Publications by authors named "Yoshihiko Hirotani"

30 Publications

  • Page 1 of 1

Approach for differentiating trophoblast cell lineage from human induced pluripotent stem cells with retinoic acid in the absence of bone morphogenetic protein 4.

Placenta 2018 11 10;71:24-30. Epub 2018 Oct 10.

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan.

Introduction: Placental transport is the first step in chemotherapeutic safety evaluations during pregnancy. However, a well-established in vitro model is not available. We previously reported that a trophoblast layer model using differentiating choriocarcinoma JEG-3 cells (DJEGs) can be used for placental drug transport studies. However, it was necessary to increase the similarities between the syncytiotrophoblast, the main layer of the placental barrier, and the in vitro evaluation model in order for the model to be useful for placental drug transport evaluations. We focused on in vivo similarities of differentiating induced pluripotent stem cells (iPSCs). iPSCs can achieve a syncytiotrophoblast-like form and secrete human chorionic gonadotropin (hCG) following bone morphogenetic protein 4 (BMP4) treatment. However, BMP4-treated iPSCs can differentiate into several cell types. In the placental transport model, a dense syncytiotrophoblast cell layer is necessary for appropriate differentiation.

Methods: The conditions permitting differentiation of iPSCs into syncytiotrophoblasts with retinoic acid (RA) treatment without BMP4 were investigated. The presence of syncytiotrophoblast-like cells was confirmed by measurement of mRNA expression levels of breast cancer resistance protein (BCRP) and paternally expressed 10 (PEG10) in syncytiotrophoblasts. In addition, immunofluorescence imaging of cytokeratin 7 (CK7) induced in trophoblasts was performed.

Results: and Discussion: RA-induced iPSCs exhibited these syncytiotrophoblast-like features and hCG secretion was maintained for at least 28 days after treatment with RA (500 nM) without BMP4. These results suggest that RA-induced iPSCs are a suitable in vitro syncytiotrophoblast model that can be used as an indicator of drug placental transport for pharmacotherapy during pregnancy.
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http://dx.doi.org/10.1016/j.placenta.2018.10.001DOI Listing
November 2018

Effects of Capsaicin Coadministered with Eicosapentaenoic Acid on Obesity-Related Dysregulation in High-Fat-Fed Mice.

Biol Pharm Bull 2017 ;40(9):1581-1585

Faculty of Pharmacy, Osaka Ohtani University.

Obesity-induced inflammation contributes to the development of metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. In this study, we investigated whether the combination of eicosapentaenoic acid (EPA) and capsaicin could protect against high-fat diet (HFD)-induced obesity and related metabolic disorders. The experiments were performed using male C57BL/6J mice that were fed one of the following diets for 10 weeks: standard chow (5.3% fat content) (normal group), a HFD (32.0% fat content) (HFD group), or a HFD supplemented with either 4% (w/w) EPA (EPA group) or a combination of 4% (w/w) EPA and 0.01% (w/w) capsaicin (EPA+Cap group). Our results indicated that the body, fat and liver tissue weights and levels of serum glucose, insulin, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, aspartate aminotransferase, and alanine aminotransferase were significantly higher in HFD group mice than in normal group mice (p<0.05 in all cases). However, the body and fat tissue weights and serum glucose levels and homeostasis model assessment of insulin resistance were significantly lower in EPA+Cap group mice group than in HFD and EPA group mice (p<0.05 in all cases). Thus, our study suggests that the combination of EPA and capsaicin might be beneficial for delaying the progression of obesity-related metabolic dysregulation and subsequent complications.
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http://dx.doi.org/10.1248/bpb.b17-00247DOI Listing
May 2018

Enhanced Understanding of the Levels of Palliative Care in Pharmacy Students Through Participating in Clinical Training in Hospitals.

J Pharm Pract 2017 Jun 18;30(3):313-317. Epub 2016 Mar 18.

3 Faculty of Pharmacy, Laboratory of Clinical Pharmaceutics, Osaka Ohtani University, Tondabayashi, Osaka, Japan.

Objective: A palliative care knowledge survey was conducted involving pharmacy students to examine their perceived usefulness and the educational effect of clinical training in hospitals.

Methods: A questionnaire sheet was distributed to fifth-year pharmacy students before and after clinical training. The questionnaire consisted of questions to clarify the details of palliative care-related training in hospitals and students' knowledge of such care. The respondents were divided into 2 groups: those who participated in palliative care team (PCT) rounds (group A: 57) and those who did not (group B: 57).

Results: The mean total correct answer rate markedly increased after training in group A, from 37.9 to 47.1% (P < .01). Such an increase was also observed in the domains of philosophy and pain in this group ( P < .01). In contrast, group B did not show differences in the mean correct answer rate between before and after training; there was no significant increase in the rate in any domain.

Conclusion: Pharmacy students' knowledge was enhanced by participating in the PCT, confirming the usefulness of such participation during training as part of palliative care education.
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http://dx.doi.org/10.1177/0897190016637528DOI Listing
June 2017

[The Current State of Inappropriate Drug Use among Elderly Assisted-Living Residents].

Gan To Kagaku Ryoho 2015 Dec;42 Suppl 1:43-4

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Faculty of Pharmacy, Osaka Ohtani University.

Previous studies have reported that elderly assisted-living residents use multiple drug combinations and inappropriate drugs.The aim of this study was to assess the drug use and its consequences in residents of a nursing facility.We examined the prescriptions of all residents in a nursing facility in Osaka from their medical records.Of the total 67 residents, 48 were women.The average age of the residents was 86 years, the average number of prescription drugs they took was 6.4, and the average number of diseases present was 4.9. Correlation between the number of diseases and the drugs taken was significant (p<0.05), but the correlation between the degree of independence for activities of daily living and the number of the drugs taken was not significant.The most commonly present health condition was bone fracture.About 50% of the residents used a psychotropic drug and prescription drugs such as amantadine and hydroxyzine, which are not advisable for elderly people.It is necessary for the elderly to avoid the use of drugs that cause delirium and drowsiness, and future studies should focus on methods to prevent disuse syndrome in the elderly.
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December 2015

Effects of eicosapentaenoic acid on hepatic dyslipidemia and oxidative stress in high fat diet-induced steatosis.

Int J Food Sci Nutr 2015 28;66(5):569-73. Epub 2015 May 28.

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohatani University , Tondabayashi, Osaka , Japan.

We investigated the ability of eicosapentaenoic acid (EPA) to prevent high-fat diet (HFD)-induced obesity and non-alcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed standard chow (5.3% fat content), an HFD (32.0% fat content) or an HFD + EPA (1 g/kg/day EPA for the last 6 weeks) for 12 weeks. Serum total cholesterol, hepatic triglyceride and total cholesterol levels were significantly increased in the HFD group, in comparison with those of normal mice (p < 0.01). In contrast, hepatic triglyceride and total cholesterol levels were significantly decreased in the HFD + EPA group, in comparison with those of the HFD group (p < 0.05). In addition, EPA decreased the body weight of obese mice and improved hepatic function. Hepatic superoxide dismutase activity and glutathione levels were significantly decreased in obese mice, but increased with EPA administration. Our data suggest that EPA supplementation has a beneficial effect on NAFLD progression.
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http://dx.doi.org/10.3109/09637486.2015.1042848DOI Listing
May 2016

[Evaluation of the pharmaceutical stability of polaprezinc/sodium alginate gargle solution containing lidocaine].

Gan To Kagaku Ryoho 2015 Feb;42(2):207-10

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University.

Objective: A gargle solution(L-P/AG)for the treatment of painful stomatitis was prepared by adding lidocaine to a polaprezinc/sodium alginate gargle solution(P/AG), and its pharmaceutical stability was evaluated.

Methods: L-P/AG was stored at 5, 25, and 40°C. The strengths of polaprezinc and lidocaine were determined. The viscosity and pH of L-P/AG were also determined, and its appearance was evaluated.

Results: When stored at 5 or 25°C in a dark place, L-P/AG showed neither reduction in the strength of either drug nor did it show a change in the viscosity, pH, or appearance. When stored exposed to light at 40°C, L-P/AG showed reductions in the strength of both drugs, as well as in viscosity and pH; furthermore, a change in appearance was noted.

Discussion: L-P/AG prepared for the treatment of painful stomatitis remains pharmaceutically stable for 28 days when stored at 25°C in a dark place.
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February 2015

[Thoughts and suggestions of pharmacists who participated in a home medical care training workshop in a local area].

Gan To Kagaku Ryoho 2014 Dec;41 Suppl 1:47-9

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University.

We organized a home medical care training workshop to offer community pharmacists an opportunity to advance home medical care by allowing pharmacists in regional medicine to collaborate with local pharmacist groups. A questionnaire was administered to all participants after the workshop. On average, participants rated the overall quality of the workshop as 8.46 out of 10. Our results revealed that 72.5% of participating pharmacists were experienced in home medical care, with the majority having between 5 and 10 years of experience. Participants suggested that the qualities necessary for effective home medical care were knowledge of home-based care, positive attitude, and coordination with different home medical care staff members. Participants also made suggestions for lectures in future workshops (e.g., upskilling to improve home medical care expertise). In conclusion, participants in a home medical care training workshop primarily desired to learn skills for home medical care. To this end, consecutively holding the workshop and a cooperation support system with other medical and care professionals would be indispensable.
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December 2014

[Opinions of and conscious changes in pharmacists who participated in home medical care training workshop:].

Gan To Kagaku Ryoho 2013 Dec;40 Suppl 2:159-60

We organized a home medical care training workshop to offer community pharmacists an opportunity to learn more about home medical care. The workshop consisted of lectures by the doctor, the nurse, and the pharmacist. A questionnaire was handed out to all the participants once the workshop had ended. On an average, the participants rated the overall quality of the workshop as 8.1 out of 10. Our results revealed that 62.7% of the participating pharmacists were experienced in home medical care, with the majority having between 1 and 5 years of experience. Most pharmacists with experience in home care had provided services such as delivering medicines to or instructing patients on the use of medicines at patient homes. Participants suggested that the qualities necessary for providing effective home medical care were knowledge of home-based care and a positive attitude, among others. Participants also made suggestions for lecture contents in future workshops, such as contract procedures or specific cases of home medical care. Furthermore, participants expressed many positive opinions such as the desire to hear the views of other professionals on home medical care. In conclusion, participation in the home medical care training workshop increased the participants' desire to learn and perform home medical care. This indicates that a subsequent workshop with the cooperation of other professionals is indispensable.
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December 2013

[Nutritional assessment employing the malnutrition universal screening tool for patients with colorectal cancer undergoing outpatient chemotherapy].

Gan To Kagaku Ryoho 2013 Sep;40(9):1185-8

Nutrition Support Team, Ikeda Municipal Hospital, Japan.

Objective: We surveyed the nutritional status of patients with colorectal cancer undergoing outpatient chemotherapy using the malnutrition universal screening tool(MUST)to examine its usefulness and association with adverse events.

Methods: We examined the use of the MUST and the incidences of adverse events in 34 patients with advanced or recurrent colorectal cancer who had undergone outpatient chemotherapy between April and December 2010.

Results: The high-risk patients requiring nutritional care intervention comprised 47. 1%(16 patients)of the study population, and these patients exhibited significant decreases in body weight and body mass index. The incidences of appetite loss and fatigue were significantly higher in the high-risk group than in the low-risk group.

Discussion: Precautions against adverse events may prevent a worsening of the nutritional status of patients with colorectal cancer. Thus, nutritional assessment is necessary in patients undergoing outpatient chemotherapy. Furthermore, the MUST appears to represent a very useful simplified nutritional screening method for the nutritional management for these patients.
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September 2013

Protective effects of the herbal medicine goshajinkigan in a rat model of non-alcoholic fatty liver disease.

Biomed Res 2012 Dec;33(6):373-6

Laboratory of Clinical Pharmaceutics, Osaka Ohatani University, Nishikiorikita, Tondabayashi Osaka, Japan.

This study was designed to investigate the effect of an herbal medicine-goshajinkigan (GJ)-on the regulation of total body weight, as well as liver and adipose tissue weights in rats fed a highfat diet (HFD) and drinking of 30% sucrose (HFDS) (HFD; the rats received 19.6% energy from carbohydrates, 18.2% from proteins, and 62.2% from lipids; total energy, 506 kcal/100 g). Control rats were fed a standard diet (the rats received 60.5% energy from carbohydrates, 26.2% from proteins, and 13.3% from lipids; total energy, 360 kcal/100 g). Over a period of 12 weeks, rats were allowed free access to either the standard diet or HFDS containing 0, 1, or 3% GJ. In comparison with the control group, the HFDS rats showed a significant decrease in overall body weight and adipose tissue weight, and an increase in liver weight at 12 weeks. GJ treatment significantly reversed the HFDS-induced decrease in body and adipose tissue weight and reduced the elevated liver weight dose-dependently. Similarly, GJ reduced the elevated serum aspartate aminotransferase levels observed in HFDS rats. These results suggest that GJ may have the potential to alleviate damage to the liver in subjects with long-term consumption of HFDS.
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http://dx.doi.org/10.2220/biomedres.33.373DOI Listing
December 2012

[A questionnaire survey for pharmacists participating in a home medical care training workshop].

Gan To Kagaku Ryoho 2012 Dec;39 Suppl 1:70-3

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University.

To clarify the issues associated with promoting pharmacists' participation in home medical care(HMC), we performed a questionnaire survey for pharmacists who participated in a HMC training workshop. The cumulative number of participants in the workshop was 284; the majority of the participants was from mid-sized pharmacies and had been working for over 10 years. The rate of pharmacists engaged in HMC was 69% and their main practices were "drug delivery to patients" and "drug administration guidance for patients at home". Many participants responded that the key items for HMC were "cooperation with people with different type of jobs", "a wide pharmaceutical knowledge", and "effective involvement with patients and their families". The present main issues regarding HMC were "low pharmaceutical care fees", "deficiency of pharmacists", and "insufficient collaboration with people with different type of jobs". In order to resolve these issues, it is necessary to construct a cooperation system with other medical and welfare-related societies and to continuously organize such workshop.
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December 2012

Application of terahertz absorption spectroscopy to evaluation of aging variation of medicine.

Anal Sci 2011 ;27(2):209-12

Nagahama Institute of Bio-science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829, Japan.

The absorption spectra of three kinds of medicines both before and after the expiration date: Amlodin OD(®) (5 mg), Basen OD(®) (0.2 mg) and Gaster D(®) (10 mg) have been measured by terahertz time domain spectroscopy (THz-TDS). All the medicines show some differences in the THz absorption spectra between medicines before and after the expiration dates. X-Ray powder diffraction (XRD) studies of all medicines suggest that the polymorph of the main effective compound is not changed before and after the expiration date. Therefore, the differences in the THz spectra between medicines before and after the expiration dates arise from aging variation of diluting agents and/or from modifications of intermolecular interaction between the effective compounds and diluting agents.
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http://dx.doi.org/10.2116/analsci.27.209DOI Listing
July 2011

In vitro approaches to evaluate placental drug transport by using differentiating JEG-3 human choriocarcinoma cells.

Basic Clin Pharmacol Toxicol 2011 Feb 18;108(2):138-45. Epub 2010 Oct 18.

Osaka Ohtani University, Japan.

Human choriocarcinoma cells have been used as models for studying transcellular drug transport through placental trophoblasts. However, these models allow the transport of low-molecular-weight drugs through intercellular gap junctions. This study aimed at investigating the differentiation patterns of JEG-3 choriocarcinoma cells under different culture conditions and establishing the appropriate model of in vitro syncytiotrophoblast drug transport. Paracellular permeability was estimated by measuring the transepithelial electrical resistance (TEER) across JEG-3 cell layers. The mRNA expression levels of non-expressed in choriocarcinoma clone 1 (NECC1) and breast cancer resistance protein (BCRP), and those of E-cadherin (ECAD) and cadherin-11 (CDH11), which are adherens junction-associated proteins related to fusogenic ability of syncytiotrophoblasts differentiated from cytotrophoblasts, protein expression levels were considered as the differentiation signals. The highest TEER values were obtained in the JEG-3 cells cultured in the Dulbecco's modified Eagle's medium (DMEM)/Ham's F-12 (1:1) mixed medium (CS-C(®) ; Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan). By comparing the TEER values and the differentiation signals, the authors identified at least five JEG-3 cell-differentiation patterns. The differentiation pattern of JEG-3 cultured in CS-C resembled the syncytiotrophoblast-like differentiation signal characterizations in vivo. In conclusion, the syncytiotrophoblast-like models of differentiating JEG-3 cells cultured in CS-C might be appropriate for evaluating drug transport across the placental trophoblast.
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http://dx.doi.org/10.1111/j.1742-7843.2010.00634.xDOI Listing
February 2011

Reduction of opioid side effects by prophylactic measures of palliative care team may result in improved quality of life.

J Palliat Med 2010 Apr;13(4):401-6

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka, Japan.

Purpose: In February 2002, the palliative care team was established in Ikeda Municipal Hospital to improve palliative care. We investigated changes in the incidences of side effects related to opioids, and evaluated palliative care team activities.

Methods: Regarding inpatients for whom narcotics were prescribed in our hospital in the years of 2002 (from October 1, 2002 until September 30, 2003), 2004 (from October 1, 2004 until September 30, 2005), and 2006 (from October 1, 2006 until September 30, 2007), we surveyed the rates at which laxatives or antiemetics were prescribed, frequency of defecation/its state before and after the start of narcotic therapy, frequency of nausea/vomiting, and dietary intake.

Results: The proportions of patients in whom laxatives were simultaneously prescribed during opioid therapy in 2002, 2004, and 2006 were 43.5%, 78.7%, and 75.6%, respectively. The proportions of those in whom antiemetics were combined with opioids were 45.7%, 78.7%, and 78.0%, respectively. The incidences of constipation were 50.0%, 39.3%, and 37.8%, respectively. Those of nausea/vomiting were 30.4%, 21.3%, and 9.8%, respectively. Those of anorexia were 65.3%, 39.4%, and 15.4%, respectively.

Conclusions: These results suggest that palliative care team activities facilitated appropriate drug prescription during opioid therapy, reducing the appearance of side effects, with likelihood of improved quality of life.
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http://dx.doi.org/10.1089/jpm.2009.0355DOI Listing
April 2010

Terahertz absorption spectra of original and generic ceftazidime.

Anal Sci 2009 Dec;25(12):1483-5

Nagahama Institute of Bio-science and Technology, 1266 Tamura, Nagahama, Shiga 526-0829, Japan.

The absorption spectra of ceftazidime and its generic versions (Modacin, Mosyl, and Mobenzocin) have been measured by terahertz time domain spectroscopy (THz-TDS). Differences in the THz absorption were observed between the original and generic versions. The results show small, but significant differences in the states of ceftazidime hydrate between the original and generic versions. THz-TDS can be used to evaluate the stability of medicines as well as to control their quality.
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http://dx.doi.org/10.2116/analsci.25.1483DOI Listing
December 2009

Changes of midazolam pharmacokinetics in Wistar rats treated with lipopolysaccharide: relationship between total CYP and CYP3A2.

Innate Immun 2008 Oct;14(5):291-7

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.

It has been reported that infection interferes with drug metabolism, resulting in changes in pharmacokinetics. In this study, we investigated the effects of lipopolysaccharide (LPS) on hepatic total cytochrome P450 (CYP), CYP3A2, and CYP2C11 contents in a transient, LPS-induced, endotoxemia model of rats. In addition, to assess the effects on CYP3A2 activities, the pharmacokinetics of midazolam (CYP3A2 substrate) and 1-OH-midazolam (metabolite of midazolam) were investigated. Hepatic total CYP contents were significantly low until day 3 (P < 0.05) but returned to the control level on day 5. Hepatic CYP3A2 contents were significantly decreased on day 1 until day 5 (P < 0.05) but returned to the control level on day 7. Hepatic CYP2C11 contents were continuously low until day 7, and lowest on day 3. The AUC of 1-OH-midazolam was significantly decreased on day 1 after LPS administration (P < 0.01). In conclusion, LPS (5 mg/kg) challenge decreased hepatic total CYP, CYP3A2, and CYP2C11 contents and also decreased the activities of hepatic CYP3A2. It took at least 7 days for hepatic total CYP and CYP3A2 to recover to control levels, and it was suggested that the changes of hepatic total CYP contents might correlate with those of hepatic CYP3A2 contents and activities. Additionally, it is shown that their changes might reflect the recovery process from inflammation.
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http://dx.doi.org/10.1177/1753425908095956DOI Listing
October 2008

Protective effects of lactoferrin against intestinal mucosal damage induced by lipopolysaccharide in human intestinal Caco-2 cells.

Yakugaku Zasshi 2008 Sep;128(9):1363-8

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiorikita, Tondabayashi City, Japan.

Indirect evidence suggests that lactoferrin (Lf), a major iron-binding protein in human milk, induces enterocyte growth and proliferation, depending on its concentration and affects the function and permeability of the intestinal mucosa. The bacterial endotoxin (lipopolysaccharide, LPS) is known to cause mucosal hyperpermeability in vivo. However, protective effects of Lf against LPS-mediated intestinal mucosal damage and barrier function in epithelial cells are not yet fully clarified. The aim of this study was to investigate whether Lf can reduce the cellular injury and alter epithelial hyperpermeability caused by LPS in human intestinal Caco-2 cells. When cell viability was measured by a WST-1 assay (tetrazolium salt-based assay), the protective effects against LPS-induced damage to Caco-2 cells were observed at doses of 800 and 1000 microg/ml Lf. The barrier function of Caco-2 monolayer tight junctions was assessed by measuring transepithelial electrical resistance (TEER) and permeability of FITC-labeled dextran 4000 (FD-4). The treatment of Caco-2 cells with Lf at doses of 400 and 1000 microg/ml significantly increased TEER as compared to treatment with LPS alone for 2 h (p<0.05). Further, at doses of 400 and 1000 microg/ml, Lf inhibited the enhancement of LPS-mediated permeability in Caco-2 cell monolayer. The results of this study suggest that Lf may have protective effects against LPS-mediated intestinal mucosal damage and impairment of barrier function in intestinal epithelial cells.
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http://dx.doi.org/10.1248/yakushi.128.1363DOI Listing
September 2008

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

Yakugaku Zasshi 2008 Sep;128(9):1347-53

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiorikita, Tondabayashi City, Japan.

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.
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http://dx.doi.org/10.1248/yakushi.128.1347DOI Listing
September 2008

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

Yakugaku Zasshi 2008 Sep;128(9):1311-6

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohatani University, 3-11-1 Nishikiorikita, Tondabayashi-City, Japan.

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.
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http://dx.doi.org/10.1248/yakushi.128.1311DOI Listing
September 2008

Effects of CpG-DNA from Escherichia coli on digoxin pharmacokinetics.

Biol Pharm Bull 2008 Jun;31(6):1226-9

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.

Deoxyribonucleic acid (DNA) from bacteria or viruses has been reported as one of the pathogen-associated molecular patterns (PAMPs) and a substance that can induce endotoxemia-like inflammation in animals. However, there has been no report on digoxin pharmacokinetics in the inflammation induced by bacterial DNA containing unmethylated CpG motifs (CpG-DNA). In this study, we investigated the effects of CpG-DNA on digoxin pharmacokinetics. We determined the degree of lipopolysaccharide contamination in CpG-DNA solution and examined the changes in digoxin pharmacokinetics in rats after CpG-DNA administration. In addition, plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nitrite/nitrate (NOx) were determined after CpG-DNA administration (5 mg/kg, i.p.). The AUC0-24 of digoxin increased significantly on Day 1-3 and CL/F decreased on Day 1 and Day 2 after CpG-DNA administration. On Day 7 after CpG-DNA administration, there were no significant differences in AUC0-24 and CL/F compared with the control group (without CpG-DNA administration). However, Kel remained relatively unchanged throughout the experiment. Plasma TNF-alpha concentrations were significantly increased at 1 h and plasma IL-1beta concentrations were significantly decreased at 6 h after administration of CpG-DNA, while plasma NOx concentrations were significantly increased at 12 h after CpG-DNA administration, compared with the control group. These findings suggest that CpG-DNA (5 mg/kg) induces a transient inflammatory condition, and that AUC0-24 and CL/F of digoxin were altered after CpG-DNA administration. Digoxin pharmacokinetics recovered within 7 d after CpG-DNA exposure.
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http://dx.doi.org/10.1248/bpb.31.1226DOI Listing
June 2008

Changes in digoxin pharmacokinetics treated with lipopolysaccharide in Wistar rats.

Biol Pharm Bull 2008 Jun;31(6):1221-5

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.

Lipopolysaccharide (LPS) is a highly bioactive substance that can cause local as well as systemic damage to various organs of both humans and animals, even at very low doses. However, there are a few reports on drug pharmacokinetics during endotoxemia. In this study, we analyzed the pharmacokinetics of digoxin (a therapeutic agent for cardiac insufficiency) as a probe drug for a two-compartment model in a rat model of endotoxemia induced by LPS for 5 d. Digoxin was given to Wistar rats intravenously (i.v.), orally (p.o.), and intra-intestinally using an in situ closed-loop method (loop). The AUCi.v. was significantly increased in the LPS (+) group throughout the experiment (p<0.05). There was significant decrease in V2 (volume of distribution of tissue compartment) on Day 1-3 (p<0.05). On Day 1-2 after LPS administration, the AUCp.o. was significantly increased in the LPS (+) group (p<0.05). The AUCloop was significantly increased throughout the experiment (p<0.05). The elimination rate constant was unchanged. Thus LPS administration affected the absorption but not the excretion of digoxin. The findings of this study suggest that digoxin absorption increased and the volume of distribution of tissue compartment decreased after LPS administration (5 mg/kg, i.p.). It appears that digoxin pharmacokinetics recover over 3 d after LPS administration.
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http://dx.doi.org/10.1248/bpb.31.1221DOI Listing
June 2008

Assessment of palliative care team activities--survey of medications prescribed immediately before and at the beginning of opioid usage.

Yakugaku Zasshi 2008 Feb;128(2):299-304

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi City, Japan.

We established the Terminal Care Study Group, consisting of physicians, pharmacists, and nurses, in September 2001, and developed the group into the Palliative Care Team. We have surveyed the state of concomitant medications immediately before and at the beginning of opioid usage (except injections) to assess the role of the Palliative Care Team. The survey period was 3 years from October 1, 2002 to September 30, 2005. While the frequency of the prescription of non-steroidal anti-inflammatory drugs (NSAIDs), laxatives, or antiemetics before the beginning of opioid administration did not differ significantly among the 3 periods, that at the beginning of opioid administration increased significantly in 2003 compared with 2002, and increased further in 2004. Many of the drugs used were those that were recommended in our cancer pain management program. Thus, the activities of the Palliative Care Team are considered to have led to proper measures for the control of the major adverse effects of opioids such as constipation and nausea/vomiting in addition to pain control in accordance with the WHO's pain ladder, and also contributed to improvements of the patients' QOL.
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http://dx.doi.org/10.1248/yakushi.128.299DOI Listing
February 2008

[Proceedings of clinical pharmacy research with the cooperation of community and hospital pharmacist and pharmacy school].

Yakugaku Zasshi 2007 Nov;127(11):1801-4

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohatani University, Nishikiorikita, Tondabayashi City, Japan.

The new pharmaceutical education system starts in Japan, those constructions are performed at a lot of universities aiming at the execution of a common examination and the clinical training, and the workshop for directive pharmacists have been held actively since last year. Moreover, various educational lectures, open lectures, and the training lectures for on-site pharmacist's upskilling are carried out. However, a technical training and the lecture for research approach that supports the pharmacist in a pharmaceutical clinical research are little at the chance to learn the research methods. Now, many joint researches with university initiative or a university is performed, and the institution of presentation inexperience at academic society also exists in terms of a regional element, a staff arrangement side, etc, and also when the continuation is difficult, it looks mostly. It is necessary that the teacher of pharmacy school almost arranged in the whole country support positively a clinical research by the nearby pharmacist, and also it seems that a clinical teacher's role is large in the cooperation of pharmacy school and the medical institution. Moreover, in order to elucidate the scientific basis (mechanism) of a problem suggestion in the clinical spot, basic research in a pharmacy school is also required. We always need to advance a pharmaceutical clinical research by considering the basic research by pharmacy school in medical institution, considering clinical research by medical institution in pharmacy school, while cooperating mutually. In this article, I show how to advance pharmaceutical clinical research.
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http://dx.doi.org/10.1248/yakushi.127.1801DOI Listing
November 2007

Effects of capsaicin on cellular damage and monolayer permeability in human intestinal Caco-2 cells.

Biol Pharm Bull 2007 Oct;30(10):1982-6

Laboratory of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.

Recent studies suggest that capsaicin (Cap), a major constituent of hot pepper, may affect the function and permeability of the intestinal mucosa in vitro. However, the relationships between the dose of Cap and the barrier and/or transporter functions on intestinal epithelial cells are unknown. The aim of this study was to investigate whether Cap initiates cellular injury and alter epithelial permeability in Caco-2 cells. Cellular toxicity, as measured using a lactate dehydrogenase release assay, was not observed at high concentrations of Cap (up to 300 microM). When cell viability was measured by a WST-1 assay (tetrazolium salt-based assay), damage to Caco-2 monolayers was observed at doses of 200 and 300 microM of Cap. The barrier function of tight junctions was assessed by measuring transepithelial electrical resistance (TEER) in Caco-2 cells. Treatment of Caco-2 cells with Cap at doses above 100 microM significantly decreased the TEER compared to treatment with buffer alone for 2 h (p<0.05). We next examined the effects of Cap on the activity of P-glycoprotein (P-gp) found on transcellular transporters. At doses of 100 and 200 microM, Cap inhibited the transport of rhodamine 123 by P-gp-mediated efflux in Caco-2 cells. Cap thus exhibited inhibitory effects on P-gp. The results of this study indicate that Cap, a dietary phytochemical, causes functional and structural changes in Caco-2 cell monolayers at noncytotoxic doses (less than 100 microM of Cap). The concomitant administration of Cap with drugs that are substrates of P-gp might increase the plasma concentrations of such drugs.
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http://dx.doi.org/10.1248/bpb.30.1982DOI Listing
October 2007

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

Yakugaku Zasshi 2007 Sep;127(9):1509-13

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Nishikiorikita, Tondabayashi City, Japan.

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.
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http://dx.doi.org/10.1248/yakushi.127.1509DOI Listing
September 2007

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

Biol Pharm Bull 2007 May;30(5):1015-20

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohatani University,

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.
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http://dx.doi.org/10.1248/bpb.30.1015DOI Listing
May 2007

Effects of lipopolysaccharide on intestinal P-glycoprotein expression and activity.

Eur J Pharmacol 2007 Jun 12;565(1-3):220-4. Epub 2007 Mar 12.

Department of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takastuki, Osaka 569-1043, Japan.

It is well known that pharmacokinetics is often altered by changing the expression and activity of P-glycoprotein during sepsis. However, there have been few reports about expression and activity of P-glycoprotein in the small intestine during sepsis. We examined the levels of intestinal P-glycoprotein expression and activity using a rat sepsis model induced by lipopolysaccharide (LPS, from Escherichia coli). LPS was administered to male Wistar/ST rats intraperitonealy (i.p.) at 5 mg/kg. The small intestine was excised before and 1, 3 and 7 days after LPS administration, and the intestinal P-glycoprotein expression was determined using Western blot analysis. The activity of P-glycoprotein was evaluated by measuring the efflux of rhodamine-123 (Rho123) in rats using an in situ single perfusion method. The changes of permeability via the paracellular route were evaluated by measuring the amount of fluorescein isothicyanate-dextran 4400 (FD-4) in a similar way. On Day 1 after LPS administration, both the level of P-glycoprotein expression and the total amount of Rho123 excreted into the intestinal lumen decreased significantly, but levels of both AUC2-95 and CLtot were not significantly different as compared with the control group. On Day 3, the total P-glycoprotein, including intestinal P-glycoprotein, might have been induced by sepsis, and then the excretion of P-glycoprotein substrate drugs into the intestinal lumen increased more than that of the control group. On Day 7, all pharmacokinetic parameters returned to the control level. Thus the intestinal P-glycoprotein function recovered within 3 days of LPS administration.
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http://dx.doi.org/10.1016/j.ejphar.2007.02.058DOI Listing
June 2007

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

Biol Pharm Bull 2006 Nov;29(11):2327-30

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohatani University, Tondabayashi, Japan.

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.
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http://dx.doi.org/10.1248/bpb.29.2327DOI Listing
November 2006

Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats.

Biol Pharm Bull 2005 Sep;28(9):1635-8

Department of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Osaka, Japan.

Cisplatin-induced nephrotoxicity is related to an increase in lipid peroxidation and oxygen free radicals in a kidney. In the present study, we investigated the effect of the dietary antioxidants, capsaicin (Cap), against cisplatin-induced lipid peroxidation and nephrotoxicity in rats. Nephrotoxicity induced by treatment with a single dose of cisplatin (5 mg/kg body weight i.p.). The animals were divided into 4 groups. Cap (10 mg/kg/d) was given by gavage from the same day of cisplatin injection. Cisplatin administration resulted in significant increases in the kidney weight as a percentage of the total body weight, urine volume, serum creatinine, and blood urea nitrogen by about 132, 315, 797, and 556% in comparison with the control rats, respectively (p < 0.05). Also, the renal tissue from the cisplatin-treated rats showed significant decreases in the kidney glutathione (GSH) content and superoxide dismustase (SOD) activity and a significant increase in malondialdehyde (MDA) production in comparison to the values at 0 h (p < 0.05). Seven days after Cap plus cisplatin treatments, the renal damage induced by cisplatin recovered to a significant statistically level. In addition, Cap prevented the rise of MDA and the reduction of SOD activities. These results suggest that Cap has protective effects against cisplatin-induced nephrotoxicity and lipid peroxidation in rats.
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http://dx.doi.org/10.1248/bpb.28.1635DOI Listing
September 2005

Immunochemical characterization and measurement of neuronal type nitric oxide synthase in human neuroblastoma NB-OK-1 cell using novel anti-synthetic peptide antibody and specific immunoassay system.

Regul Pept 2002 Jun;106(1-3):115-23

Laboratory of Pharmaceutical Sciences, Osaka University Graduate School of Medicine, Suita, Japan.

We developed a sensitive and specific immunoassay system for human neuronal nitric oxide synthase (hnNOS) using synthetic hnNOS(998-1024) peptide and anti-hnNOS(998-1024) antibody. The novel antibody and radioimmunoassay system revealed a typical nNOS protein in human neuroblastoma NB-OK-1 cell (160 kDa, 180 fmol/10(6) cells). The kinetic parameters of the enzyme were K(m)=4.88 microM and V(max)=4.34 pmol/min/mg protein for L-arginine. On incubation of NB-OK-1 cell for 24 h, betamethasone phosphate decreased both nNOS-immunoreactivity (nNOS-IR) and enzymatic activity in the cell dose-dependently. On the other hand, pituitary adenylate cyclase activating polypeptide(1-38) (PACAP38) increased both nNOS-IR and enzymatic activity at concentrations of 10(-10) and 10(-9) M, but inversely decreased both at 10(-7) M. These suggest the positive and negative implications of endogenous NO in proliferation and differentiation of the cell, which support mitogenic activity of NO generated by nNOS in the cell. The present findings also provided evidence that the quantitative change of nNOS protein controls the integrated activity of the enzyme in the cell and, in turn, substantiate the validity and reliability of the present immunoassay system for hnNOS and its practical usefulness.
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http://dx.doi.org/10.1016/s0167-0115(02)00059-9DOI Listing
June 2002
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