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We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study.Patients with MDD who have insomnia symptoms (a score of7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study.Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline.Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

Background The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. Case presentation The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. Conclusions The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD.

Aim According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice. Methods We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM). Results The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively. Conclusions After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD.

Long-term clinical training programs started as part of a 6-year pharmacy course in May 2010. In order to provide training approaches more appropriately and efficiently, it is necessary for teaching facilities to develop effective training systems and curriculums. In Kobe City Medical Center General Hospital, a pharmacy residency system was instituted in 2009, and, based on this, a preceptorship program for clinical training was adopted. In this study, the influence of pharmacy residents as preceptors on clinical training was evaluated based on training reports submitted by 26 students, consisting of a total of 1238 pages; residents' comments were observed in 31.3% of them. Changes in students' awareness were also noted; in the course of training, they became more aware of the responsibility and role of pharmacists, and such awareness appeared to provide a basis for their future goals. Further, although most of the residents' comments were initially made for encouragement, concrete advice gradually increased with time. Residents' commitment to clinical training as preceptors may have facilitated students' understanding of the significance of training, while promoting their own development.

Purpose. Three products can be used in Japan for the reconstitution of cytotoxic agents: PhaSeal, Chemo CLAVE and Chemo Mini Spike (CMS). The low preparation volume may be affected by residual-related volume in their devices. In this study, the residual-related error in their devices was examined and compared. Method. The blank of each component of these devices was weighed using a precision electric balance. After ejecting distilled water (DW) for injection, each was weighed again with the balance. In addition, for etoposide in the cases of PhaSeal and Chemo CLAVE, the components of the devices were similarly weighed. Result. The weight gains of each device after ejecting DW were as follows: CMS-V (440 mg) greater than the combined components of Chemo CLAVE (128—171 mg)/CMS-MT (123 mg) greater than the combined components of PhaSeal (13—56 mg). For etoposide, the weight gains of PhaSeal (208 mg) and Chemo CLAVE (223 mg) showed no significant difference. The priming volume of each device was calculated from the specific gravity of water. The residual-related volume was ‘CMS-V > Chemo CLAVE, CMS-MT > PhaSeal’, although this was very slight in actual situations. Conclusion. The residual-related volume was marked in its low preparation volume. In water-soluble drugs, the residual volume of PhaSeal was lowest of the devices in this study, but in viscous drugs, such as etoposide, the residual volume of PhaSeal was almost identical to Chemo CLAVE; that is, the residual volume of these devices was affected by the solution property. The residual-related volume in the devices will lead to errors; therefore, residual-related errors need to be considered in the use of these devices.

Nausea and vomiting are major adverse reactions in cancer chemotherapy and affect patients’quality of life.Though medical institutions have revised their antiemetic therapy guidelines,there have been few evaluations of the revisions especially for the continuous administration of anticancer drugs.We revised our guidelines for antiemetic therapy in the continuous administration of anticancer drugs and then investigated the effect on the incidence of nausea and vomiting and cost of antiemesis.Our subjects were 39 patients receiving high dose FP therapy (Day 1 : cisplatin 80mg/m2 ; Day 1-5 : 5-fluorouracil 800 mg/m2)for esophageal cancer at Kobe City Medical Center General Hospital.A conventional antiemetic therapy group (conventional group) received granisetron 3mg on Day 1 (20 patients),and a revised antiemetic therapy group (revised group) received granisetron 3mg plus dexamethasone (DEX) 20mg on Day 1 and DEX 4-12mg on Day 2-5 (19 patients).The incidences of nausea and vomiting in the conventional group were 80.0% and 30.0%,respectively and in the revised group 52.6% and 15.8%,respectively.There were significant decreases in the incidences of nausea and vomiting in the revised group as compared with the conventional group on Day 2,3 and 5 and Day 3,respectively.The occurrence of vomiting was 0.80±1.88 times in the conventional group and 0.21±0.54 times in the revised group.The cost of antiemesis for 1 course was 16,701±15,103 yen for the conventional group and 9,691±3,326 yen for the revised group.These results suggested that our revised antiemetic therapy for the continuous administration of anticancer drugs could reduce the incidence of nausea and vomiting as well as the cost of antiemesis in cancer chemotherapy.

75歳, 男性。1995年に左足縁原発の悪性黒色腫に対して腫瘍切除術および左鼠径リンパ節郭清術施行後, 術後補助化学療法を行った。しかし, 1999年, 左大腿部にIn-transit転移が生じ, 集学的治療を開始した。その後, 左大腿部の転移病巣は増大傾向を示すものの, 内臓転移は認めなかった。しかし, 2006年9月から左大腿部の転移病巣は急速に拡大し, 同部からの出血 (Hbの低下: 13.0→6.3g/dl)により輸血を要するまでになった。そこで, 院内製剤モーズ軟膏を使用したところ, 出血, 滲出液の漏出が著明に減少するとともに, 転移病巣の縮小および悪臭が抑制され, 患者のQOLの改善が得られた。

The effects of a propolis extract obtained by supercritical fluid extraction on sensitivity to chemotherapeutic agents were examined in HeLa cells and resistant sublines thereof. In addition, the actions of propolis and caffeic acid phenethyl ester (CAPE), a constituent of propolis, on the multidrug efflux transporter P-glycoprotein/MDR1, were evaluated in paclitaxel-resistant HeLa/TXL cells (MDR1-overexpressing cells). In HeLa cells, the sensitivity to paclitaxel and doxorubicin, substrates of MDR1, was unchanged in the presence of propolis. In HeLa/TXL cells, propolis increased sensitivity to these MDR1 substrates. The accumulation of Rhodamine123, also a substrate for MDR1, by HeLa/TXL cells increased in the presence of 50 microg/mL, but not 10 microg/mL, of the extract. However, the growth inhibition of HeLa/TXL cells by paclitaxel was not changed by CAPE, although the accumulation of Rhodamine123 increased significantly in the presence of 100 microm, but not 1 nM or 1 microm, CAPE. Collectively, the extract was suggested to inhibit the function of MDR1 and to increase the sensitivity to MDR1 substrates in HeLa/TXL cells, effects likely to be caused by constituents other than CAPE.

According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice.We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM).The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively.After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD.

We developed a novel support system for more effective and safer cancer chemotherapy, whose major aims were to improve pharmaceutical care by reinforcing prescription checking, providing higher quality medical information and standardizing guidance for cancer patients.Protocols consisting of the dosages, dosing schedules and adverse reactions of anticancer drugs and procedures for their admixture were the key element of our support system. Prescription checking parameters included patient height, weight, body surface area, type of cancer diagnosed, dosage and dosing schedules. For patients who had received the same protocol for the same type of cancer previously, the dosage was checked using past dosage data, laboratory data and adverse effect information. In order to standardize guidance given to patients, we had the system automatically produce adverse effect monitoring and check sheets and used this information together with that obtained from patients to prepare information that would aid consultation. This helped avoid adverse events and ensure that anticancer jobs were used properly, which made cancer chemotherapy more effective and safer.The support system enabled valuable information on cancer chemotherapy to be provided to doctors, nurses and pharmacists. We therefore consider it to be a useful tool in chemotherapy for cancer patients.

A four-week practical hospital training course for undergraduates at Takarazuka Municipal Hospital has been conducted since 1998. The curriculum at our hospital consists of three elements, i.e., lectures on hospital pharmacy, the dispensing service and the clinical pharmacy service. Regarding the clinical pharmacy service, a case study had token a long time for the purpose of learning the actual services. In this study, we compared the results of the new curriculum with those of previous curriculums to establish a more effective and practical curriculum for undergraduates. Our curriculum showed no significant difference with the findings of other reports. Next, we investigated the student' s awareness by questionnaire. The results showed that most students developed on increased awareness of the pharmacist' s daily practice by the end of the practical training course. However it also showed a tendency that their interests in pharmacy practice differed according to their future courses and the university they were studying.From these results, further progress therefore appears to still be obtainable by increasing the cooperation between pharmaceutical universities and hospital pharmacies. In addition, it was considered that our curriculum should be further improved by better meeting the needs of students during the practical training course.

The dosage regimen of a drug eliminated predominantly through the kidney need to be adjusted for the patients with renal disease. The objective of the present study was to establish a quantitative approach to precisely predicting the renal clearances of basic drugs using N -1-methylnicotinamide (NMN). A variety of experimental acute renal failure (ARF) in rats were prepared and N -acetylprocainamide (NAPA) was used as a model drug. The renal clearances of NAPA were significantly decreased in rats with ARF, resulting in significantly increased plasma concentrations. Remarkable reduction in clearance ratios ( CL ratio ) was observed, indicating that the impairment in tubular and glomerular function did not proceed in a parallel manner. The renal clearance of NAPA ( CL rNAPA ) was better predicted from the renal clearance of NMN ( CL rNMN ) than from GFR. A mathematical equation was also constructed to estimate the CL rNMN from the NMN plasma concentration. Therefore, the renal clearance of basic drugs excreted predominantly from the kidney can be easily and more accurately estimated based on the concentrations of endogenous NMN to provide a precise dosage regimen for patients with renal failure.

We developed a computer program for drug information for patients using File Maker Pro® software package (ver 4.0). This program consists of four databases : 1) a main database which manages data of drug efficacies, the initial symptoms of serious side effects, cautions, drug interactions, 2) standardization for drug efficacies, 3) standardization of the initial symptoms of serious side effects, and 4) information on the package insert for drugs.These four databases enabled pharmacists to provide standardized drug information rapidly not only to patients but also to other medical staff members.Moreover, these four databases connected with a relational function of File Maker Pro® enabled us to automatically update the data on drug efficacies and initial symptoms of serious side effects by in putting the drug code numbers designated by the Ministry of Health Labor and Welfare into this program.These results suggested this program to be useful for the standardization of drug information and the automatic updating of the data.

The purpose of antihypertensive therapy is not only to normalize the blood pressure but also to prevent severe or fatal complications of the cardiovascular system. Since the presence or absence of target organ failure and major dangerous factors influence the prognosis of hypertension, an appropriate evaluation of these risk factors is important. It is therefore necessary to consider such complications when evaluating antihypertensive therapy.In this investigation, we examined the current state regarding the use of antihypertensive drugs and their associated complications in Takarazuka City Hospital, to establish a more effective and safer pharmacotherapy from the pharmacist's viewpoint.A total of 312 patients (138 males, 174 females) who received antihypertensive drugs at the Department of Internal Medicine in our hospital between August 23rd and 27th, 1999 were included in this study. The patients' records were examined with regard to age, the medication received and the complications observed.The most common form of treatment, regardless of age, was calcium channel blockers (Ca blockers), followed by angiotensin converting enzyme inhibitors (ACE-I), and finally α-, and β-adrenergic blockers (α and β blockers, respectively).The rates of congestive heart failure (CHF) and ischemic heart disease (IHD) tended to increase with age. On the other hand, those of endocrine metabolic diseases such as diabetes mellitus (DM), hyperlipidemia and gout were either unaffected or tended to decrease with age.The peculiar use ratio of diuretics in patients with CHF was higher than that in non-CHF (p< 0.05). The use of β blockers was slightly higher in IHD. The ratio of a blockers correlated with the rates of DM (p< 0.05) and hyperlipidemia (not significant).In conclusion, due to the variety of the patient profiles and the clinical backgrounds antihypertensive drug therapy has thus become a complex issue. In addition, GL is not applicable in all cases. However, the results of this study suggest that the current state regarding the use of antihypertensive drugs and their associated complications in our hospital was similar to that in previous reports. It is therefore necessary to further accumulate and analyze such findings including the types of treated diseases, the indications and dosage of each applied drug to establish more effective and safer antihypertensive pharmacotherapies.

A 74-year-old female has been diagnosed with stage IIIB rectal cancer in 2003. Following anterior resection, she received adjuvant chemotherapy with three different regimens. In August 2005, she was started on a modified FOLFOX6 regimen, and the sixth cycle of chemotherapy induced a severe hypersensitivity reaction (HSR). Immediate cessation of the infusion resulted in a disappearance of the allergic reaction 60 min later. Blood tests just after the reaction demonstrated a marked elevation of immunoglobulin E to 300 IU L-1 (normal range: -1). This change implies the involvement of a type I reaction in the HSR. In addition, a drug lymphocyte stimulating test against oxaliplatin and levofolinate calcium (an isomer of leucovorin calcium) gave values of 696% and 107 % respectively, as compared with control serum. This suggests that the patient had an adverse reaction not only of type I but partly of type IV allergic reaction also. Oxaliplatin appears to have caused a HSR in this Japanese patient, and thus pharmacists, physicians, and other medical staff must keep a careful watch of a patient's clinical condition during chemotherapy including oxaliplatin. J Oncol Pharm Practice (2007) 13: 233—235.

The current status of treatment with sorafenib, and factors affecting the duration of treatment in patients started on sorafenib for hepatocellular carcinoma from July 2009 until April 2011 in the Department of Gastroenterology at Kobe City Medical Center General Hospital, were examined. Of 21 patients, 12 were able to continue the administration of sorafenib for more than one month, but 9 had to be discontinued within one month due to disease progression, worsening of general condition, and severe adverse reactions. In the group that was discontinued early, the rate of discontinuation due to side effects such as general fatigue, diarrhea, and hepatic encephalopathy was higher than in the long-term treatment group. On the other hand, hand-foot syndrome developed only in one case in both groups. The median value of PIVKA- II at the start of treatment in the long-term and early discontinued treatment groups were 672.5 and 14, 203 mAU/mL, respectively, and the values in the long-term group were significantly lower than those in the early-discontinued group (p0.05). From these results, the values of PIVKA-II at the start of sorafenib were considered to be factors affecting the continuation of sorafenib treatment. In addition, the dosing period was considered to be extended to focus on measures to take against the side effects of sorafenib within the early phase. Therefore, it was considered that these factors improved the effect of treatment with sorafenib in patients with hepatocellular carcinoma.

Agaricus blazei Murill (ABM; Japanese name: Kawahiratake or Agarikusutake) extract is a widely used dietary supplement. However, limited information is available on the effects of the extract on the effectiveness of the chemotherapeutic agents. In this study, we examined the effects of ABM extract (Kyowa Wellness Co., Ltd.) on sensitivity to chemotherapeutic agents, paclitaxel and doxorubicin as MDR1/P-glycoprotein substrates, and cisplatin and 5-fluorouracil as non-substrates, in human cervical carcinoma HeLa cells, and paclitaxel-resistant and cisplatin-resistant derivatives (HeLa/TXL and HeLa/CDDP, respectively). The extract had no growth inhibitory effects on HeLa and the resistant cells at concentrations ranging from 7.6 × 10(-4) μ g/ml to 8.0 × 10(2)μ g/ml, indicating no remarkable cytotoxic activity in vitro. In the presence of 0.1, 0.5, and 1 μ g/ml of ABM extract, sensitivity to paclitaxel, cisplatin and 5-fluorouracil did not change in HeLa, HeLa/TXL and HeLa/CDDP cells. However, the extract reduced sensitivity to doxorubicin in HeLa/TXL and HeLa/CDDP cells in a concentration-dependent manner. In conclusion, the concomitant use of ABM extract minimally affected sensitivity to various chemotherapeutic agents in HeLa cells and resistant sublines in vitro.

Fifty-six patients treated with oxaliplatin were examined in order to clarify the factors that influence the appearance of allergic reactions by oxaliplatin at Kyoto City Hospital between January 2009 and December 2009, retrospectively. The number of patients in allergic and non-allergic group was 10 and 46, respectively. Patients' characteristics, the presence of hepatic metastasis, hepatic failure and kidney failure, albumin and white blood cell counts were compared in both groups. In the allergic group, the rate of hepatic metastasis was significantly higher than that in the non-allergic group (p=0.011). In conclusion, hepatic metastasis was suggested to be a factor that causes allergic reactions after administration of oxaliplatin.

The safety of epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) plus cyclophosphamide (500 mg/m(2)) (FEC75 therapy) and docetaxel (75 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) (TC therapy) every three weeks as neoadjuvant or adjuvant chemotherapy was evaluated. Six or 9 patients received FEC75 or TC therapy, respectively. The nadir of white blood cells and neutrocyte counts in FEC75 and TC therapy were after 11-15 days and 8-11 days of chemotherapy, respectively. On the other hand, those of monocyte and reticulocyte counts were after 8-11 and 4-8 days for FEC75 and TC therapy, respectively. This suggests that there is a lag time in these parameters for the evaluation of myelosuppression in each chemotherapy regimen, resulting in the prediction of the degree of myelotoxicity by these profiles. Although 2 patients who received TC therapy encountered febrile neutropenia, the symptoms were improved by quinolones, and so granulocyte colony-stimulating factor was not needed. In addition, remarkable non-hematological side effects were not observed, and, therefore, almost all chemotherapy was performed as scheduled. From these results, FEC75 and TC therapy are considered to be safe.

The aim of this study was to examine the effects of 16 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) on P-glycoprotein/MDR1 in Caco-2 cells as an intestinal epithelial cell model. Cells were treated with NSAIDs for 24 hours, and then, the expression of MDR1 mRNA was evaluated by reverse-transcriptase polymerase chain reaction. The function of MDR1 in cells pretreated with NSAIDs for 48 hours was evaluated by measuring the cellular amount of rhodamine123, which is a substrate of MDR1. The expression of MDR1 mRNA was increased by diclofenac, fenbufen, indomethacin, and nimesulide and the tended to be increased by meloxicam, mepirizole, and sulindac. However, pretreatment for 48 hours with diclofenac, indomethacin, or nimesulide, but not fenbufen, resulted in a significant increase in the amount of rhodamine123 accumulated. Although NSAIDs without effects on the expression of MDR1 mRNA altered the accumulation of rhodamine123 significantly, the efflux of rhodamine123 from cells was unchanged. In conclusion, the expression of MDR1 mRNA in Caco-2 cells was demonstrated to be increased by treatment with some NSAIDs, although the transport function of MDR1 was unchanged. These findings imply that the NSAIDs did not cause the drug interaction via MDR1 induction.

A 49-year-old-man, a healthy carrier of hepatitis B virus (HBV), received chemotherapy with a rituximab/cyclo- phosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) regimen for non-Hodgkin's lymphoma. At the first course of chemotherapy, not only the liver function but the HBV DNA level was elevated. These symptoms were diagnosed as hepatic injury induced by HBV reactivation, and, therefore, entecavir (ETV) was started. As a result, although the treatment with ETV decreased the HBV DNA level, liver function values were remarkably elevated again (over 3 times the levels before beginning ETV). ETV was discontinued because of suspicion regarding the onset of hepatic injury it caused. After switching to lamivudine (LVD), the liver function quickly improved and no problems were observed with renewal of the R-CHOP regimen. In addition, the HBV DNA level decreased and 3 courses of R-CHOP were performed successfully. In our case, the hepatic injury was induced by ETV, although anti-HBV medicine was used for the treatment of HBV reactivation according to the guideline. Therefore, the medical staff must carefully and consistently observe patients with HBV infection after chemotherapy.

We surveyed the current status and the differences of treatment of colorectal cancer using modified FOLFOX6 regimen, in two general hospitals, Sakai City Hospital (A hospital) and Takarazuka Municipal Hospital (B hospital) between April 2005 and November 2006, retrospectively. The numbers of examined patients were 33 and 17 in A and B hospitals, respectively. The grade of myelosuppression and peripheral neuropathy were evaluated according to Common Terminology Criteria for Adverse Events v 3.0(CTCAE v 3.0)and Neurotoxicity Criteria of DEBIOPHARM(DEB-NTC). The setting of dosage was differed in two hospitals. In A hospital, the dosages of oxaliplatin, 5-FU bolus and 5-FU continuous infusion were more than 90% of the standard one at first time, and were reduced with almost same degree in the appearance of adverse effects. On the other hand, in B hospital, the dosages of these drugs were reduced about 20% even at first administration and, especially, the dose of 5-FU bolus tended to be remarkable reduction. Of adverse events, the rates of the appearance of neutropenia more than grade 3 was 21.2% and 47.1%, in A and B hospitals, respectively. No difference in peripheral neuropathy was detected at both hospitals. In conclusion, the differences in these two hospitals were detected in the dosage setting and myelosuppression, not in non-hematological adverse effects.

Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination.

We investigated the differences in safety and management of adverse events of chemotherapy among three hospitals, Sakai Municipal Hospital, Takarazuka Municipal Hospital and National Hospital Organization Osaka-minami Medical Center. The main purpose of this study was to equalize the spread of breast cancer chemotherapy regimen. The following three regimens were evaluated; epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) (EC75), epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC75) and epirubicin (100 mg/m(2)) / cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC100). Sixty-three patients were evaluated. We studied the level of myelosuppression after each regimen. As a result, there was no significant difference in neutrocyte counts at nadir after chemotherapy among hospitals and regimens. However, the values tended to be ranked EC75FEC75FEC100. In addition, we examined the risk of febrile neutropenia (FN) according to the multi- national association for supportive care in cancer (MASCC) scoring system. Almost all patients (61/63) were in the low risk group of FN, and only two patients had developed FN. At one hospital, patients receiving chemotherapy were prescribed ciprofloxacin tablets prophylactically for prexia over 38 deg C, and the patients learned from it. Thus, no marked difference in the safety (side effects such as myelosuppression) was recognized. However, management of side effects was different among these hospitals. In conclusion, it is very important to provide patients with adequate information on side effects.

Background: Platinum derivatives differ in effectiveness and safety. The purpose of this study is to compare differences in the mechanism of nephrotoxicity among these derivatives. Methods: LLC-PK1 cells were used as a model of tubular epithelial cells. Cytotoxicity was evaluated by WST-1 assay, and cellular accumulation of platinum was examined by inductively coupled plasma mass spectrometer. As indexes of necrosis and apoptosis, lactate dehydrogenase release, DNA fragmentation and caspase 3 activation were examined. Results: In terms of cytotoxicity, the derivatives ranked in the order of oxaliplatin > cisplatin > nedaplatin > carboplatin, being comparable with that for the level of platinum accumulated in LLC-PK1 cells. Lactate dehydrogenase release and DNA fragmentation were observed following treatment with all the derivatives, but were lowest for carboplatin. In terms of activating caspase 3, the order was cisplatin > nedaplatin > oxaliplatin > carboplatin. Conclusion: Cytotoxicity by the derivatives was dependent on cellular accumulation of platinum and suggested to be mediated by apoptosis and necrosis; however, contributions differed among the derivatives.

The aim of this study is to examine the factors affecting sensitivity to cisplatin, carboplatin, and oxaliplatin in human colorectal tumor cell lines.Caco-2, DLD-1, HCT-15, HCT116, LS180, SW620, and WiDr cells were used. Their growth inhibition by platinum derivatives was evaluated with a WST-1 assay utilizing succinate dehydrogenase activity. Cellular accumulation and DNA-binding of platinum were measured with an inductively coupled plasma mass spectrometer. The mRNA levels of copper transporters (hCtr1, ATP7A, and ATP7B) and organic cation transporters (hOCT1, hOCT2, and hOCT3) were evaluated by the real-time reverse transcription-PCR method using SYBR green.The cytotoxicity of platinum derivatives ranked oxaliplatincisplatincarboplatin in almost all cells used. Cellular accumulation and DNA-binding of platinum varied among the types of cells, but levels were similar on treatment with cisplatin and oxaliplatin, and lower in response to carboplatin. The levels of copper and organic cation transporter mRNAs also differed with cell type. A correlation analysis revealed that sensitivity to platinum derivatives was dependent in part on the amount of platinum bound to DNA. In addition, the cellular accumulation of platinum and level of ATP7A mRNA may be factors affecting the cytotoxicity of cisplatin, while the cytotoxicity of oxaliplatin was suggested to be affected by the levels of ATP7A and hOCT1 mRNAs.Some factors affecting the sensitivity of tumor cells to platinum derivatives were proposed, and will provide useful information for cancer chemotherapy with platinum derivatives.

Objective: To achieve a reversal of multidrug resistance (MDR) in cancer chemotherapy, it is crucial to clarify the characteristics of MDR cells generated by various types of chemotherapeutic agents and to find novel targets. Methods: Cisplatin- and paclitaxel-resistant HeLa sublines (HeLa/CDDP and HeLa/TXL, respectively) were established by continuous exposure and their cellular changes were examined based on growth inhibition assays, the transport activity of P-glycoprotein/MDR1, and a RT-PCR analysis of MDR-related factors. Results: HeLa/CDDP cells showed cross-resistance to platinum derivatives, whereas HeLa/TXL cells were resistant to a variety of MDR1 substrates. Transport activity of MDR1 was reduced in HeLa/CDDP cells and the expression of MDR1 was significantly accelerated in HeLa/TXL cells, compared with HeLa cells. In addition, the expression levels of MDR-related transporters (MRP1–5 or BCRP), βtubulin which is a target for taxanes, and apoptosis-regulated factors were comparable among the three cell lines. On the other hand, the mRNA levels of γ-glutamyl transferase, but not γ-glutamyl cysteine synthetase, were higher in HeLa/CDDP cells than in HeLa and HeLa/TXL cells. Conclusions: HeLa/CDDP cells showed decreased activity and expression of MDR1 and overexpression of \( \ifmmode\expandafter\tilde\else\expandafter\sim \fi{\gamma }{\text{-GT}} \) but not \( \ifmmode\expandafter\tilde\else\expandafter\sim \fi{\gamma }{\text{-GCS,}} \) whereas the activity of MDR1 in HeLa/TXL cells was significantly enhanced. Thus, the molecular changes to HeLa cells caused by continuous exposure to cisplatin or paclitaxel were in part clarified, and therefore an understanding of the cellular changes induced by chemotherapeutic agents will be necessary to establish a strategy for reversing MDR.

We investigated the distribution and stability of pirarubicin in human blood obtained from 12 healthy volunteers. The distribution of pirarubicin into blood cells showed marked temperature- and concentration-dependencies and the Arrhenius plot for pirarubicin uptake in blood was biphasic. Therefore, pirarubicin appears to be taken up into blood cells by a carrier-mediated system. Pirarubicin was mainly enzymatically metabolized to pirarubicinol in blood cells, but pirarubicin was not metabolized into doxorubicin in either blood or plasma. On the other hand, in plasma, pirarubicin was degraded to unknown inactive compounds instead of pirarubicinol. It is therefore suggested that blood cells serve to protect against the degradation of pirarubicin into inactive compounds in blood. Accordingly, when the monitoring of pirarubicin and its active metabolites is carried out in patients, both blood and plasma must be frozen immediately after blood collection.