

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Hospital pharmaceutical preparations (HPP) are used in patients whose complications are not well controlled by the commercially available drugs or injections. The use of HPP is effective when HPP are proposed through clinical pharmacy services. A questionnaire was developed to evaluate the use of HPP and then was sent to 49 hospital pharmacies who belong to the Hokkaido Association for Hospital Pharmaceuticals.
As a result, 32 institutions replied to questionnaire, thus indicating a recovery rate of 65%. HPP, including mixtures of injectable drugs, were used at 30 out of 32 institutions. According to the questionnaires, 11 hospitals manufactured 24 HPP which were used during clinical pharmacy services. Half of these preparations were used to care for adverse symptoms, such as stomatitis, induced by the cancer chemotherapy.
The use of HPP prepared by clinical pharmacy services is closely related to patient's symptoms. The practical use of HPP is not only considered to improve drug compliance and the QOL of patients, but are also thought to enhance the general capabilities of pharmacists in clinical pharmaceutical practice.

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The present study was designed to examine the cost-effectiveness of Flomoxef (FMOX) and Cefmetazole (CMZ) in the prophylactic antibiotic therapy after colorectal cancer surgery. Fifty-eight patients (47 in the FMOX group and 11 in the CMZ group), who underwent surgery for colorectal cancer at the First Department of Surgery of our hospital, were investigated. There was no significant difference between the 2 groups regarding the mean treatment period, the prophylactic effect of infection, or in changes in the white blood cell count (WBC), C-reactive protein (CRP), and serum creatinine (Cr) during the treatment period. However, the mean cost of treatment was significantly higher in the FMOX group than in the CMZ group, thus suggesting that the prophylactic effect of CMZ may be more cost-effective. Further evaluations of pharmacotherapy based on cost effectiveness may thus become one of the important duties of hospital pharmacists in the future.

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To investigate the problems associated with the use of the Flutide^® inhaler, its clinical use by patients was evaluated. Twenty-one of 33 patients who were examined in this study were found to have made some type of mistake when using the Flutide^® inhaler. Elderly patients had more mistakes than younger patients, and males had a higher frequency of mistakes than females. Some subjects made mistakes during self-inhalation, even though they had been able to correctly use the inhaler on initial consultation. We thus consider that comprehensive initial consultations demonstrating the correct use of this inhaler are necessary. In addition, follow-up consultations are also required to ensure that the patients are indeed correctly using this device, although it is reported to be easier for patients to use the powder-type preparations than metered-dose inhalers. tended to make

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In 1996, the Department of Clinical Pharmacy at the Education and Research Center of Kyoto Pharmaceutical University was established to enrich the education program of pharmaceutical health care and sciences, and to also be used as a pre-training program for undergraduates before taking part in externships at hospitals or pharmacies. In the following year, the training center of clinical pharmacy (a simulated pharmacy) was also founded, and has since been used for the practical training of pharmaceutical health care and sciences for third-year undergraduate students. We herein describe our findings of an unregistered questionnaire survey of the undergraduate students' view, while also evaluating and discussing the effectiveness of this training program.
Almost all students considered undergoing the practical training to be useful and necessary for them, because their scores before and after the training were 4.24 and 4.56 points on a scale of 5 point maximum, respectively. The students also evaluated each part of the training program, with mean values before and after the practice 3.75-4.01 and 3.70-4.39, respectively. The students did voice various opinions regarding the practical training program. Consequently, the students are satisfied with the practical training programs at present, however, we will have to continually improve such programs to better meet the students needs.

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We investigated the appearance of various factors causing fluctuations in the metabolic fate of theophylline (TP) in pneumoconiosis outpatients. Concurrent drug use, congestive heart failure, and smoking were found to be fluctuation factors. There were 4 patient groups, 3 with one of these factors each and a control group with none of the factors. We investigated the correlations between the TP dose and the serum concentration and between age and the serum concentration/dose (C/D) ratio in these 4 groups. The relationships between the dose and serum concentration were as follows : control group : Y=1.377X (p<0.0001), concurrent drug use group : Y=1.408X (p<0.0001), congestive heart failure group : Y=1.695X (p<0.0001), and smoking group : Y=1.025X (p=0.0002). Linearity was obtained for each, and a significant difference (p<0.05) in the regression line was only seen between the congestive heart failure and smoking groups. In addition, compared with the control group, the serum concentration tended to rise when receiving a high dose in the congestive heart failure group. No significant correlation was found between age and the C/D ratio in any of the groups, but the C/D ratio was lower in the smoking group than in any of the 3 other groups (p<0.05).
The above results suggest that when administering TP to pneumoconiosis patients one should pay special attention to fluctuation factors in order to decrease the TP clearance (TPCL) due to congestive heart failure when administering high doses of drugs, in patients with an increased TPCL due to smoking.

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For the self-treatment of hypoglycemia in diabetic patients receiving oral hypoglycemic drugs or insulin injection, we attempted to prepare quickly disintegrating glucose tablets to make them easy to swallow without drinking water. Tablets containing 2, 5 and 10% microcrystalline cellulose were prepared by direct compression at forces of 0.04, 0.06 and 0.12t/cm². The hardness and water absorption properties were measured as characteristics of the tablets. Changes in the blood glucose level after the oral administration of two tablets were examined using hypoglycemic male rabbits given a subcutaneous injection of one unit of insulin. The intra-oral disintegration time of the glucose tablets was measured in three healthy volunteers who were each administered five tablets.
The hardness of the tablets increased as the concentration of microcrystalline cellulose and force of compression increased. The highest value of hardness was 5.27kg (10%, 0.12t/cm²), and the lowest was 1.11kg (2%, 0.04t/cm²). The water absorption rate increased with the concentration of microcrystalline cellulose. The intra-oral disintegration time of the glucose tablets increased as the compression force increased. The minimum value was 83s (2%, 0.04t/cm²) and the maximum 203s (10%, 0.12t/cm²). The results of a multiple regression analysis showed that the tablet hardness correlated closely with the concentration of microcrystalline cellulose in the tablets and the compression force applied. The factors influencing the characteristics of the glucose tablets prepared in this study could be quantitatively analyzed by a multiple regression analysis.

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To examine the effectiveness of metformin (Met) in combination with sulfonylurea (SU) or α-glycosidase inhibitor (α-GI) or both SU and α-GI, 120 type 2 diabetes mellitus with obesity and insulin resistance have been included in a prospective study at both outpatient and inpatient clinics at Tokyo Metropolitan Futyu Hospital. Met treatment of 500mg or 750mg/day was administered in all groups.
A significant reduction in the hemoglobin A _1c levels along with improvements in the insulin resistant index were observed for the α-GI + Met group after 6 months, and also for the Met monotherapy, SU+ Met and SU+α-GI+Met groups after 12months. Only 7 patients showed transitional adoversed effects such as gastrointestinal symptoms (nausea and vomiting), but no patient experienced lactic acidosis.
In conclusion, 1) as indicated in the Japanese medication insert, the effectiveness of Met in combination use with SU was confirmed in patients previously found to be poorly controlled with SU monotherapy. In addition, the effectiveness of the non-indicated use of Met was also suggested under the following two conditions : 2) Met monotherapy in type 2 diabetes mellitus who did not respond to diet therapy was also effective ; 3) The addition of Met is also effective in patients whose glucose levels were previously poorly controlled with bothα-GI and α-GI + SU. Further study is necessary to increase the adoptions for Japanese medication inserts for type 2 diabetes mellitus patients.

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We have been recording instructions for medication management and instruction tasks (i.e. pharmaceutical care and counseling for inpatients) using the focus charting^® (FC) system. In the present study, we improved the FC system by employing check lists, and thus examined the utility of this new method. The patient focus of the medication management and instruction plan was determined based on information on patient compliance and adverse events, and pharmaceutical management was performed for each focus. The medication management and instruction history were recorded according to the basic FC system, with entry A (action) being recorded by the check list system. As a result, the minimum standards for pharmaceutical management could thus be established, to obtain a uniform quality for each patient. In comparison to the conventional FC system, the number of instructions increased, but the mean job time required to disseminate such instruction was significantly shortened. These results suggest that the present system is very useful for performing medication management and instruction tasks.

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Rifampicin's ability to induce hepatic-microsomal enzymes is well known. As a result, rifampicin has often been implicated in drug interactions by reducing the effectiveness of many drugs that are metabolized by the hepatic-microsomal enzyme system. One such well known interaction is that of rifampicin and warfarin. The concomitant administration of rifampicin and warfarin results in the need for an unusually high maintenance dose of warfarin in order to obtain the desired therapeutic effect.
The interaction between warfarin and rifampicin was investigated. The patients treated with rifampicin were selected from the prescription database file made for the prescriptions order entry system, and which contains all the prescriptions filled for the inpatients and outpatients. Thirty patients were treated with rifampicin between July 2000 and June 2001. Four of them used warfarin concomitantly during the study period. Decreased INR values were observed in all patients between 5 and 10 days after the initiation of rifampicin therapy. To maintain proper INR, rifampicin therapy resulted in the need for a two-to three-fold increase in the warfarin dosage. Subsequently, low INR/Dose values were observed during the concomitant use of warfarin and rifampicin (30%-50%). A decrease in the anticoagulant activity of warfarin frequently occurs when rifampicin is used concomitantly. After the initiation and discontinuation of rifampicin therapy, frequent coagulation tests are required in patients treated with warfarin. In conclusion, warfarin should be used with caution when rifampicin is used concomitantly.

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