We investigated the usefulness and effectiveness of iontophoresis (IP) for the delivery of lidocaine in local anesthesia during shunt puncture for patients undergoing dialysis since IP has not previously been used for this purpose. Initially, we determined the optimal dosing time and concentration of lidocaine in 14 healthy adults by the pin prick method, finding that the administration of a 1% lidocaine solution by IP for 15 min induced significant local anesthesia and the anesthetic effect was comparable to that achieved by Lidocaine tape (Penles^®) for 120 min. These two methods of administering local anesthesia were also similar as regards adverse reactions. We then investigated the usefulness of IP for delivering the 1% lidocaine solution for 15 min in obtaining local anesthesia for shunt puncture in 14 patients undergoing dialysis. Again there was no marked difference in the local anesthesic effect between IP and Penles^®. The incidence of adverse reactions, however, was significantly lower with IP than with Penles^®, though there was no difference in the degree of patient satisfaction. These findings suggest that the administration of lidocaine via IP is superior to Penles^® as a method of delivering lidocaine, and would be useful for patients undergoing dialysis who have forgotten to apply Penles^® before dialysis sessions at a hospital and patients in whom the puncture site has to be changed due to dermal disorders.

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We prepared data sheets to consolidate information on adverse reactions occurring in combination chemotherapy. Using them, we monitored adverse reactions due to combination therapy consisting of vincristine, nimustine, carboplatin, interferon-β and radiation therapy (VAC-F-R) in 50 patients with brain tumors, and evaluated their severity using the Common Terminology Criteria for Adverse Events v.3.0. The incidences of adverse reactions due to the VAC-F-R protocol were then compared with that for adverse reactions due to existing monotherapy. With VAC-F-R, a high incidences were observed for appetite loss (86%), nausea (68%) and vomiting (34%), and the incidences of leucopenia and thrombocytopenia with grade 3 or higher were 60% and 24%, respectively. Vomiting and fever could be prevented by pretreatment with a 5-HT₃ receptor antagonist and non-steroidal anti-inflammatory drugs. While the incidences of the unpreventable adverse reactions were 1.5-to 5-fold greater than those seen with monotherapy, there was no difference in the time of the nadir for leucopenia and thrombocytopenia as compared to monotherapy with nimusitine.
Our efforts to consolidate information on adverse reactions due to a particular chemotherapy regimen have helped decrease their severity in cancer patients and improve their quality of life.

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Anti-microbial drugs are used for both the treatment and prevention of microbial infections. Though they are used under the guidelines issued by various academic societies, physicians play an active role in the selection of anti-microbial drugs and determination of their dosages. Pharmacists should therefore actively participate in the design of prescriptions for anti-microbial drugs. We studied the effect of pharmacists' interventions in the use of injective anti-microbial drugs by comparing their use in in-patients before and after intervention.
When pharmacists intervened, no aggravation of patients' conditions or anti-microbial resistance occurred, leading to a significant decrease in anti-microbial drug usage and duration of their administration. During the time of our study, our hospital's Infectious Committee established a system for the appropriate use of anti-microbial drugs suggesting that the interventions by pharmacists in the treatment of patients had been seen as important.

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Valproic acid (VPA) and phenytoin (PHT) are commonly used as antiepileptic drugs. They are metabolized by various pathways, and their metabolites are mainly excreted in the urine and bile. Studies on their metabolism in humans have been mainly performed after administration as a single drug but very few have been done for the case that these antiepileptic drugs are administered with each other. In this paper, we studied the effect of the co-administration of these drugs on their individual metabolism in humans. The concentrations of the antiepileptic drugs and their metabolites in urine and plasma were measured by liquid chromatography-mass spectrometry (LC-MS). In two patients administered only VPA as an antiepileptic agent, 60.9% of the dose (54.3%, 67.6%) was excreted as VPA-glucuronide (VPA-G). This result was similar to that reported in other papers. However, when VPA and PHT were co-administered in 5 patients, the excretion of VPA as VPA-G was 49.4±10.5% (mean±SD). This result was lower than that reported in other papers. VPA-G was detected in the blood of 2 of the five patients. The urinary excretion amounts of p-hydroxyphenyl-phenylhydantoin (p-HPPH), and p-HPPH-G for the five patients given PHT as well as VPA were 2.0, 0.8, and 40.3%, respectively, of the amount of PHT administered. The urinary excretion percentage of p-HPPH-G was lower than that reported in other papers. These results indicate that the co-administration of VPA and PHT reciprocally inhibited each other's glucuronidation and reduced the urinary excretion percentage.

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In consideration of the proposal to base the rational use of biapenem, a carbapenem antibacterial agent, on pharmacokinetic/pharmacodynamic (PK/PD) theory, we created software to support the planning of biapenem administration based on a PK/PD approach using the Monte Carlo simulation. The software was created using a macro-program written in visual basic language for applications on Microsoft Excel. To predict values for the PK/PD parameters ‘time above the minimum inhibitory concentration (T>MIC)’ and probability of target attainment for approved biapenem dosage regimen against various bacteria populations, the Monte Carlo simulation was performed for 10000 subjects using the Crystal Ball^® embedded pharmacokinetic program MULTI-Win. Variability in pharmacokinetic parameters and MIC distributions were obtained using OMEGACIN^® package insert data and data from a nationwide antibiotics-susceptibility test surveillance program, respectively. When the software was used for a patient with severe pneumonia and renal failure who was undergoing haemodialysis, several dosage regimens were recommended based on T>MIC predicted from the patient's data, thereby demonstrating its clinical usefulness. Our software proved effective as a tool for supporting biapenem administration planning for individual patients, and rational use based on PK/PD theory concerning antimicrobial agents.

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It has been reported that nutritional management is an important therapeutic strategy since it may improve the results of treatment for all kinds of patient, leading to reduced incidence of infection, shortened hospital stays and savings in medical costs. In recent years, the importance of nutritional management has been emphasized in Japan, and many institutions now have a Nutrition Support Team (NST), our hospital one of them.
In the present study, changes in the nutrient intake and serum albumin (Alb) levels, a nutritional index of protein, were examined after one month of NST intervention in our hospital. Following NST intervention, mean energy and protein levels increased from 24.6±10.5 kcal/kg/day to 30.9±13.3 kcal/kg/day (n=10) and from 0.9±0.3 g/kg/day to 1.2±0.5 g/kg/day (n=10), respectively, both significant increases.
With regard to serum Alb, the mean level was as low as 2.6±0.7 g/dL (n=10) when NST intervention started and the level had not increased even after 1 month of intervention, probably because patients who were in a relatively severe hyponutritional state were included in those subjected to NST intervention. Since it seemed that the extra-vascular pool of Alb was very reduced in these patients and that it was difficult to raise Alb levels within 1 month, we consider that NST intervention should be initiated as early as possible.

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Recently, though various SPD (Supply Processing and Distribution) systems have been introduced, no progress has been made in their application to drug inventory management. In the present study, we created an SPD-system for drug products utilizing electronic patient records (EPR) and a medication support system, and examined its usefulness.
The introduction of the system greatly reduced the number of people and time required, and improved the efficiency of inventory control. It reduced the amount of money spent on drug stocks by 34.3% in six months, and in the drug storage room reduced the amount of money spent on drug stocks by 36.3% and the number of drugs by 38.7%. As a result, the amount of money actually spent on purchasing drug stocks dropped to 30.5% of the previous level. Our SPD-system provides great economic efficiency by not requiring outsourcing and has improved cash flow. It should therefore make a big contribution to hospital management.

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In order to relieve oral mucosal pain topically, we prepared a 2% mefenamic acid (MA) spray using carboxyvinyl polymer (CP, 0.25% and 0.5%) and compared it with a MA spray prepared using sodium polyacrylate (PANa, 0.2%). In the stability and dispersion tests, the MA content of the 0.25% and 0.5% CP sprays had not changed 28 days after preparation under 5 test conditions (4°C without shading, 25°C without shading, 37°C without shading, 4°C with shading, 25°C with shading). However, the MA content of the spray prepared using 0.2% PANa had decreased 3 days after preparation, demonstrating that CP was better as a dispersion agent. When the sprays were used for healthy volunteers, the salivary concentration of MA for the 0.5% CP spray was higher than that achieved with the 0.25% CP spray (0.25% CP : 3.47±1.03 mg, 0.5% CP : 4.98±1.23 mg, P<0.05).
The clinical efficacy was tested in 89 out-patients (age ranging from 18 to 91 years) with eight different diseases exhibiting oral mucosal pain, who received the 0.25% CP spray (n=48) or the 0.5% CP spray (n=41). Sixty-one patients showed an analgesic effect on application of MA spray (0.25% CP : 30 patients, 0.5% CP : 31 patients) and the mean onset of action was 1'58"±1'10" (0.25% CP : 1'56"±1'13", 0.5% CP : 2'01"±1'09").
In the case of hyperesthesia and decubitus ulcer, the analgesic effect was 100% suggesting that regardless of the concentration, MA sprays using CP are very effective in patients with oral mucosal pain other than that due to oral mucostitis.

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To ensure that highly cytotoxic cancer chemotherapy can be performed effectively and safely, it is essential to have patients understand the chemotherapy regimen they are receiving in such aspects as the efficacy of the anti-cancer agents being used, their possible adverse effects and how they will be handled, and points requiring caution in daily life. To achieve this, pamphlets applicable to a wide variety of regimens were prepared on the basis of a consensus among clinicians in various related departments, and were given to patients at the discretion of the hospital. A pharmacist provided instruction on the respective drugs using the pamphlets and conducted a questionnaire survey to determine patients' assessments of this instruction. The results of the questionnaire showed that 95.8% of the patients surveyed found it “Useful”, 77.1% answered that they felt “Relieved” and 72.9% answered that they had “No increase in anxiety”. On the other hand, 12.5% of the patients complained of “Anxiety” and 16.7% answered that “Some points are difficult to understand”. The findings of the present study indicated that it is very useful for a pharmacist to give relevant information to patients receiving a variety of drug regimens using pamphlets, and patients should ask any questions or mention any anxieties they may have when receiving such instruction.

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Very little information is available on the quality of generic products. In this regard, it has recently been reported that several adverse reactions, among them angialgia and phlebitis, occurred when generic versions of injectable ritodrine hydrochloride products were used in pregnant patients and that these adverse reactions subsided when the generic products were switched to the original product. This suggests that the generic products contained impurities that caused the adverse reactions. It is therefore essential to determine the constituents of generic products and compare them with those of the original product.
On doing this for the original and generic ritodrine hydrochloride products using high performance liquid chromatography, we found that 4 out of the 8 generics examined contained significantly higher amounts of impurities than the original product. In addition, it seemed that the generics contained unidentified impurities that were not present in the original product. For the other four generics, there was no difference in the proportion of impurities between them and the original product. These results suggest that there can be a great difference in quality between the original product and some generics. We must therefore choose generics based on quality information to minimize unpredictable adverse reactions so that more cost effective therapy may be achieved.
In the present study, we obtained information on the quality of a particular group of generic products, but we feel it is necessary to gather information on more generic products to ensure safety when using them.

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In recent years, combination therapy with IFNα-2b and ribavirin has become a standard treatment for chronic hepatitis C. However, combination with ribavirin often causes severe hemolytic anemia which reduces of the effect of therapy.
The total clearance of ribavirin (CL/F) calculated in consideration of sex, age, body weight and creatinine serum concentration is correlated with the serum concentration of ribavirin in the 4th week of therapy. In the present study, we evaluated the usefulness of CL/F based rivabirin dosages and to do this, analyzed the serum concentration of ribavirin and change in hemoglobin levels in both patients who received a CL/F based ribavirin dosage and patients who received a body weight based ribavirin dosage. Based on the CL/F based ribavirin dosage, the patients who received a body weight based ribavirin dosage were divided into an overdose group, an optimum dose group and a low dose group. In the optimum dose group, there was a significantly small change in the hemoglobin level and the rates for dose reduction and withdrawal of ribavirin were low, as compared with the overdose group. In both the optimum dose group and the CL/F based dosage group, most patients had a serum ribavirin concentration of 2000-2500 ng/mL in the 4th week of therapy, which has been advocated as a safe and effective serum concentration range for ribavirin.
In conclusion, our findings suggest that ribavirin dosage adjustment based on CL/F is useful for achieving safety and effectiveness in combination therapy with IFNα-2b and ribavirin.

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The quality of the human-machine interface (HMI) in computerized physician order entry (CPOE) systems is a key factor affecting the error rate in the process of entering medication orders. The operation and functions of the HMI in CPOE systems vary among hospitals, since there is still no standardized HMI. Such differences in the HMI may lead to mistakes ; for example in drug selection and specification of the dosage regimen. The aims of this study were to investigate the usage of CPOE systems in hospitals and analyze the problems with their HMIs, by means of a questionnaire sent to doctors who use them. Replies were received from a total of 227 doctors in 17 hospitals. Nine hospitals used systems only requiring the input of up to two characters to display a list of drugs and 38.5% of their users said that they usually input no more than two characters. For greater reliability, however, CPOE systems should require users to input at least 3 characters to select a branded drug.
The questionnaire found that no doctors felt negative towards computer-based dosage checking systems so they should be incorporated into CPOE systems. Among users who were familiar with two or more systems, 80.6% felt that there were significant differences in their operation.
In conclusion, we feel that the optimization and standardization of the HMIs of CPOE systems are essential for reducing medication errors arising in their use.

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An electronic medical records system was introduced in Okayama University hospital in May, 2003. We connected this system to the narcotics management database in the department of pharmacy to enable narcotics management to be performed properly and efficiently. The new system allows the content of narcotics prescriptions input by doctors to be reflected in the medical records. Simultaneously, this information, which consists of the prescription number, date, amount of drug and name of the department and the ID number, name, and the age of the patient, is transmitted to the narcotics management database in the department of pharmacy using Microsoft Access. It is used to make various records such as medicine lists, usage records of narcotics injections, receipt and supply lists.
The transmission of electronic clinical record data to the narcotics management database has shortened the time for the management of narcotics as compared with the previous manual practice and has helped raise the efficiency of narcotics management.

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Furanocoumarin derivatives such as bergamottin and 6',7'-dihydroxybergamottin are inhibitors of CYP3A4 and have been isolated from grapefruit juice. We developed a sensitive and specific enzyme-linked immunosorbent assay for these furanocoumarin derivatives and used it for screening a large number of citrus fruits, vegetables and crude drugs for them. On testing the juice and peel of 25 citrus fruits, significant reactivity was observed with the juice of 4 of them : sweetie, melogold, banpeiyu pummelo and red pummelo and in the case of peel, significant reactivity was observed for 4 fruits : sweetie, melogold, sour pummelo and natsudaidai. For most of the citrus fruits, the peel showed a stronger reaction than the juice. Seven vegetables were tested and only slight reactivity was observed for 4 of them : parsley, celery, Italian parsley and mitsuba. Among the twenty crude drugs tested, significant reactivity was observed for 2 : angelica dahurica root (byakushi) and bitter orange peel (touhi). These findings suggest that 4 of the citrus fruits and 2 of the crude drugs tested would exhibit strong drug interactions.

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In recent years, there has been a growing trend to use generic drugs. In view of this, we sent a questionnaire to 39 generic drug manufacturers (belonging to the Japan Generic Pharmaceutical Manufactures Association) to investigate the situation of information provided for them.
Twenty-six companies (recovery rate 66.7%) responded and their answers revealed that product information is openly provided for 80% of generic drugs ; for instance the results of dissolution tests and stability tests conducted on packaged products, biological equivalency data, and clinical information. In product summaries, the results of dissolution tests were provided for 56.1% products, and stability data for 19.6% of products. Serum concentration to time curve data was provided in an interview form for 85% of products and in package inserts for 53.3%. For more than half of all the generic drugs, information on only 3 items was available on the Internet. Further, there were wide differences among the manufacturers in the amount of drug information provided.
It was felt that manufacturers with fully functional information delivery systems already in place were making efforts to supply good quality information. Those in the process of creating information delivery systems should complete them as quickly as possible and such efforts would serve to further expand the use of generic drugs.

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We continuously injected 9 antimicrobial drugs (Viccillin^®, Pentcillin^®, Unasyn-S^®, Pansporin^®, Cefmetazon^®, Rocephin^®, Sulperazon^®, Flumarin^®, Fosmicin-S^®) intravenously into the rabbit pinna vein. For the dissolution of the drugs, we used a 0.9% isotonic sodium chloride as the physiological saline solution in a volume of either 50 mL or 100 mL. We conducted pathological examinations consisting of number of white blood cells (WBC), production of the C-reactive protein (CRP) and vascular lesion characteristics of the pinna vein as a means of determining the appearance of adverse reactions. There was no significant change in these pathological indications between before and after administration of the solutions, and there were no histological changes. This suggested that a change in volume of physiological saline used for dissolution from the usual 100 mL to 50 mL causes no problems in solubility.

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