In this review, we outline the new developments in pharmaceutical practice, education and research achieved by the Department of Pharmacy of the University of Tokyo Hospital in the 15 years from 1990 to 2004.
In pharmaceutical practice, we created 1) a computer-aided total dispensing system linked to a system for the efficient examination of prescriptions, a parallel dispensing system for countable and uncountable drugs incorporating several automatic dispensing support devices, and a drug usage consultation system for outpatients using Drug Information Sheets, Drug Information Cards and leaflets, and 2) a total dispensing system for injectable drugs including those for intravenous hyperalimentation (IVH) for inpatients and home parenteral nutrition (HPN).
In the area of new dosage forms, we developed several original non-commercial, high level medications designed to improve the QOL of patients, such as buprenorphine sublingual tablets and suppositories and retinoic acid aqueous gel ointment. We also started providing consultation to patients in wards and support for raising the quality of medical treatment, and created a drug information system for medical staff and patients. Other achievements were the development of a therapeutic drug monitoring system (TDM) for organ transplantation and a total clinical research trial management system based on new GCP.
In the area of education, we created a pharmaceutical education program for bed-side training (BST) for undergraduate students of the Faculty of Medicine and a training program on pharmaceutical practice for undergraduate students of the Faculty of Pharmaceutical Sciences. We also developed a practical training program for newly graduated trainee pharmacists and a continuing education program for post-graduate pharmacists.
In the area of clinical research, we review the following four major projects : 1) Drug interactions between the new quinolone antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs), 2) PK/PD analysis of QT prolongation induced by drugs for non-cardiovascular diseases, 3) Quantitative evaluation of pharmacological effects and adverse effects of β-blocking agents based on the receptor occupancy theory, and 4) Clinical research on genotyping of drug metabolizing enzymes for the purpose of creating tailor-made treatments.

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Since 1988, hospital pharmacists in Japan have been developing clinical pharmacy services for inpatients whose aims are to promote proper drug use and effective risk management. Health insurance reimbursement fees for inpatient pharmaceutical care services have increased tremendously since 1988 and this indicates that pharmaceutical care services are highly valued.
In the United States, studies evaluating drug use are fairly common and the cost effectiveness and efficacy of pharmacist intervention have been well documented. However, in Japan there have been few such studies. At our hospital, we devised a “pharmaceutical care evaluation list”, and have used it on a trial basis to evaluate pharmaceutical care practiced for gynecology and obstetrics inpatients. During the period from October 2001 through March 2002, for a total of 286 patients, there were 101 instances of pharmacist intervention. Seventy-six instances involved duplication of therapy, improper drug use and questionable dose adjustment. In 25 instances, additional drugs or drug changes were recommended to prevent or reduce adverse effects. Of 101 recommendations made by a pharmacist, 97 (96%) were accepted by physicians.
At our hospital, pharmacist intervention in drug therapy has proved to be cost effective and helpful in promoting proper drug use and good risk management.

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The leukocyte migration test (LMT) was performed on 54 patients suspected to be suffering from drug-induced blood disorders in order to identify the allergenic drugs responsible. It was also performed on 42 patients who had been receiving the drugs but had not manifested any allergic symptoms (patients without hypersensitivity to drugs).
Leukocytopenia was noted in 72.2% of the 54 patients suspected of suffering from drug-induced blood disorders, throm-bocytepenia in 42.6% and erythrocytepenia in 42.2%. The positive rates for the LMT were 66.7% in these 54 patients and 7.1% in the 42 patients without hypersensitivity showing that the positive rate was significantly higher in the patients suspected of suffering from drug-induced blood disorders than in the patients without hypersensitivity to the drugs (p<0.0001, X²-test). The positive LMT rate was 88.5% in a short latent period (<10 days) group and 46.4% in a long latent period (10 days) group. Thus, the LMT positive rate was significantly higher in the short latent period group than in the long latent period group (p<0.01, X²-test). In addition, the incidence of serious blood disorder cases was significantly higher in the short latent period group than in the long latent period group (p<0.01, X²-test).
Our findings indicate that the LMT is a valuable method for identifying allergenic drugs in drug-induced blood disorders and that drug allergies are greatly involved in the pathogenesis of short latent period blood disorders.

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In our institution, the data management technique used for CRC activities during clinical trials and clinical studies conducted after marketing was introduced into PMS (Post Marketing Surveillance) in October, 1999. Through obtaining the evaluation item, laboratory and adverse drug reaction data needed for surveillance from the site of treatment and recording them as source data, we have been aiming to raise the quality of PMS data.
We investigated the implementation status of the CRC data management technique in the period from April, 2002 to March, 2004 and discuss the findings in this report.We focused on the strong subjective element in making judgments concerning abnormal changes in laboratory values connected with safety and felt that obtaining a coefficient of variation for each laboratory parameter would enable reference values to be provided, which would lead to more objective judgments. Total bilirubin (TB) had the largest coefficient of variation, followed by BUN, ALT, and AST. Electrolytes such as Na, K, and Cl, had very small coefficients of variation.
The utilization of post-marketing clinical laboratory data was also reviewed, through which we found that in the case that no data was available for the time directly before beginning administration, data for a period up to 3 months prior to administration could be used. Doing this enabled the amount of missing measurements to be gradually reduced and the use of available data to be expanded.

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Medical errors in cancer chemotherapy cause serious harm to patients. As pharmacists, we have to be actively involved in ensuring that anti-tumor drugs used in chemotherapy are used properly. In our hospital, doctors in charge of chemotherapy have been obliged to submit patient protocol sheets to the Department of Pharmacy since October 2002. Up to the end of September 2003, a total of 159 patient protocol sheets had been submitted by doctors from 8 different departments. We examined these patient protocol sheets together with the patient drug profiles. Inquiries were made concerning 53 cases and prescriptions were changed for 23 cases. Thus medical errors were avoided through liaison between ward pharmacists and doctors in some cases. We consider that our system is useful for ensuring that anti-tumor drugs are used properly and plan to improve it further in the future.

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In the present study, we tested 7 slimming supplements imported by individuals from China for pharmaceutical adulterants using a combination of GC/MS and HPLC/photodiode-array systems. Adulterants detected were the appetite suppressants fenfluramine (FEN), which has been banned in the US since 1997 for damaging heart valves, N-nitroso-fenfluramine (NFE; FEN derivative), which has caused life-threatening liver damage and mazindol (MAZ), a sympathomimetic amine similar to an amphetamine. Two of the supplements contained FEN (3.8 and 1.5 mg/capsule) and one each contained NFE (4.9 mg/capsule) and MAZ (0.2 mg/capsule). Such supplements are potentially hazardous to health but people are unaware of the risks since they do know that drugs have been added. In the case of pharmaceuticals, extensive efficacy and safety testing must be conducted before they can be approved for sale. However since dietary supplements are considered to be nutritional foods rather than pharmaceuticals, such testing is often not conducted. Furthermore, the feeling of the public that dietary supplements are not harmful in any way frequently leads to overuse and clinical problems. It would therefore be a good idea for pharmacists to provide advice to consumers and health care professionals regarding the benefits and risks of dietary supplements.

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At Ikeda Municipal Hospital, we created an order entry system for the dispensing and mixing of injections in November 2003. We then compared the numbers of injections that pharmacists mixed and administered to patients, the rates for injections mixed by pharmacists, return rates for injections mixed by pharmacists and dispensing error rates between the four months before and after introducing the system. Compared to before the introduction of the system, the number of injections that pharmacists mixed and administered to patients increased by about 40%, the rate for injections mixed by pharmacists increased by 2% and the return rate for injections decreased by approximately 1%. The dispensing error rate decreased to 0.26%, a marked drop from the 2.23% error rate before introducing the system. Based on these results, we felt that our order entry system for the dispensing and mixing of injections was very useful.

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We conducted a survey of the terms used to describe epileptic seizures in package inserts to clarify the inconsistency in such terms and considered whether they could be due to the changeover to the revised classification of epileptic seizures.
On the basis of clinical syndromes, and electroencephalograms (seizure types and interictal expressions), the terms used to describe epileptic seizures in classifications from before 1981 were brought into line with those in the classification of the International League Against Epilepsy (ILAE) drawn up in 1981. We investigated the terms used for epileptic seizures and their degree of adherence to the new classification system for the package inserts of 42 original epilepsy products which were selected by doing searches using the key word “antiepileptics” h in a general search and epileptic seizures for a search in the “indications” section on the website of a package insert information provider (http://www.pharmasys.gr.ip/; as of April, 2003).
The terms used for epileptic seizures in the package inserts were based on the revised classification, old classifications, or both classifications. Further, about half of the package inserts used both the revised and the old terms in the same item and in some of the descriptions of the terms, the old term was used after the new one. Only one of 9 pharmaceutical products marketed since 1981 conformed to the new classification.
The results of the present study suggest that the inconsistencies in epileptic seizure terminology in package inserts is not due to the changeover from the old to the revised classification.

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Congestive heart failure is the most common reason for admission to hospital. For such patients, various interventions by nurses could enhance quality of life and reduce the need to be readmitted at a later date. As patients' lack of compliance regarding medication and diet are frequently contributory factors in early readmission, both nurses and pharmacists should play a more active role in patient education, for which purpose it would be necessary to have a greater knowledge of the medical treatment and care of patients. In this regard, as we were unsure of whether nurses had an adequate knowledge of the pharmacology required for the medical treatment of cardiovascular diseases or not, we conducted a questionnaire survey of nurses working in cardiology and cardiovascular surgery wards. The departments of pharmacy and nursing collaborated on administering the questionnaire, which asked questions concerning the contraindications and precautions of medicines used in such treatment. Correct response rates were 92%, 83%, 90%, 90% and 95%, for carvedilol, carperitide, digoxin, amiodarone and dopamine, respectively.
It is essential for nurses working in cardiology to have a perfect knowledge of the points targeted by the questionnaire because they concerned the basic pharmacology of medicines regularly used. This was particularly so for Carvedilol, a β-blocker, which was frequently used for ischemic heart disease as well as chronic heart failure.
The nurses may not have had a sufficient knowledge of the pharmacology of the drugs targeted by the questionnaire because there were limited opportunities for them to acquire it in the course of their work. The results of our questionnaire indicated that pharmacists need to provide the optimum amount of drug information to nurses. We also feel that it may be necessary to draw up educational programs for them in collaboration with physicians and senior nurses.

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We report on a case of rhabdomyolysis induced by Shakuyaku-kanzo-To, a herbal medicine for spastic muscle pain. The patient was a 76-year-old female who received Shakuyaku-kanzo-To (TJ-68) and dichlofenac for lumbago. Fifteen weeks later, she was admitted to hospital because of liver dysfunction as determined from increases in AST, ALT and LDH. She was diagnosed with rhabdomyolysis due to marked elevation of CPK and myogloblin levels. The hypertension, hypokalemia and reduced renin and aldosterone levels that were also noted suggested that the rhabdomyolysis was associated with pseudoaldosteronism caused by the licorice extracts contained by Shakuyaku-kanzo-To. We confirmed that blood levels of glycyrrhetinic acid (257 ng/mL), a licorice component known to induce pseudoaldosteronism, were high and found the serum cortisone/cortisol ratio (O.09) to be low indicating reduced activity of 11 β-hydroxysteroid dehydrogenase, which catalyzes the conversion of cortisol to cortisone. The results we obtained suggested that blood glycyrrhetinic acid levels and cortisone/cortisol ratios could be used as diagnostic indicators for pseudoaldosteronism caused by herbal remedies containing licorice extracts.

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