Temozolomide (TMZ) and concomitant radiotherapy are often used to treat newly diagnosed glioma, followed by adjuvant therapy. TMZ causes severe lymphocytopenia, thereby increasing the risk of opportunistic infection (OI). We analyzed the risk factors of lymphocytopenia. Between October 2006 and December 2009, we examined 43 patients aged between 22 and 83 years (average age, 64 years) with primary glioblastoma (n=32), anaplastic oligoastrocytoma (n=4), anaplastic astrocytoma (n=2), anaplastic oligodendroglioma (n=2), anaplastic ependymoma (n=2), and unknown tumor (n=1). The patients received a combination of postoperative radiotherapy (5 days per week for 6 weeks; total dose, 60 Gy) and daily oral TMZ (75 mg/m²; 42 days). A total of 37 out of 43 patients completed combined radiochemotherapy. Hematologic toxicities were graded according to the Common Toxicity Criteria version 4.0: leukopenia grade 3/4, 9%; neutropenia grade 3/4, 7%; lymphopenia grade 3/4, 61%. The non-hematological toxicities observed were as follows: fatigue, 83%; nausea, 74%; and vomiting, 33%. Multivariate analysis results suggest the following lymophocytopenia risk factors: female, body weight loss, and on trimethoprim- sulfamethoxazole. These results suggest that risk factors can predict severe lymphopenia during TMZ and concomitant radiotherapy.

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To study whether the monitoring of serum high sensitivity C-reactive protein (hs-CRP) would be a unique biomarker of cardiovascular risks, being independent of serum LDL-cholesterol, in patients with or without glucose intolerance receiving an HMG-CoA reductase inhibitor (statin), we conducted a meta-analysis study on the data retrieved from MEDLINE, Cochrane Central Register of Controlled Trials, Japan Medical Abstracts Society. Fifty-four placebocontrolled randomized clinical trials consisting of 34,746 patients (841 of them were documented as having glucose intolerance and 18,572 were not) were analyzed. Results showed that patients receiving one of the statins expressed a significant decrease in the weighted mean difference (WMD) of hs-CRP with a 95% confidence interval (CI) (−0.53 mg/L; −0.63 to −0.42, p<0.001)and that of LDL-cholesterol (−50.8 mg/L; −54.4 to −47.1, p<0.001) as compared to those receiving placebo. While statins produce a smaller reduction in the WMD of serum hs-CRP in patients with glucose intolerance (−0.54 mg/L; −0.92 to −0.17, p<0.001) than those without (−0.73 mg/L; −1.09 to −0.37, p<0.001), the difference was not significant. Weighted Spearman's correlation analysis showed no significant correlations between the changes in LDL-cholesterol and hs-CRP after statin therapy in overall patients and subgroups consisting of those with or without impaired glucose tolerance. In this context, we concluded that hs-CRP may be a unique cardiovascular risk factor, not substitutable for LDL-cholesterol, in patients receiving statins irrespective of glucose intolerance.

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The effect of non-steroidal anti-inflammatory drugs (NSAIDs) on methotrexate (MTX) dosage, corticosteroid dosage, rheumatoid arthritis (RA) activity and laboratory data in MTX-treated patients with RA was investigated retrospectively. The MTX dosage was significantly increased in 67% of the control patients, while in only 33% of the NSAID-treated patients, MTX dosage was increased (p<0.05). A significant reduction of corticosteroid dosage (p<0.05) and RA activity (p<0.01) in the control patients was observed. Changes in several laboratory data of RA patients during the observation period were similar between the two patient groups.

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The plasma concentration of phenytoin, when coadministered orally with an enteral formulation, is markedly decreased compared with that when phenytoin is administered alone. However, the mechanism behind this interaction has yet to be clarified. Here we tried to clarify the mechanism by rat intestinal loop perfusion method. Drug concentrations were measured by HPLC. Enteral formulations affected the intestinal absorption of phenytoin, but their inhibitory effects varied. Moreover, a good correlation was observed between the inhibitory effect and the osmotic pressure of the formulations. However, the lipid components in the formulations did not affect the absorption of phenytoin, and no effect on perfusate pH was recognized. These results indicate that the osmotic pressure of the enteral formulations affected the intestinal absorption of phenytoin. A defined formula containing various peptides had a greater inhibitory effect than that predicted from its osmotic pressure. The contribution of peptide transporters to the intestinal absorption of phenytoin was studied. Cephalexin and cephradine, as typical substrates of peptide transporters, markedly inhibited the absorption. These results indicate that osmotic pressure and peptides in the perfusate were the major factors responsible for the inhibitory effects of the enteral formulations on the intestinal absorption of phenytoin.

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We surveyed temporal changes in pemetrexed-induced hematotoxicity in patients with non-small cell lung cancer (NSCLC) in order to determine the appropriate time for measuring blood cell counts during the administration of pemetrexed monotherapy to outpatients. In total, 19 inpatients with NSCLC who were treated with pemetrexed at the Nagara Medical Center from July 2009 to April 2011 were included in our study. The time from administration of pemetrexed until the nadir of white blood cells, thrombocytes, and hemoglobin was reached was 9.5, 10.5, and 12 days, respectively. In an ambulatory setting, the date of physician visit and blood tests to monitor hematotoxicity should be set after considering the time taken to reach the nadir levels of each blood cell and the individual's tendency of hematotoxicity.
Next, we investigated the average temporal changes of white blood cells, thrombocytes, and hemoglobin after the administration of pemetrexed in the aforementioned patients, and we plotted graphs of each average temporal change. Then we created a leaflet using these graphs, and after pharmacists explained to outpatients administered pemetrexed about hematotoxicity using the leaflet, we conducted a questionnaire survey of them. As a result, the leaflet was useful for the following items: comprehensibility of the need for blood tests, simplicity of the leaflet using graphs, removal of the concern regarding hematotoxicity, and comprehensibility of the word of caution regarding hematotoxicity in daily life.

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We conducted a questionnaire survey in pharmacists working in community pharmacies in order to clarify the relationship between measures for dispensing mistakes by environmental improvements of pharmacies and measures for human error. Simultaneously, we surveyed the main causes of dispensing mistakes relating to human factors. Questionnaires were distributed to 692 pharmacists working in community pharmacies. Valid questionnaires were collected from 486 pharmacists. (Valid collection rate: 70%) The results revealed that the highest risk factor of dispensing mistakes relating to human factors is the psychological and mental situation, which is 69% of all causes relating to human factors. And 7 factors were extracted from the factor analysis of 24 items relating to measures for dispensing mistakes by environmental improvements of pharmacies. Covariance structure analysis clarified the relationship between the 7 factors relating to environmental improvements of pharmacies and 3 factors relating to measures for human error. In addition, we constructed a novel path model that reveals the relationship between measures for dispensing mistakes by environmental improvements of pharmacies and measures for human error. Our model can be used to estimate what kind of environmental improvements of pharmacies we should implement as measures for human error, which includes an arrangement of prescription shelves by the order of the Japanese syllabary in a pharmacy where pharmacists having less knowledge and experience work, and therefore it can be helpful in risk management in community pharmacies.

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An important aspect of medicinal treatment is having the patient take the medicines prescribed by the doctor. However, a previous questionnaire about medication compliance and adherence showed that approximately 50% of patients forget to take their medicines. In this study, the status of patient medication-taking behavior and factors affecting adherence were investigated through a survey involving 226 patients who presented at Gifu Municipal Hospital from November 2009 to February 2010. The survey items included patient characteristics (age, sex, occupation, side effects, allergies, etc.), medication status (dosing time, medicine formulations), and factors affecting medication adherence (awareness of taking medication, awareness of illness and medicines, life rhythm, character, relationship of trust with doctor or pharmacist, use of medicine information leaflets). Overall, 73% of patients took medicines as directed. Evaluation by medication adherence status revealed that patients with poor adherence most frequently forgot to take their medicines after lunch and between meals. A separate factor analysis of good and poor medication adherence groups showed significant differences between the groups for 18 of 30 factors. Then, using Customer Satisfaction analysis and excluding factors related to personality, 4 factors for improvement were selected from the remaining 16 factors. These findings suggest that patient medication adherence increases when the factors of “regularity of life rhythm”, “regularity of meals”, “trust in pharmacists”, and “use of medicine information leaflets” are improved.

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A simple suspension method has been developed for the administration of tablets and capsules through a nasogastric tube. Tablets or capsules were suspended in hot water (55℃) without grinding or opening. Valganciclovir hydrochloride (VALIXA^®), a drug often prescribed to protect patients from cytomegalovirus infection after organ transplantation, was dispensed via a crushing method to recipients unable to take food or liquids by oral administration.
The interaction of VALIXA^® tablets with other medicines in a simple suspension has not been investigated, even though VALIXA^® is commonly used in combination with immune-suppressant drugs and several other medicines. Thus, we sought to examine the effect of co-administering suspensions of drugs combined with VALIXA^® tablets prescribed for transplant recipients. Valganciclovir hydrochloride was mixed with a variety of other therapeutics including prednisolone (PREDONINE^® tablets), ursodeoxycholic acid (URSO^® granules), sulfamethoxazole-trimethoprim (BAKTAR^® granules), mycophenolate mofetil (CELLCEPT^® capsules), tacrolimus (PROGRAF^® capsules), sucralfate (ULCERLMIN^® fine granule), and fluconazole (DIFLUCAN^® capsules), and the residual content of valganciclovir was evaluated by a high performance liquid chromatography assay. Our results indicated that over 90% of the original valganciclovir remained in the drug mixture suspension. In a practical test of delivering such suspensions by nasogastric tube, we observed that suspensions did not block either the catheter or injection syringe, and upon flushing, no residual drug suspension remained in the device.
In conclusion, this study suggests that VALIXA^® tablets in combination with a variety of other medicines may be administered to patients by a simple suspension method.

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