Ki Yon Rhew

The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts

Endoplasmic reticulum (ER) stress is closely connected to autophagy. When cells are exposed to ER stress, cells exhibit enhanced protein degradation and form autophagosomes. In this study, we demonstrate that the chemical chaperone, 4-phenylbutyric acid (4-PBA), regulates ER stressinduced cell death and autophagy in human gingival fibroblasts. We found that 4-PBA protected cells against thapsigargin-induced apoptotic cell death but did not affect the reduced cell proliferation. ER stress induced by thapsigargin was alleviated by 4-PBA through the regulation of several ER stress-inducible, unfolded protein response related proteins including GRP78, GRP94, C/EBP homologous protein, phospho-eIF-2α, eIF-2α, phospho-JNK1 (p46) and phospho-JNK2/3 (p54), JNK1, IRE-1α, PERK, and sXBP-1. Compared with cells treated with thapsigargin alone, cells treated with both 4-PBA and thapsigargin showed lower levels of Beclin-1, LC-3II and autophagic vacuoles, indicating that 4-PBA also inhibited autophagy induced by ER stress. This study suggests that 4-PBA may be a potential therapeutic agent against ER stress-associated pathologic situations.

Immunoadjuvant activity of icariin that induces Th1-type antibody in mice.

The adjuvant effect of icariin from Epimedium koreanum on the immune responses to bovine serum albumin (BSA) in mice was examined. Mice were immunized on days 1 and 22 intraperitoneally (i.p.) with one of the following: an emulsion form of BSA mixed with Incomplete Freund’s Adjuvant (BSA/IFA) or with Complete Freund’s Adjuvant (BSA/CFA) or BSA plus icariin mixed with IFA (BSA/Icariin/IFA). One week after the booster, polyclonal sera were collected from these animals to determine IgG isotypes specific for BSA in the sera and then spleens of these animals were harvested to evaluate IFN-γ and IL-4 produced in the splenocyte cultures. In order to determine the DTH (delayed type hypersensitivity) response, BSA was administered into the footpads of mice that were immunized as described above and the degree of footpad-swelling was measured. Data from these experiments showed that the icariin combined with BSA (BSA/Icariin/IFA) provoked the most abundant of IgG production in mice and enhanced the Th1-lineage development of IgG2a and IFN-γ productions (p < 0.05), whereas BSA/IFA resulted in a highest ratio of IgG1 to IgG2 and most dominant IL-4 production, indicating a Th2 response. This pattern of immunity was confirmed by the DTH determination revealing that icariin-containing formula caused the highest footpad-swelling followed by BSA/CFA and BSA/IFA, respectively. In addition, hemolytic assay showed that icariin at a dose of 1000 μg/mL caused no hemolysis when compared with a water-treated mouse. All of these data indicate that icariin has the immunoadjuvant effect which may enhance Th1-immune response, suggesting that icariin as an adjuvant would be beneficial in the treatment of Th1-disordered diseases.

Ginsenoside Rd induces protective anti-Candida albicans antibody through immunological adjuvant activity

The role of an antibody against candidiasis is controversial. However, a certain Candida albicans surface epitope produces a protective antibody. Yet, its isolation is difficult. In this study, we investigated if ginsenoside Rd from Panax ginseng has an immunoadjuvant ability to induce surface mannan extract (CASM) to produce a protective antibody. Mice were immunized twice i.p. with an emulsion form of CASM mixed with one of the following: IFA [CASM/IFA], or CFA [CASM/CFA] or Rd with IFA [CASM/Rd/IFA]. One week after the booster, these mice were challenged i.v. with live C. albicans and their survivability was measured. Results showed that four of five CASM/Rd/IFA-vaccinated mice survived during the entire 110 day-observation period, whereas CASM/IFA- or CASM/CFA-vaccinated mice died within 19 and 23 days (P<0.05). The antiserum from CASM/Rd/IFA-immunized mice transferred the protection to naïve mice, whereas antiserum from CASM/CFA-given mice was not protective although CASM/CFA induced an antibody four times greater than CASM/Rd/IFA. IgG isotyping revealed that CASM/Rd/IFA-vaccine produced the most abundant IgG and IgG2a-resulting in the highest ratio (1.32) of IgG2a to IgG, which is helpful in treating Th2-oriented candidiasis. In contrast, the formulae lacking Rd had these ratios less than 1. This strongly indicates that Rd could enhance Th1 immunity. Cytokine profiles and DTH further confirmed the Th1 dominance. Rd caused no hemolysis. Combining all of these data together, Rd can enhance Th1-response to CASM in mice. This protects mice against disseminated candidiasis by eliciting higher titers of Th1 type antibody and a Th1-dominant immune response.

Comparison of two Candida mannan vaccines: the role of complement in protection against disseminated candidiasis.

We have previously shown that Candida albicans mannan extract encapsulated in liposomes [Lipo-mann] or conjugated to a protein (bovine serum albumin) [Conju-mann] induces the production of antibody in BALB/c mice with normal complement system that protect against disseminated candidiasis. In this present study, we determined the protective abilities of two formulae in a C5-deficient mouse model of disseminated candidiasis. It is known that the lack of C5 is known to aggravate candidal infection. In experiments, BALB/c or C5-deficient mice-DBA/2J and AKR mice, were immunized with one of the formulae before intravenous challenge with live C. albicans yeast cells and their degrees of survivability were measured. Results showed that Conju-mann was 100% protective in BALB/c mice against disseminated candidiasis, whereas only 60% of Lipo-mann immunized mice survived the entire 50 day observation period (p < 0.05). With the DBA/2J strain, Conju-mann resulted in a partial protection, but Lipo-mann had no protection. The conjugate vaccine enhanced the resistance of AKR mice, which resulted in three survivors of the five Conju-immunized AKR mice until the end of 50 day observation period (p < 0.05). Lipo-mann showed little protection in AKR mice. By agglutination analyses, it was determined that there was the same level of production of polyclonal antisera specific to the mannan regardless of the mouse strains. All data indicate that both formulations require complement in the protection. However, Conju-mann appears to be superior to Lipo-mann because the conjugate vaccine is protective even in the absence of C5. These observations suggest that the conjugate vaccine can be an excellent vaccine formulation against C. alibicans infections.

Perceived needs of pharmaceutical care services among healthcare professionals in South Korea: a qualitative study

Purpose To explore the need for pharmaceutical care services, key features of desirable pharmacy services, and perceived barriers for advancing the services in hospital environments with doctors and nurses who are key co-workers of the interdisciplinary team care services.Methods Semi-structured, in-depth interviews with eighteen doctors and fifteen nurses employing purposive and snowballing sampling strategies were conducted in ten hospitals in South Korea. Results The level of pharmaceutical care was varied across regions or institutions in South Korea. The concept of pharmaceutical care was insufficiently defined, and tended to be limited to some parts of medication counseling. Through pharmaceutical care services, doctors desired to acquire comprehensive drug information from and to share clinical responsibilities with pharmacists. Nurses wished to lower their burdens of medication counseling services from their daily practices. Doctors and nurses asked for pharmacists providing essential and carefully selected medication information to their patients in a patient-centered manner. The listed barriers to pharmaceutical care included the lack of appropriate systems for reward, insufficient accessibility to patient records by pharmacists, ambiguous role descriptions of pharmacist, and absence of effective communication among professionals. Conclusion A successful pharmaceutical care service model should allow efficient exchange of information among healthcare professionals to build inter-professional trust and to provide a continuity of care both in terms of time and setting. As prerequisites of such system, it was warranted to develop clinical evidence and an appropriate reward system for pharmaceutical care services.

Famciclovir as an antiviral agent for a patient with acute renal failure

Case Acyclovir is a widely administered medication for viral infection but is well known for its nephrotoxicity. To date, few studies regarding the safety of alternative antiviral agents have been reported. This study reports the case of a patient with renal dysfunction who suffers from acute herpes zoster (shingles) on her back. While renal function deteriorated with the use of acyclovir, the patient’s symptoms improved and baseline renal function recovered when she was treated with famciclovir. Conclusions Famciclovir could be taken as a first-line antiviral agent for patients with acute renal failure.

Service design oriented multidisciplinary collaborative team care service model development for resolving drug related problems

Our goal was to help prevent drug-related morbidity and mortality by developing a collaborative multidisciplinary team care (MTC) service model using a service design framework that addressed the unmet needs and perspectives of diverse stakeholders. Our service model was based on a “4D” framework that included Discover, Define, Design, and Develop phases. In the “discover” phase, we conducted desk research and field research of stakeholders to identify the unmet needs in existing patient care services. We used service design tools, including service safaris, user shadowing, and customer journey maps to identify pain and opportunity points in the current services. We also performed focus group discussions and in-depth interviews with stakeholders to explore the needs for improved services. In the “define” phase, we generated the service concept by mind mapping and brainstorming about the needs of stakeholders. The service concept was defined to be a Patient-oriented, Collaborative, Advanced, Renovated, and Excellent (P-CARE) service. We named the service “DrugTEAM” (Drug Therapy Evaluation And Management). In the “design” phase, we designed and refined four prototypes based on results from validation tests for their application towards following services: 1) medication reconciliation, 2) medication evaluation and management, 3) evidence-based drug information, and 4) pharmaceutical care transition services. During the “develop” phase, we implemented four services in a longitudinal chronic care model, considering the time spent by patients for each inpatient and outpatient setting. In conclusion, this is a study to develop a collaborative MTC service model using service design framework, focused on managing the unmet needs of patients and healthcare providers. As a result of implementing this service model, we expect to strengthen the professional relationship between pharmacists and stakeholders to ultimately create better patient outcomes.

A Machine Learning Approach to Classification of Case Reports on Adverse Drug Reactions Using Text Mining of Expert Opinions

In this paper, we present a machine-learning approach to classify case reports on adverse drug reactions according to the causal relationship of adverse drug reactions (ADR). For this purpose, the Naive Bayes classification algorithm is combined with text mining technique, and applied to textual data of expert opinion on ADR case reports in the Korea Adverse Event Reporting System database. The proposed algorithm classifies the case reports into three categories such as possible, probable, and unlikely based on the causal relationship. Our experimental results show that the precision and recall of data belonging to possible is much higher than the other data belonging to probable and unlikely. We believe that our approach can be used not only for signal but also for prediction and prevention of ADRs.

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

OBJECTIVES To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners.

N-Nitrosodimethylamine induced lung fibroblast cell death is associated with JNK activation

N-Nitrosodialkylamines are considered a potential health hazard for humans. Among various N-nitrosodialkylamines compound, N-nitrosodimethylamine (NDMA), was applied to lung cells, MLG. In order to examine the effect of NDMA in lung cells, cell death was first examined. NDMA induced cell death in a dose-dependent manner. Mitogen activated protein kinase (MAPK) involvement was tested using SP600125 for JNK, SB203580 for P38 MAPK, or PD98059 for ERK. SP compound induced a significant reduction of cell death, compared with other inhibitors. NDMA induced an increase in expression of ER stress response proteins, including GRP78, IRE-1α, CHOP, GRP94, p-eIF2α, p-JNK, or sXBP-1. Pretreatment with SP compound regulated expression of CHOP, the transcription factor associated with proapoptotic gene induction. This study showed that NDMA-induced cell death was resulted due to JNK activation. ER stress was also induced in the toxic situations. Study of the meaning of ER stress will be necessary in the near future.