The purpose of this study was to evaluate the distribution of CPT-11 and its active metabolite, SN-38, in both pleural and pericardial fluid after intravenous administration.
Two patients with lung cancer were intravenously treated with 60mg/m² CPT-11 on days 1, 8, and 15. The CPT-11 was detected in the pleural fluid 1.5 hrs after the start of intravenous infusion, and its level reached a maximum 24 hrs later. Similarly, the active metabolite SN-38 was detected in the pleural fluid 1.5 hrs after the start of intravenous infusion. In addition, the SN-38 concentration in the pleural fluid was almost as high as that in the plasma 24 hrs later. These results suggest that intravenously administered CPT-11 may penetrate into the thoracic cavity and therefore be metabolized into SN-38 there. The maximum concentrations of CPT-11 and SN-38 in the pleural fluid to the corresponding plasma levels were 20. 4 % and 28. 5%, respectively. In addition, the AUCs of the lactone form of SN-38 were much lower than that of the carboxyl form in the pleural fluid.
CPT-11, SN-38 and SN-38 glucronide all showed similar pharmacokinetics in the pericardium to that in plasma.

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Guanidine hydrochloride, which is known to be effective in the treatment of Lambert-Eaton myasthenic syndrome, is very hygroscopic. Therefore, the mixture of the drug and lactose dispensed at hospital pharmacies tends to easily liquefy even under ordinary storage conditions because of poor compatibility. In this study the physicochemical and chemical stabilities of commercially available guanidine salts, namely hydrochloride, nitrate, carbonate, and sulfate, were investigated at various relative humidity levels. The critical relative humidity of the hydrochloride salt was significantly lower than the others and it was also more hygroscopic than the other three salts, however, nitrate was found to be sufficiently stable regarding humidity. The powder maintained a good flowability after long storage periods. The optimal diluent was selected to use in powders consisting of guanidine hydrochloride in order to stabilize the physicochemical and chemical properties. No solidification or change in appearance were observed in the mixture of the drug and magnesium aluminometasilicate (Neusilin^® US₂) as diluent and moisture adsorbent. The flow property (angle of repose) of this mixture was also investigated.

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The department of pharmacy which is a member of the Infection Control Committee in Kouseiren Chu-nou Hospital provided a systematic program of vancomycin (VCM) therapeutic drug monitoring (TDM) and consultations regarding the suitable dose and administration interval etc. of VCM for both patients and physicians. However, in many cases the initial dosage and dose interval were empirically decided by the physician.
In the present study, we retrospectively examined three nomogrames that were recommended as the rough standard for determining the initial dosage and dose interval, in comparison to the Bayesian method, based on our hospital data collected from adult MRSA patients. We also compared our findings with the Moellering's method, Matzke's method, Maeda's method and the Population mean methods.
Maeda's method did not predict the serum trough and peak levels that reach poisonous ranges. Maeda's method was found to be a safe method. In addition, Maeda's method was found to reach the therapeutic ranges the most frequently of the four methods. Furthermore, the calculations for Maeda's method were simpler than the other three methods. Accordingly, it is possible to easily calculate the initial dosage and dose interval in the clinical field. The serum VCM concentrations should thus be measured for each patient, as soon as possible, to correct the dosage using the Bayesian forecasting technique, because the therapeutic ranges sometimes deviate from the predicted range.

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The most important aspect of an indwelling inter vascular catheters is to maintain the patency of the catheter. We recently developed a Heparin Lock Flush Solution Kit for use with center vein catheters (only in use at our Hospital). The kit consists of a syringe filled with 9 mL of normal saline (NS) and 1 mL of heparin (1000 IU/mL). We performed the following tests to evaluate the stability, sterility, seal, and dust identification in the preparation. The stability and sterility data indicated that heparin maintained its potency and had no bacterial contamination for 3 months. Testing the seal of the syringe indicated that the seal remained patent at a temperature range of 5°C to 60°C. We also found that even if we sterilized a syringe made of polypropylene using ethylene oxide gas (EOG), no toxins (i.e., ethylene oxide, ethylene chlorohydrin, ethylene glycol) were produced. Next, we examined the preparation time and cost to evaluate the practical benefit of developing the kit. According to our results, the estimated preparation time and cost were 43% and 29% less than for previous methods, respectively. Finally, we put a label on the medicine kit to prevent any misuse by the medical staff.

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To elucidate the effect of the concomitant usage of other drugs on the occurrence of mucositis during and after chemotherapy, we investigated prescriptions for pediatric patients with hematological cancers at Kanazawa University Hospital, focusing particularly on drugs that have an adverse effect of xerostomia.
The patients were divided into two groups consisting of methotrexate-treated (MTX group) and other-anticancer-drug-treated patients (non-MTX group). The occurrence of mucositis in the MTX group was significantly higher than in the non-MTX group.
In the MTX-group, the number of concomitantly used drugs during a one-week period after chemotherapy was 6.18 in patients with mucositis and 2.95 in patients without mucositis. In the non-MTX group, there were 3.38 or 3.56 concomitantly used drugs in patients with or without mucositis, respectively.
The concomitant drugs were divided into xerostomia-inducing and non-xerostomia-inducing drugs and there-after were classified into pharmacological groups. The occurrence of mucositis was higher among patients using xerostomia-inducing drugs than among those using non-xerostomia-inducing drugs with an exception of diuretics, and this tendency was more prominent in the MTX group than in the non-MTX group. It was recently documented that mucositis was significantly associated with xerostomia during 5-fluorouracil chemotherapy. Therefore, it is assumed that the concomitant usage of xerostomia-inducing drugs reduced the saliva flow, leading to mucositis.
We conclude that the concomitant use of xerostomia-inducing drugs is one of the factors that influence the occurrence of mucositis during chemotherapy with MTX and other anticancer agents. It is recommended that the use of xerostomia-inducing drugs should thus be avoided as much as possible to decrease the occurrence of mucositis during chemotherapy.

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The concomitant use of oral iron preparations and antacids causes iron to form macromolecular polymer thereby reducing its absorption as a result of a pH elevation in the stomach. We measured the Iron recovery after ultrafiltration to assess macromolecular polymer using sodium ferrous citrate (SFC) and ferrous sulfate (FS) preparations plus eight types of antacids Aluminum hydroxide (Al), Magnesium oxide (Mg), Calcium carbonate (Ca), and Sodium bicarbonate (NaHCO₃) preparations and four combinations.
The samples were mixed under two conditions : (1) a mixture of the maximum single oral dose of each iron preparation and an antacid dissolved in a hydrochloric acid solution adjusted to various pH levels (4, 5, 6, 7, 8, and 9) (2) pH not adjusted. Iron recovery rate was measured using the O-phenanthroline method after ultrafiltration (fractions with a molecular weight of 10, 000).
As a result, we obtained the following results : (1) the iron recovery rate decreased according to elevation of pH. In addition, macromolecular polymer formation was pH dependent. The iron recovery rate of FS when mixed with all antacids except Mg was less than 60 % at a pH of 7. The iron recovery rate of SFC was not less than 60% at a pH of 7 with any antacid. (2) the iron recovery rate of FS when mixed with Ca, NaHCO₃, the Al + Mg combination and Mg was less than 60%. The iron recovery rate of SFC was less than 60 % with only Mg.
FS formed macromolecular polymer in the presence of Ca, NaHCO3, the Al+Mg combination and Mg. As a result, the iron absorption was suggested to decrease when FS was administered with these antacids. SFC showed little formation of macromolecular polymer in the presence of antacids, and it was therefore suggested that the absorption would only be slightly influenced by the concomitant use of SFC with antacids. Therefore, the formation of macromolecular polymers differed between the two oral iron preparations, FS and SFC, when mixed with antacids. These findings suggest that iron absorption may differ between FS and SFC in concomitant use with antacids.

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Allopurinol is often used for the treatment of patients suffering from gout and hyperuricemia. However, adverse effects due to the accumulation of oxipurinol, the main active metabolite of allopurinol, have been reported in patients with renal insufficiency. Therefore, in order to prevent such adverse effects, some guidelines for the optimal dosage of allopurinol have been advocated. To evaluate these guidelines, the serum oxipurinol concentration in 101 patients with hyperuricemia treated with allopurinol was measured by HPLC. The serum oxipurinol concentration/dosage increased (p< 0.01) as the creatinine clearance level decreased. In addition, to evaluate the optimum dosage based on the renal function, Ccr was classified into three groups (Ccr≤30mL/min, 30mL/min<Ccr≤50mL/min, Ccr< 50mL/min).
A positive correlation was observed between the dosage of allopurinol and the serum oxipurinol concentration in each group (Ccr≤30mL/min, Ccr< 50mL/min : p< 0.01 30mL/min< Ccr : ≤50mL/min : p< 0.05).
Regarding the serum oxipurinol concentration/dosage in each group, it increased as the creatinine clearance level decreased (p< 0.05).
Based on our findings, the optimal dosages of allopurinol in each group in Japanese are considered to be as follows :
1) Ccr≤30mL/min : 50mg/day
2) 30mL/min< Ccr≤50mL/min : 100mg/day
3) Ccr< 50mL/min : 200mg/day

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When a novel additional adverse effect is reported for a marketed medicine, the medical information leaflet has to be revised to inform physicians and pharmacists of this. Pharmacists are responsible for informing patients of early warning symptoms to avoid the subsequent appearance of severe adverse effects. However, at present, patients may suffer from severe adverse events because such symptoms may remain unrecognized until the medicine is on the market. As a result, investigations to predict and prevent novel additional adverse effects of medicines are required. In this study, we investigated a novel additional adverse effect classified as a pharmacological effect based on the drug safety update (DSU). As a result, skin disorders including toxic epidermal necrolysis and Stevens Johnson syndrome, and pseudomembranous colitis have become evident as additional adverse effects of antibiotics, with a high incidence. In addition, neuroleptic malignant syndrome and aplastic anemia have also been reported as adverse effects of central nervous system agents.
Therefore, it is important to provide patients with information about the early warning symptoms related to such adverse effects, even though such adverse effects are not contained in the patient information leaflet.

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Patient education is believed to be an effective treatment in patients with diabetes mellitus, and diabetes mellitus education classes play an important role in patient education. During this study, we evaluated the effects of a diabetes mellitus education class that was developed as a result of the findings of an antidiabetic drug-awareness questionnaire entitled : “Self-diagnosis for Proper Drug Use.”
Eighty patients participated in the diabetes mellitus education class that was held at our hospital from January to April 1999. A total of 66 patients (65.7+ /-8.6yr, 31 male, 35 female, BMI 22.3+ /-4.4kg/m²) who replied to the questionnaire “Self-diagnosis for Proper Drug Use” were included in the study. Sixty-five patients who attended the “Drugs Often Used for Diabetes Mellitus” lecture between October 1999 and January 2000 were included as controls. The questionnaire “Self-diagnosis for Proper Drug Use” focused on group work, and included questions that the patients could easily answer about their medication. Changes in blood sugar control index (HbAlc value) were measured when patients attended the education class, and 6 months and 1 year after the class.
In the group taking a self-diagnosis for proper drug use and controls, the mean HbAlc level at 6 months was (6.36+/-1.01%), (6.88+/-1.14%) and that of about 1 year was (6.44+/-1.40%), (6.74+/-0.82%). However, in comparison to the controls, a significant difference was seen in the degree of improvement in HbAlc levels about 6 months and 1 year later (p = 0.02). These findings suggest that the diabetes mellitus education class that was introduced by“ Self-diagnosis for Proper Drug Use” had a positive influence on patients with diabetes and thereby helped these patients to achieve proper blood sugar control levels.

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Recently, pharmaceutical care is increasing in importance. Pharmacists must provide pharmaceutical counseling services that can satisfy all patients. However, there are limitations in manpower and a lot of effort has to put devoted to using such manpower as effectively as possible. With this in mind, we developed a medication consultation support system for pharmacists to achieve an improved medical quality. As a result, labor saving results were obtained in document preparation of medication histories, laboratory test histories, and medication instruction records. Furthermore, the total work need to create medication instruction daily reports, monthly reports, etc. also decreased. As a result, the time and work pressure experienced by pharmacists decreased while the overall quality of this system was maintained.

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We retrospectively examined the effects of the combination of zonisamide (ZNS) on the serum valproate (VPA) concentrations in 10 epileptic patients. The serum VPA concentrations at a steady state in VPA and ZNS combination therapy was about 1.1 times as high as those in VPA monotherapy (p<0.01). Furthermore, the extent of change in the VPA concentrations ((VPA concentration in the combination therapy of VPA and ZNS) / (VPA concentration in the VPA monotherapy)) tended to increase in proportion to the serum concentration of ZNS. These results suggest that the pharmacokinetic interaction between these drugs may be clinically negligible, however the serum VPA concentrations should be carefully monitored when the serum ZNS concentration is high.

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Dissolution tests of acetaminophen filled into the gelatin capsules (SHIONOGI QUALICAPS, Japan) and hydroxypropylmethylcellulose (HPMC) capsules (SHIONOGI QUALICAPS, Japan) were performed after the cap-sules were stored under conditions of 30°C/60%RH for one year, 40°C/75%RH for 6 months, or 60°C for one week. The Japanese Pharmacopoeia 1st fluid, acetic acid buffer (pH4.0), Japanese Pharmacopoeia 2^nd fluid and purified water were used as dissolution media. The dissolution profiles of the gelatin capsules changed significantly in comparison to those of the initial profiles after the capsules were stored at 40°C/75%RH for 6 months or 60°C for one week. On the other hand, no delay in dissolution was observed for the HPMC capsules.
Dissolution tests were additionally conduced using three commercially available HPMC capsules (SHIONOGI QUALICAPS, Japan ; CAPSUGEL, USA ; SHOGHUN, Korea), and the dissolution profiles of the HPMC capsules of SHIONOGI QUALICAPS were thus found to be independent of the dissolution medium, while the others showed different dissolution profiles depending on the dissolution medium.

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We have recently instituted an audit system with the goal of maintaining and improving quality in pharmaceutical management and counseling services, i.e., pharmaceutical care practices. This system was created to improve the quality of record keeping for counseling services. The audit system is composed of 5 supervising pharmacists. A meeting is held once a month, and an audit is carried out concerning the patient compliance instruction documents, medication history and practice records of 2 clinical departments. In addition, methods for improving business efficiency are also discussed. We herein report on the specific guidance given to the supervising pharmacists of each clinical department, based on a total of 12 audit conferences. As a result, four problems were identified : (1) fundamental description issues, (2) record keeping modes, (3) insurance demands, (4) pharmaceutical perspective. The following improvements were instituted after notifying the relevant pharmacists and all other pharmacy staff of these problems : a reduction in the leakage of specific items, corrections of the records explaining the pharmacological effects, establishment of a drug interaction checklist, simplification of laboratory data records, simplification of the format, utilization of a problem list field, and other issues. The role of this audit system in maintaining and improving the quality of pharmaceutical management and counseling services has become increasingly important because as the counseling services for patients continue to expand.

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In February 2000, a Drug Safety Emergency Bulletin reporting that some patients taking Benzbromarone developed fulminant hepatitis as a side effect was reported on newspapers and TV. We made a counter survey regarding how patients received this news. The aim of the present study is to consider how a pharmacist should behave when a similar situation occurs in the future.
We selected patients taking Benzbromarone from the medication records and checked their liver function value from their charts. We discussed with the doctor about the patients whose liver function values indicated abnormal levels.
After discussions with doctors, we decided to give the information to the patients and surveyed them individually. We recorded the contents on their medication records and the records of our inquiries.
Seventy-five% (43/57) of the patients noticed the report and their reactions varied. Some patients did not know about the reports or did not recognize that the medicine reported was the same as one they were taking. We also gave information positively to these patients.
After giving the information, 81 % (47/58) of the patients continued to take Benzbromarone. We thought that a positive explanation given by pharmacist could minimize the anxiety of such patients, as a result, they were taking the medicine with an increased understanding.
As a result of the survey, we found how the patients reacted to the side effect reports and recognized again that it was important to communicate with the patients individually in such instances.

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To study the realities of medications that patients fail to pick up, we devised a system of countermeasures for medications that are not picked up by new and returning outpatients. We then compared the countermeasures before with the countermeasure after using our plan. For new outpatients, we routinely telephoned them after work. If there was no answer, then we sent them a letter by mail at the start of next day's work. For returning outpatients, we sent them a letter by mail similar to that sent to new outpatients if not received within a week. At the same time, we placed a notice on the chart in order to request that the doctor contact the outpatients.
As a result of these countermeasures, for new outpatients, the rate of abandoned medicines decreased from 54% to 38%. For returning outpatients, there was a significant decrease from 26% to 10%. No medications were abandoned as result of these notices. The cooperation by doctors, pharmacists and secretaries made this countermeasure plan a success.

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When a pharmacist informs a patient of premonitory symptoms to prevent any adverse effects of each prescribed medicine, such instructions are often to complicated to be understood by the patients, mainly due to the fact that numerous medicines have a wide range of adverse effects, and furthermore, an such adverse effects have many premonitory symptoms. We attempted to make a computer aided adverse effect informing program to assist pharmacists. This program arranges the symptoms according to their order of importance, and gives the probable information of adverse effect, which is not mentioned in the package leaflet. The most frequent and common premonitory symptoms of adverse effect were suggested to be fever and fatigue as a result of running the program when many individual patient prescription data were inputted.
The incorporation of this program into the computer system that manages the patient's medicine history will be useful for pharmacists to inform patients of understandable premonitory symptoms and to monitor any potential adverse effect.

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Regarding the management of blood preparations, since September 1995 the Ministry of Heath, Labour and Welfare has had to make and/or to keep documentary records such as the product name, date of dispensing, the patient's name and lot number and so on. At Yamanashi Medical University Hospital, to cope with deleterious accidents caused by blood preparations, we developed a new system for the management of blood preparations. This system consists of a printing system for confirmation labels for blood prescriptions and a computerized management system concerning the medication. In this study, the effect of this new management system on the rational use of blood preparations was evaluated. Compared with the former system, the time required to dispense blood preparations decreased from about 500 to 170 seconds per case. Furthermore, based on a questionnaire to medical doctors and/or nurses, it appeared that this system could reduce the time required to manage blood preparations and improve the rational use of injectable drugs.

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Our hospital established a Center for Clinical Research of New Drugs and Therapeutics in April 1999. The Center consists of 6 departments : i.e. departments which help to coordinate clinical research, which help to manage the investigated drugs, preview clinical research study protocols, coordinate clinical research, educate research staff and support clinical research at other medical institutions. Pharmacists are involved in all 6 departments of the Center and have been playing various roles. Under this situation, the Institutional Review Board (IRB) started to review investigator-initiated clinical research on drugs, regarding the study protocol, written information (IC) for trial subjects and other information about the drugs beginning in January 2000. All research was performed according to the new Good Clinical Practice, but studies were initiated without providing sufficient compensation in cases of severe adverse drug reactions. The IRB reviewed thirty-four clinical research protocols from January 2000 to December 2001 and an average of 1.5 cases were reviewed by the IRB per meeting. The average reviewing time was 28 minutes (max. 68 minutes). Sixteen, eight, eight and two protocols of clinical research involved Phase III, I/II and II trials and medical instruments, respectively. Considerable clinical research has been performed by such departments as Internal Medicine I, II and Urology, in particular.
We recognized that considerable clinical research has been performed with unapproved drugs at our hospital. After the IRB review, pharmacists played various important roles, e.g. dispensing test drugs, preparing some manufactured drugs and confirming the written informed consent. However, up to now the clinical research coordinator (CRC) has not sufficiently supported these studies. The CRC should thus support this research by improving the quality of these studies and the safety performance for patients.

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