Malignant gliomas are the most common primary central nervous system tumors. Standard therapy is surgical resection, where possible, and radiotherapy. Since adjuvant chemotherapy only provides a modest survival benefit, new therapies are necessary. Recently developed agents, such as temozolomide (TMZ), irinotecan, and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), have demonstrated efficacy against malignant gliomas. A novel oral alkylating agent, TMZ shows good penetration in the central nervous system, and it has largely replaced nitrosoureas in the treatment of gliomas. Recently, a randomized trial in which newly diagnosed glioma patients were treated with TMZ and radiation achieved enhanced survival rates. In particular, better survival rates were observed in patients with a methylated promotor of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene which encodes an alkyltransferase. Another clinical study revealed that polymorphisms found in genes encoding topoisomerase I inhibitor irinotecan-metabolizing enzymes (UGT1A1) were associated with the occurrence of severe irinotecan-induced toxicity. Overexpression of EGFR appears to be correlated with the grade of glioma and it has been reported that specific mutations in the EGFR gene are correlated with clinical responsiveness to the EGFR-TKI gefitinib. In order to achieve innovative treatment strategies in the future, it is therefore important for clinical pharmacists to have a good understanding of glioma at the molecular level since this will help in identifying patients most likely to benefit from a specific therapy. We hope that personalized medication for glioma based on genetics will increase drug efficacy and prevent or reduce adverse reactions, which in turn will improve clinical outcomes and decrease the overall costs of therapy.

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To evaluate the quality of the original theophylline sustained-release dry-syrup product and 4 generic versions on the market, we conducted a content uniformity test, dissolution test, bioavailability test, and bitter taste test on these products. Serum theophylline concentrations of the original product were investigated in 3 rats according to a test that was divided into 2 different particle sizes with the following results. For the whole preparations, the mean content was about 20% and changing the pH did affect the dissolution rate for any preparation. However, when the preparations were divided into 2 different particle size ranges, there was a large variation in content for the different particle size categories for all preparations. For preparation A, particles of less than 75μm in particle size had the highest content, for preparation B particles from 150 to 300μm had the highest content, preparation C had the highest content in the 75-150μm particle size range and the highest content for preparations D and E was in particles of over 300μm in size. For preparation A, the ratio of the content of particles of less than 75μm in size to that of particles of 150 to 300μm was about 1.7 and the ratio of the area under the concentration time curve for these 2 particle size ranges was about 2.1. In the taste test, all preparations were found to be masked sufficiently against bitterness just after administration, but 2 preparations were not sufficiently masked at 15 seconds after administration. These results suggest that some of the generic products are superior in quality to the original one and some are inferior.

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A simple suspension method has been developed for the administration of tablets and capsules by tube in which the tablets or capsules are allowed to disintegrate in hot water (55°C) without grinding or opening. However, since the stability of drugs at 55°C has been a matter of concern, in the present study, we investigated drug stability for 8 agents which are frequently administered by tube. Recovery was compared between the simple suspension method and the conventional crushing method, and the stability of each drug after making suspensions of several drugs at the same time was also investigated.
For the simple suspension method, the recovery of each drug was nearly 100% at 10 min and 2 hrs after making the suspensions. Recovery was also almost 100% on making a suspension of 3 agents at the same time. However, by the conventional crushing method, recovery for some drugs was less than 90%, with that for zonisamide being as low as 59%. This could be due to the adherence of drugs during the grinding, mixing and packaging processes.
In conclusion, the simple suspension method was considered to be a valid method of suspension since the tested drugs were stable in hot water at the temperature used for the simple suspension method. It was also considered to be valid in terms of reduced variability in the actual dosage compared with the conventional crushing method.

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It is common practice to divide rectal suppositories to obtain appropriate doses for children. However, information on how to divide suppositories and achieving accurate doses is limited. The purpose of this study was to determine optimal directions for dividing acetaminophen suppositories based on the active ingredient content of the divided portions. We also conducted a questionnaire survey of parents regarding their children's use of suppositories.
There was no significant difference in the acetaminophen content of each portion when Anhiba 200^® was divided horizontally, longitudinally, and diagonally to obtain acetaminophen half dosages. Uniformity of acetaminophen content was also obtained when three other suppositories available in Japan were divided in the same manner. However, when Fever A II^®, a suppository sold in the US, was divided, the content of the two halves was not uniform.
Twenty-eight of the 43 parents surveyed had previously divided suppositories. More than half of them (57.1%) said that they divided suppositories by cutting them horizontally, followed by 35.8% who cut them diagonally and 7.1% who cut them longitudinally. Parents who had received instruction from medical staff cut suppositories either horizontally or diagonally.
In view of our findings, we propose that pharmaceutical companies provide information on the content uniformity of suppositories when divided and pharmacists advise that suppositories are divided in a particular direction based on such information.

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Anthracyclines play an important role in the treatment of breast cancer and various regimens containing doxorubicin (A) and epirubicin hydrochloride (E), e.g., AC (doxorubicin+cyclophosphamide), EC (epirubicin hydrochloride+cyclophosphamide), and FEC (fluorouracil+epirubicin+cyclophosphamide) are widely used in clinical oncology. However, anthracyclines frequently cause inflammation or pain at the site of injection and along blood vessels. To determine the cause of phlebitis and venous pain due to these agents, we designed an experimental study to investigate factors considered to be associated with these symptoms, such as titratable acidity, osmotic pressure, and pH, for the 2 epirubicin preparations available for the FEC regimen : Farmorubicin^® (freeze-dried formulation) and Farmorubicin^® RTU (ready-to-use injection solution). We compared Farmorubicin^® and Farmorubicin^® RTU when diluted with various concentrations of saline, 5% glucose, and distilled water, and with or without dexamethasone. The titratable acidity of Farmorubicin^® RTU was 3.4 mEq/L, far less than the 7 mEq/L reported to sometimes cause phlebitis and venous pain, which suggests that the titratable acidity of Farmorubicin^® RTU is not connected with phlebitis or venous pain. The pHs of Farmorubicin^®, Farmorubicin^® RTU and dexamethasone were 4.5 to 6.0, 2.5 to 3.5, and 7.0 to 8.5, respectively. The osmotic pressures of Farmorubicin^®, Farmorubicin^® RTU, and dexamethasone were all 282 mOsm/kg. Thus pH could be modified by adding small amounts of dexamethasone, which is normally used prior to FEC therapy to avoid nausea, vomiting, and hypersensitivity to Farmorubicin^® RTU, and doing this might prevent the phlebitis and venous pain that occur during injection of Farmorubicin^® RTU.

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Recently, high dose gentamicin (GM) has started to be used for the treatment of Duchenne muscular dystrophy (DMD). Previously, since the intravenous infusion of GM for 1h once a week at a dose of 7.5 mg/kg/day had caused no significant adverse events in a course of therapy lasting 6 months, we decided to try conducting such therapy for four courses in the present study. We continuously assessed renal function by monitoring serum creatinine, serum cystatin C (Cys-C), serum urea nitrogen (BUN), urinary β₂-microglobulin and urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Serum creatinine levels were found to be much lower than the normal range, while, at 0.65 to 0.78μg/mL, serum Cys-C levels, were within the normal range and so was BUN, suggesting that the glomerular filtration rate in the DMD patients receiving GM therapy was being maintained in the normal range. Therapeutic drug monitoring of GM indicated that it was being rapidly eliminated from the systemic circulation though a slight elevation of urinary NAG activity in 1 patient indicated the possibility of impaired renal proximal tubules. It will thus be necessary to optimize our patient management strategy.

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Therapeutic drug monitoring (TDM) of blood concentrations is recommended in treatment with vancomycin (VCM). The relationship between the clinical effects of VCM and PK/PD parameters, however, has still not been sufficiently clarified and few studies on PK/PD parameters in elderly patients have been performed to date. In this study, PK parameters correlating with clinical efficacy were determined using a two-compartment Bayesian model in 63 elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) infection who were treated with VCM. This was done through comparison of a VCM-effective group (39 patients) and a non-effective group (24 patients) using logistic regression analysis. Blood trough level [odds-ratio=1.150, 95% confidence interval=1.012-1.307, P=0.0323] and AUC [odds-ratio=1.011, 95% confidence interval=1.005-1.017, P=0.0004] were identified as factors correlating with clinical efficacy. In receiver operating characteristic (ROC) curve analysis, the optimal cutoff values of the AUC and blood trough level were determined to be as follows-AUC : 420μg/mL · hr (sensitivity : 69.2% ; specificity : 79.2%), blood trough level : 10μg/mL (sensitivity : 66.7% ; specificity : 66.7%).
In conclusion, our results suggest that VCM exhibits a clinical effect in elderly patients infected with MRSA at blood trough levels of≥10μg/mL or an AUC of≥420μg/mL · hr. It is therefore necessary to determine the therapeutic course for VCM in consideration of AUC as well as the blood trough level.

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The purpose of this study was to evaluate the oral (in vivo) disintegration time of commercially available rapidly disintegrating tablets (RDTs), and to establish an in vitro disintegration test that may be used to predict in vivo disintegration times.
The in vivo disintegration time for the tablets tested ranged from a minimum of 8.32 sec to a maximum of 44.27 sec, information that will be useful for medication counseling and in the selection of products that will maintain high patient compliance. The in vitro disintegration times were determined using the JP XIV disintegration test apparatus in which the attached Distopper^® electronic sensor automatically determines in vitro disintegration time. The results were well correlated with the in vivo disintegration times (r²=0.88), and the slope was close to 1 for the majority of RDTs (30 of 43 products tested). In the case of the RDTs that showed poor correlation, the in vitro disintegration time became virtually equal to in vivo disintegration time when the Distopper^® sensor was modified so that the mechanical stress generated by the tongue could be simulated. Thus the optimization of the Distopper^® to more closely simulate the disintegration mechanism in the mouth enabled the in vitro testing apparatus to be applied to a greater number of RDTs. This testing method should be useful in evaluating RDT quality at the sites of manufacturing, development and medical treatment.

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Menkes disease is characterized by inhibition of the absorption and transport of dietary copper. The Okayama University Medical and Dental School uses L-histidine-copper to treat this disease and in the present study, we examined the stability of the copper histidinate injection solution used for this purpose. High-performance liquid chromatography (HPLC) performed on day 56 following injection revealed that histidine levels had dropped to 90.4%, a non-significant decrease and histamine levels were unchanged. Moreover, atomic absorption spectrophotometry revealed that copper concentrations were not significantly decreased (89.7%) between days 0 and 56. Through visual observation, we noted a gradual increase in floats from day 42 to day 56, leading us to suggest that the use of copper histidinate be limited to 1 month.
The above results should alleviate any concern about histamine-associated adverse effects.

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Hospital pharmacists' expectations of the medical representatives (MRs) of pharmaceutical companies have been increasing as their work has become more sophisticated and diversified in recent years. Since only a limited amount of information on the expectations of MRs is available, we conducted a questionnaire survey of hospital pharmacists. The questionnaire was sent to 42 national university hospitals, and 104 pharmacists from 22 hospitals responded. According to the results, much used drug information provided by MRs included safety information (78.8%), instruction on use (73.1%), and that on drug interactions contraindications (63.5%) and effectiveness (62.5%). Seventy-six percent of the pharmacists responding considered that drug information provided by MRs was reliable.
In the future, they said they would like MRs to provide information as fast as possible using information technology. They also said they would like MRs to provide more tailor-made information. Only 13.5% of the pharmacists felt that MRs fed back their requests concerning drug development to pharmaceutical company research laboratories. It is therefore necessary to find ways of improving such feedback as soon as possible.

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We previously reported that the protocols of bioequivalence studies on generic pravastatin sodium had not been standardized. The bioequivalence of generic drugs is confirmed by crossover studies using healthy volunteers. In this study, we examined protocols for bioequivalence studies on generic itraconazole (ITCZ) formulations which show poor absorption.
Based on pharmacokinetic parameters obtained from pharmaceutical companies, we evaluated the protocols for studies on 5 generic formulations and the results of these studies. The sampling schedule, number of subjects and food intake status were found to be different for each study and there were also differences in the intra-individual variation index for C_max and AUC_t.
In conclusion, it is difficult to accurately evaluate the quality of bioequivalence studies only on the basis of mean and standard deviation values that have been made publicly available.

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We conducted a retrospective study to determine whether a brand-name simvastatin (Lipovas^®) is therapeutically equivalent to a generic simvastatin (Lipodown^®). One hundred and sixty-nine subjects were chosen from among hyperlipidemia patients who had been visiting Keihanna Hospital and Matsumoto Medical Clinic. These patients had been switched from the brand name simvastatin, Lipovas^® to the generic product Lipodown^® in the course of their treatment for hyperlipidemia. Clinical data for 36 of the 169 subjects were analyzed.
Regarding efficacy, no significant differences were seen in total cholesterol levels before switching to Lipodown^® and six months after switching (217.6±36.7 mg/dL→212.4±26.1 mg/dL (at time of switch)→209.9±27.7 mg/dL, P=0.11), and this was also the case for HDL-cholesterol, LDL-cholesterol, and triglyceride levels. We also analyzed drug safety using AST, ALT, γ-GTP, BUN, Creatinine and CPK as indices and found no specific problems related to the switch to Lipodown^®. These results suggest that Lipovas^® and Lipodown^® are therapeutically equivalent, and that Lipodown^® can be used clinically in place of Lipovas^® so long as essential markers like ALT, AST, γ-GTP, and CPK are carefully monitored.

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In January 2001, we developed a program which efficiently identifies pharmaceutical problems from inpatient information and set up a computer system for making individual problem lists from such information. Problems were extracted from the inpatient information using a check list and then standardized. They were then output on problem sheets so that the pharmaceutical problems of individual patients could be identified. These problems were then checked and used in the making of individual problem lists. The proportion of patients with problem lists increased 1.5-fold after starting to run the system and the number of problem lists doubled for each inpatient, a significant increase.
The computer system we developed has made it easier to recognize pharmaceutical problems and facilitated the making of problem lists for individual patients. By doing so, it has enhanced the quality of pharmaceutical care for elderly patients and made it more efficient.

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