1.Transforming Growth Factor-β Induces Interleukin-6 Secretion from Human Ligamentum Flavum–Derived Cells through Partial Activation of p38 and p44/42 Mitogen-Activated Protein Kinases
Yuta GOTO ; Kenji KATO ; Kiyoshi YAGI ; Yohei KAWAGUCHI ; Hiroki YONEZU ; Tomoko KOSHIMAE ; Yuko WAGURI-NAGAYA ; Hideki MURAKAMI ; Nobuyuki SUZUKI
Asian Spine Journal 2023;17(6):997-1003
Methods:
HFCs were obtained from patients with LSS who had undergone decompression surgery. The cells were stimulated with TGF-β and pretreated with either the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 or the p44/42 MAP kinase inhibitor FR180204. IL-6 secretion in the cell culture medium and IL-6 messenger RNA (mRNA) expression levels were analyzed using an enzyme-linked immunoassay and real-time polymerase chain reaction, respectively.
Results:
TGF-β administration resulted in a dose- and time-dependent stimulation of IL-6 release. Treatment with SB203580 and FR180204 markedly suppressed TGF-β–induced IL-6 secretion from HFCs. Moreover, these inhibitors suppressed IL-6 mRNA expression in response to TGF-β stimulation.
Conclusions
Our findings indicate that TGF-β induces IL-6 protein secretion and gene expression in HFCs through the activation of p38 or p44/42 MAP kinases. These results suggest a potential association between IL-6–mediated inflammatory response and tissue hypertrophy in LSS, and we provide insights into molecular targets for therapeutic interventions targeting LSS-related inflammation through our analysis of the MAP kinase pathway using HFCs.
2.A Retrospective Study on the Low Dose Lamotrigine of Skin Disorders
Yosuke MORITA ; Kyohei WATANABE ; Takaaki KODAWARA ; Yumi TSUBOTA ; Ryoichi YANO ; Hitoshi TSUKAMOTO ; Nobuyuki GOTO
Japanese Journal of Drug Informatics 2022;23(4):178-182
Objective: In this study, we investigated the occurrence of skin damage following the initiation of low-dose lamotrigine.Methods: We retrospectively analyzed the incidence of skin disorders within 8 weeks of the start of lamotrigine administration, prescribing for 3 years from July 2014 to June 2016.In addition, we also confirmed the onset time of skin disorders in the low- and normal-dose groups.Results: The incidence of skin damage was 7.7 and 24.6 % in the low- and normal-dose lamotrigine start groups, respectively. The onset of skin disorders was relatively early in the normal-dose lamotrigine start group.On the other hand, no tendency was found in the low-dose lamotrigine start group because the number of cases was small.Conclusion: The initiation of low-dose lamotrigine and extension of introduction period might reduce the onset of early skin damage.
3.Segmental Arteries and Veins at Higher Lumbar Levels Can Intersect the Adjacent Caudal Intervertebral Disc in the Anterior Part of the Spinal Column: A Cadaveric Analysis
Kiyoshi YAGI ; Nobuyuki SUZUKI ; Jun MIZUTANI ; Kenji KATO ; Akira KONDO ; Yuya WASEDA ; Yuta GOTO ; Hideki MURAKAMI
Asian Spine Journal 2022;16(1):1-8
Methods:
Five formalin-embalmed human cadavers were used. We assessed the proportion of segmental arteries and veins that intersected the IVD in the L2–L5 range and their course on the anterior part of the spinal column.
Results:
The segmental arteries and veins commonly intersect the anterior part of the IVD (artery, 28.1%; vein, 42.1%). Seven of 10 (70%) segmental arteries at L2 intersected the IVD, but only one artery intersected the IVD at L3 and L4. The proportions of segmental veins that intersected the IVD were 60%, 50%, and 16.7% at L2, L3, and L4, respectively.
Conclusions
The segmental arteries and veins frequently intersect the IVD in the anterior part of the spinal column. Therefore, it is necessary to consider these individual anatomical features to prevent vascular damage during lateral lumbar interbody fusion surgery.
4.Survey on Formulations and Dosage Forms Needed by the Medical Community
Tsukasa MORI ; Nobuyuki GOTO ; Tadanori SASAKI ; Sachiko HARADA ; Masayuki YAMAKAWA ; Kyohei WATANABE ; Fumiko OHTSU
Japanese Journal of Drug Informatics 2022;24(2):121-129
Objective: In this study, we conducted a questionnaire survey of hospital pharmacists throughout Japan with the aim of identifying the most-requested in-hospital preparations and off-label use drugs, and exploring the possibility of commercializing them.Methods: The Commercialization Study Group of the Japanese Society of Hospital Pharmacists conducted a questionnaire survey on the Japanese Society of Hospital Pharmacists website targeting hospital pharmacists who are members of the Japanese Society of Hospital Pharmacists. The period of the survey was from February 1, 2019 until January 21, 2020. In the questionnaire, the respondents wrote specific product names (generic names), specifications, and dosage forms that they would like to see improved and made commercially available in a free-text format. In addition, respondents chose their reasons for wanting the product to be improved or made commercially available from a list.Results: A total of 1,627 drugs were requested to be made commercially available. After duplicates and insufficient descriptions were excluded, the total was 553. The drugs that were most frequently requested were Levothyroxine suppositories, followed by Mohs’ ointment and Ulinastatin vaginal suppositories.Discussion: This survey identified certain drugs that pharmacists want to be commercialized and the specific reasons why. In-hospital preparations not only benefit patients whose diseases are becoming more complex and difficult to treat with existing prescription drugs, but also enable pharmacists to demonstrate their abilities. We believe that the commercialization of these important in-hospital preparations and off-label drugs will help avoid various risks associated with dispensing them and enhance the pharmacy profession. For this reason, pharmaceutical drug companies should conduct further surveys on the actual use of and literature research on the efficacy and safety of the drugs that were ranked high on the questionnaire and start considering their commercialization.
5.Survey Regarding the Actual Use of Two-Dimensional Symbols Containing Prescription Information in Fukui Prefecture
Hiroshi YAMAMOTO ; Ryoichi YANO ; Akiko SAIKI ; Kyosuke TAJIMA ; Aimi IWASAKI ; Miyuki UNO ; Toshiaki IGARASHI ; Kyohei WATANABE ; Takaaki KODAWARA ; Hitoshi TSUKAMOTO ; Nobuyuki GOTO
Japanese Journal of Drug Informatics 2022;24(3):166-172
Objective: Two types of symbols have been established as industry standards in terms of two-dimensional (2D) symbols with prescription information: one for objects to be printed on prescriptions and the other for electronic versions of medication diaries. However, no studies have investigated the system for using 2D symbols in pharmacies and hospitals/clinics as well as the quality of the information actually stored in these 2D symbols. Therefore, we conducted a survey to clarify the current status and problems pertaining to prescription information sharing via 2D symbols.Methods: We distributed questionnaires to community pharmacies through the Fukui Pharmaceutical Association and asked them to cooperate with us during the survey. The list of items in the survey included the installation status of devices necessary for reading 2D symbols at each pharmacy, receipt computer in use, and status of the support issued by hospitals/clinics for reading 2D symbols. At the same time, we received 2D symbols created by community pharmacies and conducted reading tests to examine issues related to the collection of prescription information via 2D symbols at medical institutions.Results: The response rate for the survey was 21.8%. Among the 57 stores that responded to the survey, 26 (45.6%) answered that they could read prescription symbols, and 22 of them had actually used the system till date. In addition, 38 community pharmacies were able to provide the 2D symbols for medication diaries. Of the 30 provided symbols for medication diaries, 16 (53.3%) could be read as Japanese data by the barcode reader used.Conclusions: It has become clear that the 2D symbols with stored prescription information are not being completely utilized at present, as both community pharmacies and hospitals/clinics face several issues such as hardware maintenance, software updates, and time and effort required for the usage.
6.Japanese Medical Academic Organizations Surveyed on the Current Situation of Medical Information Providedto the Public on the Internet
Nobuyuki GOTO ; Hitoshi TSUKAMOTO ; Takaaki KODAWARA ; Toshiaki IGARASHI ; Kyohei WATANABE ; Ryoichi YANO ; Takamasa SAKAI ; Fumiko OHTSU
Japanese Journal of Drug Informatics 2021;22(4):193-201
Objective: The internet isflooded with drug information; however, some of it isinappropriate and thisinadequate information could expose the public to health hazards. Therefore, we conducted research on the idea of transmitting drug information to the public via the internet and the current state of the information currently provided by each academic society relevant to the field of Medical Informatics.Methods: A questionnaire was mailed to the website managers for the website of 129 specialist medical societies, all members of the Japanese Association of Medical Sciences. We conducted our research between October to November 2018. We investigated each website administrator’s opinion about offering drug information for consumers via the internet and what information each academic society is currently providing.Results: The effective response rate was 43.4% (56/129 groups). Most respondents thought that drug information overflowed in the current Internet society. Moreover, more than half of the respondents thought that the quality of drug information transmitted to the public wasinadequate. Currently, 30 of the academic groupssurveyed are providing information to the public. When providing information, they did not refer to the “Drug Guide for Patients” much. More than 80% of respondents said they would cooperate with linking to the information provided to the public. However, each academic society felt there would be many problems with doing so such as the need for a system to check the contents of the information provided and a system to perform maintenance.Conclusion: The results showed that the website administrators recognized that there is a need to improve the quality of and system for providing drug information to the public. We believe that an integrated information system can be constructed by aggregating the drug information held by each academic society. However, this cannot be realized without first solving many problems.
7.p38 Mitogen-Activated Protein Kinase Is Involved in Interleukin-6 Secretion from Human Ligamentum Flavum–Derived Cells Stimulated by Tumor Necrosis Factor-α
Kiyoshi YAGI ; Yuta GOTO ; Kenji KATO ; Nobuyuki SUZUKI ; Akira KONDO ; Yuya WASEDA ; Jun MIZUTANI ; Yohei KAWAGUCHI ; Yuji JOYO ; Yuko WAGURI-NAGAYA ; Hideki MURAKAMI
Asian Spine Journal 2021;15(6):713-720
Methods:
HFCs were obtained from patients with LSS who underwent surgery. HFCs were stimulated by tumor necrosis factor-α (TNF-α) and a p38 MAP kinase inhibitor, SB203580. Phosphorylation of the p38 MAP kinase was analyzed by western blotting. The concentration of interleukin-6 (IL-6) in the conditioned medium was measured by enzyme-linked immunoassay and IL-6 messenger RNA expression levels were determined by real-time polymerase chain reaction.
Results:
TNF-α induced the phosphorylation of p38 MAP kinase in a time-dependent manner, which was suppressed by the p38 MAP kinase inhibitor, SB203580. TNF-α also stimulated IL-6 release in both a time- and dose-dependent manner. On its own, SB203580 did not stimulate IL-6 secretion from HFCs; however, it dramatically suppressed the degree of IL-6 release stimulated by TNF-α from HFCs.
Conclusions
This is the first report suggesting that TNF-α stimulates the gene expression and protein secretion of IL-6 via p38 MAP kinase in HFCs. A noted association between tissue hypertrophy and inflammation suggests that the p38 MAP kinase inflammatory pathway may be a therapeutic molecular target for LSS.
8.Creating a Checklist and a Survey on Research That Used the Japanese Adverse Drug Event Report Database
Takamasa SAKAI ; Yukito WADA ; Akira KOKAN ; Kouichi TANABE ; Nobuyuki GOTO ; Fumiko OHTSU
Japanese Journal of Drug Informatics 2020;22(1):7-16
Objective: The purpose of this study was to create a checklist that summarizes checkpoints that should be noted when using the Japanese Adverse Drug Event Report database (JADER). After we created the checklist, we then used it to survey published academic papers that used JADER.Method: First, we created a draft checklist for research that uses JADER by citing the report of CIOMS working group VIII “Practical Aspects of Signal Detection in Pharmacovigilance”. Then, we conducted a pilot test and revised the draft checklist. Finally, the checklist was completed after the review by a pharmacoepidemiology expert. The checklist was applied to published academic papers that used JADER, and the fulfill rate of each checkpoints was calculated.Results: A “checklist of important points to be noted during research that uses the data mining method in JADER (mainly signal detection by disproportionality analysis)” was created. We also revealed problems with published academic papers that used JADER. For example, some researchers were thought to be inappropriately using JADER as a source of their research while others used an inappropriate version of MedDRA.Conclusion: The checklist created in this study summarizes key points that could be noted in research that uses JADER and is thought to contribute to an improvement in quality of research that uses JADER. Additionally, in our investigation of published academic papers that used JADER, we found the possibility that both the role of signal detection and the impact on analysis of JADER using the updated MedDRA version are not well understood.
9.Survey of Patient Comprehension of Medication Instructions for SGLT2 Inhibitors
Yoko HIRANO ; Yuki WATASE ; Yoshitomo O-OKA ; Kyosuke TAJIMA ; Takaaki KODAWARA ; Ryoichi YANO ; Kyohei WATANABE ; Hitoshi TSUKAMOTO ; Nobuyuki GOTO
Japanese Journal of Drug Informatics 2019;20(4):232-237
Objective: We evaluated patients’ degree of understanding of the effects and adverse drug reactions of SGLT2 inhibitors.Methods: We targeted 26 patients who were administered SGLT2 inhibitors during hospitalizations between April 2017 and March 2018. The survey was conducted by interviewing the patients using a questionnaire.Results: In total, 14 patients (53. 8%) were able to explain the term “efficacy.” Although 6 patients (23. 1%) understood “dehydration,” there was little understanding of “urinary tract infection” (7.7%) and “rash/erythema” (2 and 0 patients, respectively). In addition, we confirmed the details of the descriptions of adverse reactions caused by SGLT2 inhibitors with pharmacists, and found that 13 patients (50.0%) clearly received an explanation of “dehydration,” only 3 patients received an explanation of “urinary tract infection” (11.5%), and none of them comprehended “rash/erythema.” Overall, the patients’ awareness of the adverse drug reactions of SGLT2 inhibitors was low.Conclusion: Unlike common drugs for diabetes, SGLT2 inhibitors have been attracting attention as protective agents of the heart and kidneys. Therefore, it is expected that prescriptions for SGLT2 will increase in the future. Pharmacists need to explain the effects and adverse drug reactions of SGLT2 inhibitors to the patients as well as make the patients understand the pharmacological mechanisms of action of SGLT2 inhibitors.
10.Relationship between Drug-Induced Photosensitivity and Ultraviolet-Visible Absorption Spectrum and Structure
Sawako TOYOTA ; Yuna YOSHIMURA ; Reiko YANO ; Yutaka AOYAGI ; Fumiko OHTSU ; Nobuyuki GOTO
Japanese Journal of Drug Informatics 2019;21(2):70-78
Objective: To clarify the background difference between drug-induced photosensitivity and ultraviolet-visible absorption spectrum or structure and to construct useful information for prevention and prediction of drug-induced photosensitivity. Methods: We investigated whether, for 457 drugs for which the ultraviolet-visible absorption spectrum is listed in the Japanese Pharmacopoeia, there were absorption maxima in the UVA (320 nm or more and less than 400 nm), UVB (280 nm or more and less than 320 nm), or UVA and UVB (280 nm or more and less than 400 nm). Structure was investigated for the existence of “conjugated”, carbonyl, sulfone, nitro and fluorine. The case drug group was taken to be those drugs for which photosensitivity was listed as a side effect on the medical drug package insert. Using statistical software, SPSS statistics ® 24 (IBM), we performed univariate logistic regression analysis, and multivariate logistic regression analysis with a stepwise increment method (likelihood ratio) combining items with p<0.2, and calculated the odds ratio (hereinafter: aOR). The significance level was taken as 0.05. Results: There were 85 drugs in the case drug group, and 372 drugs in the control drug group. As a result of multiple logistic regression analysis, in Model 1, we placed sulfone (aOR: 4.55, 95% C.I.: 2.22-9.35), fluorine (aOR: 3.66, 95% C.I.: 1.82-7.39) and nitro (aOR: 4.46, 95 % C.I.: 1.73-11.48) in this order. In Model 2, we placed sulfone (aOR: 4, 40, 95% C.I.: 2.12-9.15), fluorine (aOR: 3.81, 95% C.I.: 1.87-7.76), UVA (aOR: 2.40, 95% C.I.: 1.37-4.18) and nitro (aOR: 3.61, 95% C.I.: 1.39-9.40) in this order. Conclusion: When a drug is developed, its ultraviolet-visible absorption spectra and structure become clear, and from this information,measures can be taken which bear the potential risk of photosensitivity in mind.


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