Enhancement of Acinetobacter baumannii biofilm growth by cephem antibiotics via enrichment of protein and extracellular DNA in the biofilm matrices.

AIMS: The aims were to determine the effects of subinhibitory concentrations of eight cephem and carbapenem antibiotics on the biofilm formation of Acinetobacter baumannii cells and examine their effects on pre-established biofilms. METHODS AND RESULTS: Effects of antibiotics on biofilm formation were assayed using microtitre plates with polystyrene peg-lids. Cefmetazole, ceftriaxone, ceftazidime and cefpirome increased the biomass of pre-established biofilms on pegs in the range of their sub-minimum inhibitory concentrations (MICs), whereas none increased biofilm formation by planktonic cells. Carbapenems had a negative effect. The constituents of antibiotic-induced biofilms were analysed. Ceftriaxone or ceftazidime treatment markedly increased the matrix constituent amounts in the biofilms (carbohydrate, 2.7-fold; protein, 8.9-12.7-fold; lipid, 3.3-3.6-fold; DNA, 9.1-12.2-fold; outer membrane vesicles, 2.7-3.8-fold and viable cells, 6.8-10.1-fold). The antibiotic-enhanced biofilms had increased outer membrane protein A and were resistant to the anti-biofilm effect of azithromycin. CONCLUSIONS: Some cephems increased the biomass of pre-established biofilms in the ranges of their sub-MICs. The antibiotic-enhanced biofilms possessed more virulent characteristics than normal biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY: Incomplete administration of certain cephems following biofilm-related Ac. baumannii infections could adversely cause exacerbated and chronic clinical results.

Direct anti-biofilm effects of macrolides on Acinetobacter baumannii: comprehensive and comparative demonstration by a simple assay using microtiter plate combined with peg-lid.

Recently, opportunistic nosocomial infections caused by Acinetobacter baumannii have become increasingly prevalent worldwide. The pathogen often establishes biofilms that adhere to medical devices, causing chronic infections refractory to antimicrobial therapy. Clinical reports have indicated that some macrolide antibiotics are effective against chronic biofilm-related infections. In this study, we examined the direct anti-biofilm effects of seven macrolides (azithromycin, clarithromycin, erythromycin, josamycin, spiramycin, fidaxomicin, and ivermectin) on A. baumannii using a simple and newly established in vitro assay system for the swift and serial spectrophotometric determinations of two biofilm-amount indexes of viability and biomass. These macrolides were found to possess direct anti-biofilm effects exerting specific anti-biofilm effects not exclusively depending on their bacteriostatic/bactericidal effects. The anti-biofilm effect of azithromycin was found to be the strongest, while those of fidaxomicin and ivermectin were weak and limited. These results provide insights into possible adjunctive chemotherapy with macrolides for A. baumannii infection. Common five macrolides also interfered with the Agrobacterium tumefaciens NTL(pCF218) (pCF372) bioassay system of N-acyl homoserine lactones, providing insights into sample preparation for the bioassay, and putatively suggesting the actions of macrolides as remote signals in bacterial quorum sensing systems.

[Introduction of Team-based Learning to Evidence-based Medicine Educational Course for Pharmacy Students].

In Japanese pharmaceutical education, the Model Core Curriculum was revised in 2013 to train pharmacists who can appropriately evaluate literature and use evidence-based medicine (EBM). However, in the investigation of EBM education at pharmaceutical universities in 2015, it was found that literature evaluation was hardly performed in the education of undergraduate students. One of the reason is the lack of EBM lecturers at each universities. Therefore, we adopted team-based learning (TBL) to educate more than 50 undergraduate students on the practical evaluation of literatures and the understanding of EBM concepts. The learning outcomes of this strategy were evaluated using the scores of individual tests before and after the class. As a result, the mean scores on the post-test significantly improved from 4.34 to 6.42 out of 10 total points (p<0.001). We further administered a questionnaire survey regarding the understanding of EBM (the mean score was 4.12). In conclusion, it was suggested that TBL for a large number was effective in EBM education for providing knowledge of literature evaluation and the understanding of fundamental concepts.

[Factors Related to the Awareness and Self-confidence of Pharmacists regarding "PRE-AVOID": Study Using VISTA Project Data].

　The objective of this survey is investigating pharmacists' recognition of and belief in the importance of doing PRE-AVOID using the drug profile book (DPB). The main survey items were: 1. Awareness and self-confidence concerning PRE-AVOID using DPB, 2.Status of educating patients of the merits of the DPB, 3. Status of educating patients of the utilities of the DPB, 4. Status of educating patients of the roles of the DPB, 5. Guidance provided on methods of DPB usage, and 6. Interactions with patients. A multiple regression analysis was performed using "Awareness and self-confidence concerning PRE-AVOID using DPB" as a dependent variable. A regression equation including three items ("Educating the roles", "Blood test", and "Not using multiple DPBs at same time") was derived for "Self-confidence in PRE-AVOID work" (R2=0.20). The item most affecting "Self-confidence in PRE-AVOID work" was "Educating the roles" (R=0.28). A regression equation with "Awareness of PRE-AVOID work" as a dependent variable was not derived. The results of the study suggest that "Educating the roles" or "Not using multiple DPBs at same time" for patients, and asking the results of "Blood test" in a medication consultation may increase pharmacists belief in doing PRE-AVOID.

How Patient-Pharmacist Communication Using the Drug Profile Book Relates to Patient's Behavior regarding Its Use.

This survey aimed to examine how patient-pharmacist communication using the drug profile book relates patient's behavior regarding its use. Among patients who visited one of the five pharmacies during the 4 months between July and October of 2013, 245 patients who had been prescribed antihypertensives were asked to complete a questionnaire. Items included patient attributes, whether the patient thought the drug profile book was useful to them ("sense of utility"), whether the patient has ever been questioned by a pharmacist while showing the drug profile book ("experience of being questioned by a pharmacist while showing the drug profile book"), and whether the patient has ever shown the drug profile book to the physician ("experience of showing the drug profile book to the physician"). In addition, pharmacists counted the frequency of patients bringing the drug profile book, and if so, the frequency of the sticker affix during the last 5 visits. 34.3% of responding patients answered that they had the "experience of being questioned while showing the drug profile book". Response rates of "frequency of bringing the drug profile book", "sense of utility", and "experience of showing the drug profile book to the physician" in the group with "experience of being questioned while showing the drug profile book" were significantly higher than those in the group without such experience. This survey indicated that experience of being questioned by a pharmacist while showing the drug profile book related patient's behavior regarding its use.

Effectiveness of Pharmacists' Comprehensive Assessment of Medication Profiles in Dementia Patients.

In Japan the prevalence of dementia has increased considerably, and pharmacists are involved in addressing these patients' medication-related problems. Here, we determined whether pharmacists' comprehensive assessment of medication profiles could reduce the burden of dementia patients' medication-related problems. In this historical cohort study 120 community pharmacies were randomly selected, and participating pharmacists completed questionnaires concerning comprehensive assessment of patient medication profiles, using a "start" questionnaire for patients prescribed medication prior to or during the study period and a "follow-up" questionnaire for patients who subsequently visited pharmacies for prescriptions. Numbers and details of problems and solutions implemented by pharmacists and identified in the start and follow-up questionnaires were compared. Changes in start and follow-up scores were also compared between patients whose problems were identified by pharmacists (identified group) and those whose problems were not (non-identified group). Data were collected for 349 patients issued medication by 60 pharmacies. The most common medication-related problems identified in the start survey were key person's understanding of donepezil (60 cases) and other dementia treatments (60 cases), and adherence to treatment (53 cases). Solutions implemented by pharmacists included gathering information regarding drug administration and dementia awareness from the key person and providing pharmaceutical counseling and instruction. Subsequently, problems related to understanding of dementia treatment, understanding donepezil, and adherence were resolved by 70.0%, 65.0%, and 58.5%, respectively. Pharmacists' comprehensive assessment of medication profiles could effectively solve dementia patients' medication-related problems.

[Nationwide study on relations between workload and outcomes of home visiting service by community pharmacists].

A nationwide survey was conducted to verify relations between the workload of home-visiting service by community pharmacists and outcomes. Data were collected on 5447 patients from 1890 pharmacies. Most (61.9%) pharmacists visited patients' homes twice monthly, spending there a net average of 20.6 work minutes. At the time of the survey, 29.8% of the patients had improvement of adherence compared with at start of home visits; 65.5% had no change, and 1.4% had gotten worse. Similarly, 41.6% had decreased unused medications, 54.4% had no change, and 2.3% had increased. Home-visiting pharmacists found adverse drug events (ADEs) caused by drug administration in 14.4% of their patients. They dealt with 44.2% of these cases by discontinuing administration of the responsible drug, 24.5% by reducing the dosage, and 18.3% by changing drugs, with a total of 88.1% having been improved. Prescription changes intended to correct problems occurred in 37.1% of the patients. In patients whom the pharmacists visited more often, a higher percent had ADEs, had their prescription changed to correct problems, and had improved adherence and unused medications. The average actual work time was longer in patients whose outcomes improved than in those whose outcomes did not. A higher involvement in homecare by pharmacists was found to improve outcomes of drug treatment.

All-trans Arachidonic acid generates reactive oxygen species via xanthine dehydrogenase/xanthine oxidase interconversion in the rat liver cytosol in vitro.

We previously reported that the all-cis isomer of arachidonic acid, the most naturally occurring isoform of this fatty acid, reduced cuprous copper ion-induced conversion of xanthine dehydrogenase into its reactive oxygen species generating form, xanthine oxidase. In the present study, the effects of all-trans isomer of arachidonic acid, in comparison with cis isomer of arachidonic acid, on the xanthine dehydrogenase/xanthine oxidase interconversion were explored. cis isomer of arachidonic acid alone did not have any significant effect on the activities of xanthine dehydrogenase and xanthine oxidase, but it inhibited the cuprous copper ion-induced conversion of xanthine dehydrogenase to xanthine oxidase in rat liver cytosol in vitro. In contrast, trans isomer of arachidonic acid elicited an increase in xanthine oxidase activity concomitant with a decrease in xanthine dehydrogenase activity, and further potentiated the cuprous copper ion-induced xanthine dehydrogenase/xanthine oxidase interconversion. In primary rat hepatocyte cultures, trans isomer of arachidonic acid increased 2',7'-dichlorofluorescein-fluorescence intensity in the cytosolic fraction from 2',7'-dichlorodihydrofluorescein, an indicator of reactive oxygen species generation. The pretreatment of allopurinol, an xanthine oxidase inhibitor, diminished the trans isomer of arachidonic acid-induced increase in the 2',7'-dichlorofluorescein-fluorescence intensity, indicating the role of xanthine dehydrogenase/xanthine oxidase in mediating trans isomer of arachidonic acid-induced reactive oxygen species generation. These observations suggest that, in contrast to all-cis arachidonic acid, all-trans arachidonic acid has the potential to enhance reactive oxygen species generation via xanthine dehydrogenase/xanthine oxidase interconversion in the liver cytosol in vitro.

[Pilot study of dementia medication compliance conducted among pharmacists providing home visits which evaluates the degree of drug compliance, as defined by numerous attributes, between patients at home and patients in a medical facility].

A survey was conducted among pharmacists providing "home-visit guidance on drug management" to patients taking medication for dementia. Factors related to medication adherence among patients and pharmacists' acquisition of patient information were then verified. The survey items were: (1) patient attributes (degree of care received, bed-ridden, family composition, and living environment); (2) the person controlling medications; (3) drug storage method and location; (4) dispensing method; (5) patient management of visiting nurses; (6) patient management of visiting physician; (7) details of pharmacist's home-visit guidance; (8) medication adherence; (9) five items related to cognitive function (short-term memory, autonomous judgment, fluctuations in level of consciousness, excitation and loss of orientation, understanding); and (10) ten items related of ADL (mobility in bed, transferring, mobility within the home or outdoors, dressing upper/lower body, eating, toilet use, individual hygiene, bathing). The t test was used to verify the number of items of patient information concerning cognitive function and physical function that pharmacists could acquire at a visit. It was suggested that pharmacists were able to acquire more patient information (①cognitive function and ②ADL) when they visited patients cared for at home, compared to facility residents (①p=0.008, ② p=0.006). Thus, it was suggested that there is a latent risk concerning the pharmacist's ability to discover problems with administration of medications among facility residents. These findings demonstrate that it is essential for pharmacists to be more proactive about providing home-visit guidance.

[Research survey on the information gathering methods, attitudes, and requests from care managers about the pharmaceutical service by pharmacists in home care].

Care Managers (CMs) were surveyed to clarify the issues involving the promotion of cooperation between care managers and pharmacists in long-term-care and explore solutions. The length of work experience, occupational background, experience of pharmaceutical service; pharmacist visit patients' home for providing medicine and pharmaceutical care into a care plan, degree of understanding on pharmaceutical service, and awareness of work involved in pharmaceutical service were studied to see whether there made differences in the requests from CMs for information on pharmacists and for information gathering methods. The χ(2) test was used to this end. The opinions and requests described by the CMs were validated through text mining. More CMs tended to obtain information and knowledge through training sessions and professional magazines than those who did so through cooperation with pharmacists on a practical level. However, the survey strongly indicated that CMs with high level of understanding and awareness of pharmaceutical service wished to obtain information on pharmacists through cooperation with them on a practical level, and CMs with low level of understanding and awareness of pharmaceutical service wished to obtain such information through training sessions and professional magazines. Results of text mining showed that CMs wished pharmacists to strengthen the cooperation with physicians and provide information on pharmaceutical service. These findings have led to the conclusion that the issues surrounding the promotion of cooperation between CMs and pharmacists centered around "work cooperation on a practical level" and "provision of information to CMs about the roles of pharmacies and pharmacists and their work."

[Study on incorporation of "management and guidance of home-visiting by a pharmacist" into a care plan -observation based on a survey of care managers-].

A survey of care managers ("CMs") was conducted to identify top priority issues in promoting the management and guidance of home-visiting by a pharmacist ("management and guidance") by focusing on the experience in incorporating the management and guidance into a care plan and its relevant factors. Major survey items included (1) number of years working as a CM, (2) basic occupation, (3) experience in incorporating the management and guidance into care plans, (4) understanding the management and guidance content, and (5) an awareness of the need for pharmacists' involvement in care plans. A χ² test was conducted to determine if the experience in incorporating the management and guidance into care plans caused a difference in the distribution of the number of years as a CM, the basic occupation, understanding of the management and guidance content, and an awareness of the need for pharmacists' involvement in care plans. A regression analysis was conducted to determine the degree of association between the incorporation experience and each item. The numbers of years working as a CM, the basic occupation, understanding of the management and guidance content, and an awareness of the need for pharmacists' involvement in care plans, were found to be associated with the experience in incorporating the management and guidance into care plans. Understanding of the management and guidance content was most closely associated. To promote pharmacists' management and guidance for home-based care, CMs need to deepen their understanding of this service.

[Survey on the attitudes of pregnant and lactating women about the use of drugs].

The purposes of this survey were to determine the attitudes and the extent of anxiety of pregnant and lactating women about drug use, and to research priority issues for pharmacists' intervention. Postpartum lactating women and mothers with children in a Growing Care Unit (GCU) in hospitals certified as Baby Friendly Hospital (BFH) were surveyed. The questions included the images the respondents had of drugs before pregnancy, the extent of anxiety about drug use, and ways to relieve it. The highest number of respondents (49.1%) did not want to use drugs often before pregnancy, but said "physician-prescribed drugs are fine". 24.5% had no negative images, and they "take drugs when necessary without worrying". An additional 14.2% did not like drugs, and "avoid them whenever possible", followed by 9.4% who did not want to use drugs, but were willing to take health food and other over-the-counter items. The respondents reported that the extent of anxiety about drug use was 79.3% during pregnancy, which was higher than 71.7% during lactation. It was not influenced by birth experience and age. "The images of drugs before pregnancy" and "the extent to which the anxiety was relieved during pregnancy" were extracted as factors related to the extent of anxiety, verifying that negative images of drugs and low degrees of relief from anxiety raise the anxiety of pregnant women. The above shows that pharmacists need to understand the anxiety of pregnant and lactating women about drug use, and the images they had of drugs before pregnancy, thereby they are expected to work actively to determine and relieve the anxiety.

Perfluorinated carboxylic acids inhibit cyclooxygenase pathway more potently than 12-lipoxygenase pathway in rat platelets.

Two perfluorinated carboxylic acids (PFCAs), pentadecafluorooctanoic acid (PDFOA) and heptadecafluorononanoic acid (HDFNA), were investigated for potential modulatory effects on the cyclooxygenase (COX) and 12-lipoxygenase (LOX) metabolisms in rat platelets. Both PDFOA and HDFNA dose-dependently inhibited the formation of a COX metabolite, 12-HHT, without any effect on that of a LOX metabolite, 12-HETE, at concentrations ranging from 10 to 100µM. These two PFCAs up to 100µM did not affect platelet membrane integrity, and COX-1 and -2 protein expression levels in Caco-2 cells. These results suggest that PDFOA and HDFNA have the potential to modify platelet function by inhibiting the COX pathway at activity level, but not at protein level.

Effects of Lipid Peroxidation-Derived Products on the Growth of Human Colorectal Cancer Cell Line HT-29.

Epidemiologic investigations indicate a close relationship between colorectal cancer and fat intake. However, to date the effects of lipid peroxidation-derived products that are formed from fat (especially free or esterified unsaturated fatty acids) on the initiation or progression of colorectal cancer have not been investigated extensively. Therefore, in the present study, we examined the effects of fatty acids, fatty acid hydroperoxides and aldehydes on the growth of human colorectal cancer cell line HT-29. At concentrations of 1 and 10 microM, linoleic, arachidonic and eicosapentaenoic acids, and 13-hydroperoxyoctadecadienoic and 15-hydroperoxyeicosapentaenoic acids had no significant effects on the growth of HT-29 cells. 4-Hydroxynonenal and 4-hydroxyhexenal had no significant effects on the growth of HT-29 cells up to 10 microM, whereas 4-oxononenal potently inhibited HT-29 cell growth (1-10 microM, 16-85% inhibition). Further experiments concerning DNA fragmentation, expression levels of Bax and Bcl-2 mRNA, expression levels of pro-caspase-3 and caspase-3 proteins, and activity of caspase-3 suggested that 4-oxononenal may increase the sensitivity of HT-29 cells to apoptosis through a decreased expression level of Bcl-2 and then increased formation of caspase-3 from pro-caspase-3.

Monochloramine produces reactive oxygen species in liver by converting xanthine dehydrogenase into xanthine oxidase.

In the present study, we assessed the influence of monochloramine (NH(2)Cl) on the conversion of xanthine dehydrogenase (XD) into xanthine oxidase (XO) in rat liver in vitro. When incubated with the partially purified cytosolic fraction from rat liver, NH(2)Cl (2.5-20 microM) dose-dependently enhanced XO activity concomitant with a decrease in XD activity, implying that NH(2)Cl can convert XD into the reactive oxygen species (ROS) producing form XO. The NH(2)Cl (5 microM)-induced XD/XO interconversion in the rat liver cytosol was completely inhibited when added in combination with an inhibitor of NH(2)Cl methionine (25 microM). A sulfhydryl reducing agent, dithiothreitol at concentrations of 0.1, 1 and 5 mM also dose-dependently reversed the NH(2)Cl (5 microM)-induced XD/XO interconversion. These imply that NH(2)Cl itself acts on the XD/XO interconversion, and that this conversion occurs at the cysteine residues in XD. Furthermore, using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate, it was found that NH(2)Cl could increase ROS generation in the cytoplasm of rat primary hepatocyte cultures, and that this increase might be reversed by an XO inhibitor, allopurinol. These results suggest that NH(2)Cl has the potential to convert XD into XO in the liver, which in turn may induce the ROS generation in this region.

Effects of patient-pharmacist communication in the treatment of asthma.

We studied the relationship between patient-pharmacist communication and asthma treatment, including patient understanding of drug therapy, ability to self-treat with inhaled drugs, and control over asthma. The study was among adult patients who had received inhaled steroidal or other drugs from community pharmacies in Hokkaido, Ibaragi, Tochigi, Kanagawa, and Osaka prefectures for at least one year. During the month of November 2007, pharmacists explained the study to patients and obtain consent before distributing questionnaires to be filled out and mailed back. Survey items covered the nature/extent of the pharmacist's explanation, the patient's degree of understanding, frequency of inhaled steroid use, frequency of asthma attacks, degree of improvement with inhaler use, skill in using inhaled drugs, and self-evaluation of communication with the pharmacist. Analysis was carried out using the 114 valid data sets obtained. The ratio of men to women was 4: 6, and the average age was 61.8 years. Compared with patients citing communication problems with pharmacists, those who had good communication received significantly higher scores in terms of understanding the purpose of inhalers, drug interactions, and side effects, and coping with attacks, as well as in indices of skill in using inhaled drugs. The degree of improvement in asthma attacks was also significantly higher among patients with self-evaluation of good communication with pharmacists. We suggest that communication between patient and pharmacist is associated with understanding of pharmacotherapy, as well as their ability to use inhaled medications and gaining good control over their asthma.

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.

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.

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.

[Availability of drug information on bioequivalence of generic products--findings of graduate interns at a university pharmacy].

Access to drug information (DI) needed to evaluate generic product bioequivalence was studied to identify problems with the current status of DI availability and encourage proper use of DI. Ten items were chosen from among the stock of branded products at the University Pharmacy, and five corresponding generics were selected for each item. Conditions of access to information on pharmacokinetic tests and dissolution tests were rated and the assigned ratings compared. In the case of pharmacokinetic parameters obtainable from makers of generic drugs, we also performed Welch's t-test to compare the difference between values reported for branded and generic products. From the standpoint of individual tests, the pharmacokinetic tests yielded higher scores on the whole than did the dissolution tests, and low scores were obtained for the half-life of blood drug concentration (T1/2). We observed a tendency for the adequacy of information to depend more upon the drug item itself than upon the nature of the test. The percentage of tests allowing for comparison with branded products varied from 0%-75% (average 49%). Parameter by parameter, the range of variation was from 35% of Tmax to 63% of Cmax. Factors precluding comparison included insufficient data on branded products, mismatch in assayed chemical species between branded and generic, mismatch between final sampling time in AUC(t) measurement, dosage inconsistency, and insufficient data on generic products. DI should be provided in a manner that facilitates comparison of information supplied by generic drug makers with data released by makers of branded products.