Correlation between the consumption of meropenem or doripenem and meropenem susceptibility of Pseudomonas aeruginosa in a university hospital in Japan.

The appropriate use of carbapenems is essential in order to prevent resistance in Pseudomonas aeruginosa. We investigated the correlation between the consumption of meropenem or doripenem and the susceptibility of P. aeruginosa to meropenem in a Japanese university hospital from 2004 to 2009. The susceptibility data of P. aeruginosa and the annual consumption of meropenem or doripenem were analyzed. The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology. Meropenem consumption decreased and doripenem consumption increased and throughout the entire investigation period, total consumption of meropenem plus doripenem was stable. Although the annual number of isolated P. aeruginosa has not changed, the annual number of isolated multidrug resistant P. aeruginosa decreased by measures against nosocomial infection. The rate of meropenem resistant P. aeruginosa decreased in a time-dependent manner. Meropenem consumption was positively correlated with the meropenem resistance rate among P. aeruginosa (r = 0.9455, p<0.01). The total consumption of meropenem and doripenem was not correlated with the meropenem resistance rate (r = -0.6601, p>0.1). These results suggested that even if the total consumption of meropenem plus doripenem was not changed, meropenem susceptibility among P. aeruginosa improved by the decrease of meropenem consumption. Although meropenem and doripenem have been suggested to show cross-resistance with each other, the reduction of meropenem consumption might be effective for preventing an increase of meropenem-resistant P. aeruginosa.

Impact of antimicrobial stewardship by infection control team in a Japanese teaching hospital.

The objective of this study is to investigate an effect on the antimicrobial appropriate use of the antimicrobial stewardship. We investigated the consumption of injectable antimicrobials from 2001 to 2007 and the administration period of specific antimicrobials (carbapenems, fourth-generation cephalosporins, anti-methicillin-resistant Staphylococcus aureus (MRSA) agents) in the individual patient. Since September 2004, the infection control team at Osaka University Hospital has been promoting appropriate use of antimicrobials through consultation, education, and weekly surveillance of specific antimicrobial usage. We obtained the amount of all antimicrobial injections as titer from the medical information database of the electronic medical chart system retrospectively. Antimicrobial use densities (AUD) were evaluated by measuring the number of doses administered/1000 patient-days. Although the number of inpatient admissions and operations increased 1.53- and 1.39-fold, respectively, in the seven years from 2001 to 2007, the expenditure on specific antimicrobials decreased markedly with AUD of specific antimicrobials decreasing from 39.6 to 29.2. The percentage of inpatients receiving specific antimicrobials decreased from 19.8% to 9.8%, and the ratio of the number of inpatients administered a specific antimicrobial within seven days to the number of inpatients administered each specific antimicrobial increased to over 60%. This led to reduction in the total expenditure of antimicrobials by about 100 million yen annually. The incidence of hospital-associated MRSA (HA-MRSA) infection decreased from 0.93% (2003) to 0.68% (2007). We can reduce the expenditure of antimicrobials without increasing incidence of the HA-MRSA by antimicrobial stewardship, and we think that appropriate use of antimicrobials is achieved progressively.

Evaluation of environmental contaminations and occupational exposures involved in preparation of chemotherapeutic drugs.

Many healthcare workers are concerned about the risk of occupational exposures to hazardous drugs. The Japanese Society of Hospital Pharmacists (JSHP) revised the "Guidelines for the Handling of Antineoplastic Drugs in Hospitals", however, the precautions and awareness of handling drugs varied in institutions. We assessed the levels of environmental contaminations in our hospital and urinary excretion of cyclophosphamide (CP) and ifosfamide (IF) in pharmacists and nurses. In environmental studies, we obtained samples by wiping the surfaces around two biological safety cabinets (BSCs) on eight days for four months. One BSC was equipped in hospital pharmacy and the other was equipped in an oncology ward, and used for preparing chemotherapeutic drugs for outpatients and for inpatients, respectively. We obtained the urine samples from 6 pharmacists and 2 nurses. We used solid phase extraction (SPE) as a convenient extraction procedure and liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) for the analysis of the samples. CP was detected on the working surfaces inside both BSCs, and detected at low levels on the back surfaces of the BSCs and at the working tables around the BSCs. IF over the LLOQ was not detected in both BSCs. CP and IF were not detected in all urine samples of pharmacists and nurses. Detection frequencies and amounts of these drugs were low levels, compared with previous reports in Japan, and our results showed that improving awareness about handling hazardous drugs could reduce the risk of the occupational exposures.

A ghrelin gene variant may predict crossover rate from restricting-type anorexia nervosa to other phenotypes of eating disorders: a retrospective survival analysis.

BACKGROUND: Patients with anorexia nervosa restricting type (AN-R) often develop bulimic symptoms and crossover to AN-binge eating/purging type (AN-BP), or to bulimia nervosa (BN). We have reported earlier that genetic variants of an orexigenic peptide ghrelin are associated with BN. Here, the relationship between a ghrelin gene variant and the rate of change from AN-R to other phenotypes of eating disorders (EDs) was investigated. METHODS: Participants were 165 patients with ED, initially diagnosed as AN-R. The dates of their AN-R onset and changes in diagnosis to other subtypes of ED were investigated retrospectively. Ghrelin gene 3056 T-->C SNP (single nucleotide polymorphism) was genotyped. Probability and hazard ratios were analyzed using life table analysis and Cox's proportional hazard regression model, in which the starting point was the time of AN-R onset and the outcome events were the time of (i) onset of binge eating, that is, when patients changed to binge eating AN and BN and (ii) recovery of normal weight, that is, when patients changed to BN or remission. RESULTS: Patients with the TT genotype at 3056 T-->C had a higher probability and hazard ratio for recovery of normal weight. The ghrelin SNP was not related with the onset of binge eating. CONCLUSION: The 3056 T-->C SNP of the ghrelin gene is related to the probability and the rate of recovery of normal body weight from restricting-type AN.

[Clinical features of paclitaxel-induced peripheral neuropathy and role of Gosya-jinki-gan].

Paclitaxel (PTX) is frequently used for a chemotherapy of breast cancer and gynecologic cancer. Besides a bone-marrow depression and hypersensitive reaction, the peripheral neuropathy is one of the serious adverse events of PTX. The mechanism of peripheral neuropathy has not been clarified, and few agents have been reported to be effective for the treatment and the prevention of that. Recently, it has been reported that Gosya-jinki-gan is useful for the PTX induced peripheral neuropathy, so we carried a retrospective study(n=82)to evaluate the effectiveness of Gosya-jinkigan with the medical records. It is suggested that peripheral neuropathy developed more rapidly in sequential administration of PTX every week than in administration in 4 weeks cycles consisting of 3 weeks on and 1 week off(5.4w vs. 9.4w). We have also found that Gosya-jinki-gan was possibly effective for the treatment and the prevention of peripheral neuropathy. Additionally Gosya-jinki-gan might be more effective for peripheral neuropathy when it is administered from the beginning of chemotherapy including PTX.

Pharmacokinetic behavior of intravitreal triamcinolone acetonide prepared by a hospital pharmacy.

PURPOSE: We developed a new hospital pharmaceutical preparation of triamcinolone acetonide (TA) for intravitreal injections using sodium hyaluronate as the vehicle. The purpose of this study was to compare the pharmacokinetic behavior of this hospital pharmacy preparation of TA (HPP-TA) to that of a commercial preparation of TA (CP-TA) in rats. METHODS: We injected the two preparations of TA into the vitreous humor of male Wistar rats. The rats were killed between days 1 and 21, and the concentration of TA in the vitreous was measured by high-performance liquid chromatography to determine the pharmacokinetic parameters. We also examined the microscopic appearance of the TA particles in these preparations. RESULTS: The elimination half-life was 6.08 days for the CP-TA and 5.78 days for the HPP-TA. A two-compartment model was suitable to approximate the pharmacokinetic behavior of HPP-TA in the vitreous body, but this model was not suitable for CP-TA, because its pharmacokinetic behavior was not sufficiently stable. The particle size of CP-TA was largest, followed by TA powder and HPP-TA. Many particles were agglutinated in the CP-TA preparation, whereas the TA particles were fine and dispersed in the HPP-TA medium. CONCLUSIONS: The TA particle size and the suspension medium are likely important factors in the preparation of a safe and stable suspension of TA. HPP-TA satisfied these requirements and should be suitable for clinical use.

Changes of intestinal mucosal and plasma PYY in a diarrhea model rat and influence of loperamide as the treatment agent for diarrhea.

Peptide YY (PYY) is produced by endocrine cells in the lower gastrointestinal tract. The main functions of PYY are antisecretory effects in the colon and inhibition of gastrointestinal motility. We chose PYY as an index of the intrinsic factor in diarrhea and examined the influence of changes induced in a diarrhea rat model by administration of 4 types of laxative and loperamide hydrochloride (loperamide) as an agent for the treatment of diarrhea. A specific radioimmunoassay was performed to determine plasma and intestinal mucosal PYY concentrations. PYY in the rat intestinal tissue extract was distributed at a high density in the lower intestinal mucosa. In the diarrhea rat model, multiple changes in PYY concentrations in the intestinal mucosa and plasma were observed. In rats administered castor oil and sodium picosulfate, the intestinal mucosal PYY levels significantly decreased in a dose-dependent manner. Plasma PYY levels significantly decreased only in rats administered magnesium citrate. Next, we examined the influence of loperamide administration on the intestinal mucosa and plasma PYY concentrations in these rats. Loperamide administration resulted in multiple changes in plasma and intestinal mucosa PYY concentrations, along with an improvement in the diarrhea. Our research showed that the endocrine hormone PYY is involved in the onset of diarrhea, the course of the condition, and the manifestation of medicinal effects in the lower intestine.

Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone.

Few studies have reported the changes in the peptide YY (PYY) levels in the intestinal tissue of rats with ulcerative colitis (UC) following oral administration of mesalazine and prednisolone. We investigated the effects of these drugs on the intestinal mucosal PYY levels in a rat model of UC. We confirmed that the PYY levels in the rat intestinal mucosal tissue were high in the lower intestinal tract. The leukocyte count and hemoglobin levels approached the normal values after administering mesalazine or prednisolone to rats treated with 3% dextran sulfate sodium (DSS). The PYY levels in the caecum and colon decreased significantly after administering DSS but increased when mesalazine was administered in a tissue-specific manner. Unlike mesalazine, the PYY levels increased in the ileum in addition to the colon and rectum after administering prednisolone. However, neither of the drugs induced any changes in the plasma PYY levels. These findings indicate that changes in the intestinal tissue PYY levels may be partially involved in the improvement of DSS-induced UC in rats following the administration of these drugs.

The pathophysiological roles of COX-1 and COX-2 in the intestinal smooth muscle contractility under the anaphylactic condition.

Various inflammatory mediators released from antigen-activated mast cells are considered to play a key role in the pathogenesis of food allergy. The aim of the present study was to determine the mechanisms underlying the antigen-induced anaphylactic responses in the rat colons. Wistar rats were sensitized by intraperitoneal injection of ovalbumin (OVA). The contractilities of isolated proximal colons of the sensitized rats were studied in the organ bath. OVA challenges of sensitized tissues induced prolonged contractile responses. The antigen-induced contractions were greatly reduced by mast cell stabilizer doxantrazole (10 microM). However, the contractions were resistant to histamine H1 receptor antagonist and prostaglandin D2 receptor antagonist. In contrast, non-selective cyclooxygenase (COX) inhibitor indomethacin (1 microM) significantly reduced the contractions by 61.0%. Furthermore, selective COX-1 inhibitor FR122047 (10 microM) as well as selective COX-2 inhibitor NS-398 (10 microM) significantly inhibited the contractions by 50.1% and 50.3%, respectively. Nevertheless, the transcript levels of COX-2 as well as COX-1 were not upregulated by OVA in the proximal colons of the sensitized rats. The present results indicate that de novo arachidonic acid metabolites synthesis by constitutive COX-1 as well as constitutive COX-2 within mast cells contribute to the altered smooth muscle contractilities in the colons under the anaphylactic condition.

Suppressive action of pituitary adenylate cyclase activating polypeptide (PACAP) on proliferation of immature mouse Leydig cell line TM3 cells.

We aimed in the current study to understand the participation of PACAP in stage-specific Leydig and Sertoli cell functions. For this purpose, clonal cell lines TM3 (Leydig) and TM4 (Sertoli) cells, derived from the testis of immature BALB/c mice, were used. PACAP-specific receptors were detected in TM3 cells, but not in TM4 cells, which were characterized as PAC1 (type I) receptors. Stimulation of cAMP accumulation and testosterone secretion were observed in TM3 cells during 1-2 h treatment with PACAP38 (10(-10)-10(-7) M) or PACAP27 (10(-11)-10(-7) M). After around 10 h treatment with 10(-11)-10(-7) M PACAP38 or PACAP27, proliferation of TM3 cells was suppressed in time- and dose-dependent manners, which was confirmed by real-time cell electronic sensing (RT-CES) system and phase-contrast microscopy. At 6 h after the addition of PACAP38, the percent cell population in G(2)/M phases increased significantly, while that in S phase showed significant decrease with little change in G(0)/G(1) phases. The results revealed that PACAP exerts, in addition to early stimulatory effect on cAMP formation-steroidogenesis, sustained suppressive effect on cell proliferation in TM3 cells by controlling progression of the cell cycle. The suppressive action of PACAP on proliferation in TM3 cells supports the stage-specific participation of the peptide in differentiation of immature mouse Leydig cells.

High-efficacy site-directed drug delivery system using sialyl-Lewis X conjugated liposome.

The aim of this study was to evaluate the new developed sialyl-Lewis X conjugated liposome (sLe XL) as a site-directed delivery system to activated endothelial cells in vivo using a murine experimental autoimmune uveoretinitis (EAU) model. Four types of nanoparticles were prepared using this liposome: fluorescein isothiocyanate (FITC) labeled sLe XL (F-sLe XL) and its vehicle (F-L), sLe XL containing dexamethasone (d-sLe XL) and liposome without sLe X containing dexamethasone (d-L). First, after a bolus injection of F-sLe XL or F-L into EAU mice, sequential tissue accumulation of FITC was examined by confocal laser scanning microscopy. Second, anti-E-selectin antibody, as a blocking antibody, was given intravenously to EAU mice prior to the injection of F-sLe XL in order to investigate the effect of the antibody on inhibition of the accumulation of F-sLe XL. Third, concentration of dexamethasone in several organs after the injection of d-sLe XL (total dexamethasone 2 microg) or free dexamethasone solution (1mg) was measured by radioimmunoassay. Accumulation of FITC was only observed in F-sLe XL treated EAU mice. F-sLe XL accumulated on the activated endothelial cells within 5 min; accumulation then was inhibited using anti-E-selectin antibody. The FITC color was dispersed sequentially to the entire retina. d-sLe XL showed selective targeting to the inflamed eye, where an approximately two-fold higher dexamethasone concentration was achieved compared with 1mg free dexamethasone. sLe XL can be a highly efficacious site-directed system in vivo. Using sLe XL as a vehicle for drug delivery, substantial pharmacologic effects with minimum side effects in inflammatory diseases should be achieved.

Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on intestinal function in streptozotocin-induced diabetic rats.

We examined the effects of Hachimi-jio-gan (HJ) on the small intestinal function in streptozotocin (STZ)-induced diabetic rats. The rats had free access to pellets containing 1% HJ extract powder for 4 weeks after STZ administration. The intestinal disaccharidase (sucrase and maltase) activity was elevated in STZ-treated rats compared with control rats, whereas it was significantly reduced by HJ administration. This suggested that HJ suppresses or delays monosaccharide production in the small intestinal epithelium. In addition, the intestinal mucosal weights and DNA contents that were significantly increased in the STZ-treated rats were restrained to the control level by HJ treatment. Simultaneously, we examined the changes in the plasma levels of glucagon-like peptide 2 (GLP-2), which is a trophic factor specific for the intestine. The plasma GLP-2 levels significantly increased in the STZ-treated rats, whereas HJ decreased the plasma GLP-2 levels. Thus intestinal mucosal weights and DNA contents correlated with plasma GLP-2 levels in diabetes-associated bowel growth. These results suggest that HJ may normalize or suppress the small intestinal disaccharidase activity and the epithelial cell proliferation mediated by GLP-2 in the animal model rats.

[Present situation and problems of the ordering system type infusion center].

We examined four problems of the ordering system type infusion center. In this system,regimen is made by chief physician and cared by the staff in the infusion center. 1) In securing of the staff, an upbringing of doctors and IV nurses are important. 2) An evidence-based regimen is necessary in order to minimize the differences of regimen made by each doctor. 3) A facility expansion might reduce an incident risk. 4) As the condition of patient suddenly changes,the chief physician of the patient should be contacted. We suggest that it is particularly important to make these problems clarified and solved by the team within the institution.

A retrospective chart review of the antiemetic effectiveness of risperidone in refractory opioid-induced nausea and vomiting in advanced cancer patients.

Nausea and vomiting are distressing symptoms in advanced cancer patients. The causes of nausea and vomiting are multifactorial. Among the causes is opioid therapy, the mainstay of cancer pain management. When nausea or other opioid side effects occur, it may hamper pain management and undermine the quality of life of cancer patients. Risperidone exerts an antiemetic effect in animals, but there has been no clinical report on its antiemetic activity. We conducted a retrospective chart review to examine whether risperidone is useful for opioid-induced nausea and vomiting in advanced cancer patients (n=20). Risperidone was given as doses of 1mg once a day. Complete response was observed in 50% of patients (10/20) for nausea and 64% (7/11) for vomiting. Sedation (n=2) was documented as an adverse effect. This observation suggests that risperidone can be an effective antiemetic drug in the treatment of refractory opioid-induced nausea and vomiting in advanced cancer patients.

Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on hyperglycemia in streptozotocin-induced diabetic rats.

The present study investigated the effects of Hachimi-jio-gan (HJ) on diabetic hyperglycemia in streptozotocin (STZ)-induced diabetic rats. After STZ administration, rats had free access to pellets containing 1% HJ extract powder for four weeks. HJ markedly suppressed hyperglycemia in STZ-induced diabetic rats at three and four weeks after the start of administration. There were also significant increases in serum and pancreatic immunoreactive insulin levels in STZ and HJ co-administering rats. However, in the present study, the number of beta cells in the pancreatic Langerhans' islets did not increase. Next, in order to investigate the action mechanism besides the glycemic control action of insulin, the expression of glucose transporter 2 (GLUT2) protein, which is involved in glucose uptake and release in the liver, was investigated. GLUT2 protein expression was increased by STZ administration but was normalized after four weeks of HJ administration. Therefore, irrespective of the structural changes in pancreatic beta-cells due to STZ, HJ increased insulin production and secretion by the pancreas and significantly suppressed GLUT2 synthesis in the liver. Amylase secretion from the pancreas was measured to assess pancreatic secretion. Amylase activity was decreased by STZ but was increased by HJ. Therefore, the effects of HJ on STZ-induced hyperglycemia in rats could be summarized as follows: besides increasing insulin synthesis and release, HJ normalizes GLUT2 protein expression in the liver to suppress hyperglycemia. Hence, the results of the present study suggest for the first time that HJ affects not only the production and secretion of insulin, but also the release of glucose from the liver.

[Comparison of antiemetic efficacy of 5-HT3 receptor antagonists in orthopedics cancer patients receiving high-dose chemotherapy].

There are no reports comparing the efficacy of 3 selective 5-HT(3) receptor antagonists (Granisetron, Ondansetron, and Ramosetron). We designed a prospective study to compare the efficacy of Granisetron, Ondansetron, and Ramosetron. Thirteen patients gave informed consent to participate in the study. We assigned them to groups taking Granisetron, Ondansetron, or Ramosetron before the high-dose chemotherapy. They themselves reported the extent of their nausea and how many times they vomited per day from the first to the sixth day of chemotherapy. We evaluated their report with PLS (Partial Least Squares) and Welch's t-test. From the results of PLS, it was suggested that CDDP contributed the most and Ramosetron the least to the extent of nausea, while Doxorubicin (ADM)/CDDP contributed the most and Ramosetron the least to the frequency of vomiting. Then we compared the antiemetic effect of the agents regarding the types of chemotherapy. It was concluded that Ramosetron might have been the most effective of the three agents in reducing nausea and vomiting, but with no significant difference.

Eye-concentrated distribution of dexamethasone carried by sugar-chain modified liposome in experimental autoimmune uveoretinitis mice.

Corticosteroid is generally accepted as a standard therapeutic agent for active inflammatory (and) autoimmune eye diseases. In an attempt to develop a system to deliver corticosteroid most efficiently to the target eye, a sialyl-Lewis X (sLe(x))-conjugated liposome was adopted as a candidate for a carrier of dexamethasone (Dexa) and tissue distribution of intravenous Dexa with the modified liposome as well as Dexa alone as control was studied in normal and experimental autoimmune uveoretinitis (EAU) mice. Intravenous Dexa (1 mg) was widely distributed in all the tissues (eye, brain, heart, lung, liver, kidney, spleen and intestine) examined in similar manner in both mice and Dexa concentration was lowest in the eye except the brain. The tissue concentrations of Dexa in EAU group were all significantly lower than those in the corresponding tissues in normal group. Intravenous Dexa (2 microg) in the modified liposome was almost concentrated to the eye in EAU mice, reaching 13.84 ng/mg tissue in contrast to 2.34 ng/mg tissue in Dexa (1 mg) alone administered EAU mice. In normal mice, Dexa was undetectable in any tissues examined and thus the effect of the modified liposome was not observed. The result supported the potentiality of sLe(x)-conjugated liposome for target-delivering of corticosteroid to inflamed eye.

Correlation between plasma glucagon-like peptide 2 levels and proliferative makers in small intestinal injury in rats induced by methotrexate administration.

Glucagon-like peptide 2 (GLP-2) is a potent intestinal epithelium-specific growth factor that has been shown to reduce the severity of inflammatory disorders of the intestine in rodent models. We examined whether a relationship exists between plasma level of GLP-2 and the degree of intestinal injury induced by chemotherapeutic agents in the rat. Methotrexate (MTX) was administrated orally for 6 consecutive days at doses of 1.25, 2.5, and 5.0 mg/kg body weight per day. Mucosal samples of rat duodenum, jejunum, and ileum were used for assessment of mucosal weight, DNA and protein content. Plasma GLP-2 levels were measured on day 8. MTX significantly reduced body weight. The values of all indices tended to decrease in all segments with increases in MTX dose. Plasma GLP-2 levels were significantly higher in the MTX 2.5 mg/kg/d group (p<0.05) and the MTX 5.0 mg/kg/d group (p<0.01) than in the control group. Correlations were found between plasma GLP-2 levels and mucosal weight, DNA and protein content. We concluded that plasma GLP-2 levels reflect the degree of intestinal injury following MTX administration in this preclinical model.

[Problems in hospital preparation of acute poisoning antagonist (methylene blue injection)].

Since some antagonists or antidotes in cases of acute poisoning are not commercially available in Japan, in many hospitals they are prepared on their premises for clinical use. However, no specific legislation for the procedures of quality assurance and informed consent of these hospital-prepared products as yet exists. Further, the standard procedures for clinical use of the hospital-prepared products have yet to be established. For the treatment of patients with methemoglobinemia, we prepared methylene blue for injectable use in our hospital. In this paper, we describe our procedures ranging from its preparation to clinical use of this product. Methylene blue injection was prepared by using reagent-grade chemicals. The quality of hospital-prepared methylene blue injection was examined in accordance with the United States Pharmacopoeia. The contents of methylene blue injection remained constant at room temperature during storage for 12-month. The sterility testing also gave negative results during the same period. In order to obtain approval for its clinical use by the in-hospital ethical committee, relevant documents such as instructions for the preparation method, product information on safety usage and consent form were created. After these procedures, clinical applications of methylene blue injection were finally initiated.