Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors and Hypothyroidism: An Analysis of the Japanese Pharmacovigilance Database.

BACKGROUND/AIM: Hypothyroidism induced by roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, was recently reported; however, information regarding roxadustat-associated hypothyroidism is still lacking. We explored the risk and time to onset of hypothyroidism associated with HIF-PH inhibitors using the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database. PATIENTS AND METHODS: The participants of this study were registered in the JADER database between April 2004 and March 2023. The association between HIF-PH inhibitors and hypothyroidism was evaluated using the reporting odds ratio (ROR) and information component (IC). We also calculated the period from the start of drug administration to the onset of hypothyroidism and determined the onset pattern using Weibull distribution. RESULTS: Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors based on the ROR [31.03, 95% confidence interval (CI)=27.81-34.62] and IC (4.51, 95%CI=4.36-4.67) values, and a strong relationship was confirmed. In addition, the median time to roxadustat-associated hypothyroidism onset was 92 days, and over 50% of cases occurred within 100 days of starting treatment. Furthermore, the onset pattern was an early failure type. CONCLUSION: There is a possible association between roxadustat and hypothyroidism. Therefore, enhanced thyroid function testing within 100 days of treatment initiation may help detect roxadustat-associated hypothyroidism. However, further research is required to confirm these findings, considering study limitations using databases of spontaneous adverse event reports.

Bibliometric analysis of Kampo medicine hotspots and trends for the decade: 2013-2022.

BACKGROUND: Kampo medicine is a traditional medicine that originated in ancient China and has since developed as a uniquely Japanese medicine. Although Kampo medicine is one of Japan's most important therapeutic modalities and numerous papers have been published recently, information on current hotspots and trends in Kampo research is lacking. This bibliometric analysis of Kampo medicine surveyed the latest research hotspots and trends. METHODS: Articles on Kampo medicine were retrieved from the Web of Science Core Collection. We used medical subject headings related to Kampo medicine and searched for publications from 2013 to 2022. The retrieved articles were analyzed for countries, authors, journals, references, and keywords related to Kampo medicine using CiteSpace, VOSviewer, and SCImago Graphica. RESULTS: A total of 1170 articles were included. The number of Kampo medicine-related publications and citations has recently increased, mainly from Japan. Author Keiko Ogawa-Ochiai published the most papers (40 papers), while Yoshio Kase had the highest frequency at 663 citations. Among the co-cited authors, Toru Kono was the most cited and had the highest total link strength. The journal with the most submissions was Evidence-based Complementary and Alternative Medicine. A comprehensive keyword and literature analysis revealed the following research hotspots: "Yokukansan and behavioral and psychological symptoms of dementia," "Ninjinyoeito and geriatric care," "Daikenchuto and postoperative gastrointestinal cancer," and "Rikkunshito and functional dyspepsia." We also identified a new research frontier by identifying an association between hochuekkito and COVID-19. CONCLUSIONS: Our findings reveal trends in Kampo medicine research, with specific hotspots and the authors and publications with the largest research impact. Collecting a large volume of literature data, analyzing the impact of studies, and identifying research hotspots, as in this study, will provide researchers with future directions for Kampo research.

Characteristics of adverse event reports among people living with human immunodeficiency virus (HIV) in Japan: Data mining of the Japanese Adverse Drug Event Report database.

The development of new anti-HIV drugs and advances in antiretroviral therapy (ART) regimens have enabled longer and more effective treatments in people living with HIV (PLWH). However, the aging of PLWHs is another issue that needs to be addressed. In addition to ART, many PLWHs frequently receive medications for various comorbidities. However, real-world data on the occurrence of adverse events in PLWHs and their causative drugs are rare. Therefore, this study aimed to clarify the characteristics of adverse event reports among PLWHs in Japan. PLWH cases with adverse events were comprehensively searched and analyzed using the Japanese Adverse Drug Event Report database (JADER). Despite changes in guideline-recommended ART regimens, anti-HIV drugs were the main cause of adverse events in PLWHs throughout the study period. However, considerable variations have been observed in the reporting rate of anti-HIV drug classes registered as causative drugs in JADER, especially for anchor drugs. In other words, the reporting rate of integrase strand transfer inhibitors has increased in recent years, while that of protease inhibitors and non-nucleoside reverse transcriptase inhibitors has decreased. Immune reconstitution inflammatory syndrome was the most reported adverse event and was frequently noticed by healthcare providers managing patients with HIV infections. The trends in adverse event reports for female and older patients differed from those for the overall population. This study may provide insights that can help in the establishment of optimal management strategies for PLWHs.

Bleeding events associated with recombinant human soluble thrombomodulin, classified according to renal function, in sepsis-induced disseminated intravascular coagulation.

OBJECTIVE: Recombinant human soluble thrombomodulin (rhsTM) is a therapeutic agent for sepsis-induced disseminated intravascular coagulation (DIC) and is associated with bleeding events. rhsTM is a renal excretion drug; however, information on the role of rhsTM in renal function is limited. MATERIALS AND METHODS: In this retrospective observational study, we assessed rhsTM-associated bleeding events according to the renal function of patients with sepsis-induced DIC. We analyzed the data of 79 patients administered a standard-dose of rhsTM for sepsis-induced DIC, at a single center. Patients were classified based on estimated glomerular filtration rate (eGFR). We measured fresh bleeding events following rhsTM administration, DIC score efficacy, and 28-day mortality. RESULTS: Fresh bleeding events were observed in 15 patients, with a significant difference in the eGFR, platelet count, and DIC scores. Furthermore, fresh bleeding events tended to increase with the deterioration of renal function (p = 0.039). The DIC scores in all renal function groups decreased after -rhsTM administration. Additionally, the 28-day mortality was less than 30% in all groups. CONCLUSION: Our results indicate that the effectiveness of the standard-dose of rhsTM is not related to renal function. However, standard-dose rhsTM therapy could potentially increase the risk of adverse bleeding events with severe renal function equivalent to G5.

Accuracy of Therapeutic Drug Monitoring of Teicoplanin at the Onset of Febrile Neutropenia.

Background and Objectives: Teicoplanin (TEIC) is an effective drug for patients with febrile neutropenia (FN); however, it has been reported that these patients may have increased TEIC clearance compared with patients who do not have FN. The purpose of this study was to study therapeutic drug monitoring in patients with FN when the TEIC dosing design was based on the population mean method. Materials and Methods: Thirty-nine FN patients with hematological malignancy were included in the study. To calculate the predicted blood concentration of TEIC, we used the two population pharmacokinetic (population PK) parameters (parameters 1 and 2) reported by Nakayama et al. and parameter 3, which is a modification of the population PK of Nakayama et al. We calculated the mean prediction error (ME), an indicator of prediction bias, and the mean absolute prediction error (MAE), an indicator of accuracy. Furthermore, the percentage of predicted TEIC blood concentration within 25% and 50% of the measured TEIC blood concentration was calculated. Results: The ME values were -0.54, -0.25, and -0.30 and the MAE values were 2.29, 2.19, and 2.22 for parameters 1, 2, and 3, respectively. For all of the three parameters, the ME values were calculated as minus values, and the predicted concentrations tended to be biased toward smaller values relative to the measured concentrations. Patients with serum creatinine (Scr) < 0.6 mg/dL and neutrophil counts < 100/µL had greater ME and MAE values and a smaller percentage of predicted TEIC blood concentration within 25% of measured TEIC blood concentrations compared with other patients. Conclusions: In patients with FN, the accuracy of predicting TEIC blood concentrations was good, with no significant differences between each parameter. However, patients with a Scr < 0.6 mg/dL and a neutrophil count < 100/µL showed slightly inferior prediction accuracy.

Time to Onset of Gemcitabine-induced Thrombotic Microangiopathy in a Japanese Population: A Case Series and Large-scale Pharmacovigilance Analysis.

BACKGROUND/AIM: Gemcitabine-induced thrombotic microangiopathy (G-TMA) is associated with a high mortality rate. However, owing to its low incidence, data on G-TMA remain limited. Therefore, a detailed review of G-TMA cases is critical to understand this adverse event. In addition, reviewing literature and pharmacovigilance analytics may be useful to characterise G-TMA. Here, time to onset of G-TMA was analysed based on available data. PATIENTS AND METHODS: We collected data for a case of TMA following gemcitabine administration at the Tokyo Metropolitan Geriatric Hospital. We also reviewed the literature on G-TMA cases in Japan from April 2000 to March 2022 to provide a case series. Moreover, we performed time-to-onset analysis of G-TMA using the data from the Japanese Adverse Drug Event Report (JADER) database. RESULTS: Our case involved a patient with pancreatic cancer who developed thrombotic thrombocytopenic purpura 13 months after starting gemcitabine treatment. From the literature reviewed, in 14 out of 17 cases, G-TMA occurred 5-8 months after treatment initiation. The analysis of data from the JADER database showed that the median time to onset of G-TMA was 161 days. Weibull shape parameter analysis showed that the pattern of onset of G-TMA represented a random failure. CONCLUSION: This study elucidated the time to onset of G-TMA in a Japanese population. Weibull shape parameter analysis showed that G-TMA may not necessarily develop in a dose-dependent manner. These results may be useful for monitoring G-TMA in the clinical setting.

[Chemical Stability after Mixing Continuous Infusion Drugs Used to Treat Cardiogenic Shock].

During the treatment of cardiogenic shock, various continuous infusion drugs are used simultaneously. However, administration from the same route may result in stability changes due to mixing of drugs. In addition, stability tests after mixing more than three types of drugs have hardly been conducted. In this study, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride were used to evaluate the chemical stability of the mixture. Chemical stability was evaluated by measuring the change in each drug concentration over time and calculating the content. The concentration of each drug was measured using an optimized gradient elution method by HPLC. In a four-drug mixed sample, noradrenaline, milrinone, dobutamine hydrochloride, and landiolol hydrochloride had retention times of 2.1 min, 5.2 min, 9.3 min, and 11.9 min, respectively. The concentration immediately after mixing each drug was almost the same as the theoretical concentration at the time of mixing each drug. Furthermore, noradrenaline, milrinone, and dobutamine hydrochloride concentrations were maintained up to 99% in each drug mixture until 24 h after mixing all the samples. However, the content of landiolol hydrochloride was 90% or less 24 h after mixing, except for two types of mixed solutions with dobutamine hydrochloride. This result suggested that landiolol hydrochloride was being degraded owing to acidic conditions. The results of this study suggest that noradrenaline, milrinone, and dobutamine hydrochloride can be administered from one route, while it is recommended that landiolol hydrochloride be administered from another route.

Understanding the Actual Use of Anti-HIV Drugs in Japan from 2016 to 2019: Demonstrating Epidemiological Relevance of NDB Open Data Japan for Understanding Japanese Medical Care.

The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan is helpful for attaining simple and comprehensive understanding of medical care in Japan. Herein, we investigated the transition of anti-HIV-drug use in Japan over a 4-year period from fiscal year (FY) 2016 to FY 2019 using data on anti-HIV drugs that were extracted from the 3rd, 4th, 5th, and 6th NDB Open Data Japan. Then, the data were stratified by mechanism of action, single-tablet regimen (STR) or non-STR, age groups, and sex and analyzed. Throughout the study period, the prescription volume for tenofovir alafenamide fumarate as the backbone drug and integrase strand transfer inhibitors as the anchor drug increased. In FY 2019, STRs constituted approximately 44% of the total combination antiretroviral therapy regimens, 1.6 times higher than that in FY 2016 (27%). With the advent of newer drugs and regimens, the differences in anti-HIV drugs prescribed to patients of different ages and sex gradually diminished; however, differences were unremarkable in the first period, especially between sexes. The NDB Open Data Japan made it relatively easy to evaluate recent trends in anti-HIV prescription in Japan, indicating its usefulness for continuous surveys in this field.

Comprehensive evaluation of antioxidant effects of Japanese Kampo medicines led to identification of Tsudosan formulation as a potent antioxidant agent.

Oxidative stress due to the overproduction of reactive oxygen species plays an important role in the pathogenesis of various diseases. In the present study, we comprehensively evaluated the antioxidant activities of 147 oral formulations of Japanese traditional herbal medicines (Kampo medicines), representing the entire panel of oral Kampo medicines listed in the Japanese National Health Insurance Drug List, using in vitro radical scavenging assays, including the 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity assay, the superoxide anion scavenging activity assay, and the oxygen radical absorption capacity assay. Three of the formulations tested, namely, Tsudosan, Daisaikoto, and Masiningan, showed the most potent in vitro antioxidant activities and were selected for further investigation of their intracellular and in vivo antioxidant effects. The results of the 2',7'-dichlorodihydrofluorescin diacetate assay demonstrated that all three Kampo medicines significantly inhibited hydrogen peroxide-induced oxidative stress in human hepatocellular liver carcinoma HepG2 cells. In addition, Tsudosan significantly increased the serum biological antioxidant potential values when orally administrated to mice, indicating that it also had in vivo antioxidant activity. The potent antioxidant activity of Tsudosan may be one of the mechanisms closely correlated to its clinical usage against blood stasis.

Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan.

ETHNOPHARMACOLOGICAL RELEVANCE: Masiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan. MATERIALS AND METHODS: Bioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway. RESULTS: From Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3µM, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway. CONCLUSIONS: Magnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development.

Inhibitory activities of selected Kampo formulations on human aldose reductase.

BACKGROUND: Diabetes complications include various symptoms such as diabetic neuropathy and cognitive disorders. Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway and is one of the causal factors of diabetes complications. In this study, the bioactivities of eight selected Kampo formulations that are currently in clinical use for diabetes complications were assessed using human AR (hAR) inhibitory activity as the primary parameter to explore the possibilities of novel clinical applications of these formulations in the treatment of diabetes complications. METHODS: The hAR inhibitory activities of four Kampo formulations that are clinically used for diabetic neuropathy, four Kampo formulations that are used for cognitive disorders, and a total of 21 component crude drugs were measured. Furthermore, the hAR inhibitory activity of Glycyrrhizae Radix preparata was measured to determine the effect of frying, which is one of the specific processing of Glycyrrhizae Radix. hAR inhibitory activity was determined by measuring the rate of decline in the absorbance of NAPH at 340 nm using 0.5 mM NADPH, 10 mM D,L-glyceraldehyde, and 3.6 mU/mL hAR in phosphate buffer solution (0.2 M, pH 6.2). RESULTS: All of the Kampo formulations exhibited significant hAR inhibitory activity; Chotosan exhibited particularly strong activity. Among the 21 crude drugs tested, adequate inhibitory activities were found for the following, in descending order of activity: Glycyrrhizae Radix > Paeoniae Radix > Chrysanthemi Flos > Cinnamomi Cortex > Phellodendri Cortex > Uncariae Uncis cum Ramulus > Bupleuri Radix. Glycyrrhizae Radix preparata exhibited an inhibitory activity that was nearly identical to that of Glycyrrhizae Radix. CONCLUSIONS: Despite their seemingly different treatment objectives, all of the Kampo formulations that are clinically used for diabetes complications demonstrated significant hAR inhibitory activity. This activity might underlie the characteristic multi-target effects of Kampo formulations. Although the overall effect of a Kampo formulation is certainly difficult to evaluate based on specific herbal medications or components, the approach as taken in this study might nonetheless contribute to further advancement in the development of new drugs via the review of proper usage and re-examination of the chemical compounds from a new perspective.

Evaluation of 147 Kampo prescriptions as novel protein tyrosine phosphatase 1B (PTP1B) inhibitory agents.

BACKGROUND: Protein tyrosine phosphatase (PTP) 1B, a negative regulator of the insulin and leptin signaling pathways, is currently considered a promising target for the development of novel therapeutic approaches used to treat insulin-resistant type 2 diabetes mellitus (IR-T2DM). In this study, we examined the PTP1B inhibitory activity of 147 Japanese prescription Kampo formulations to evaluate their potential for clinical application in IR-T2DM treatment. METHODS: We specifically defined the prescribed daily dose as 1 Unit (U), and 147 Japanese prescription Kampo formulations were screened for PTP1B inhibitory activity at a final concentration of 0.1 mU/mL. We investigated the dependence of the inhibitory activity on the concentration of the Kampo formulations that exhibited high PTP1B inhibitory activity. Their inhibition mode by kinetic analysis, inhibitory selectivities against four homologous PTPs (TCPTP, VHR, SHP-1 and SHP-2) and cellular activity in the insulin-signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, were also investigated. The statistical partial least squares regression method was used to identify the crude drugs with the greatest contribution to the PTP1B inhibitory activity of the Kampo formulations. RESULTS: Daiokanzoto, Masiningan, Tokakujokito, Keimakakuhanto and Choijokito exhibited high PTP1B inhibitory activity, which was concentration-dependent. Daiokanzoto, Masiningan and Tokakujokito inhibited PTP1B by mixed inhibition modes and exhibited different inhibitory selectivities against four homologous PTPs. Masiningan also exhibited cellular activity. Statistical analyses indicated that the constituent crude drug Rhei Rhizoma provided the greatest contribution to the PTP1B inhibitory activity of these Kampo formulations. CONCLUSIONS: High PTP1B inhibitory activity was predominantly associated with formulations that were classified as Jyokito in Kampo medicine and with a modern clinical indication of constipation. Currently, there is no clinical treatment for IR-T2DM that uses a mechanism of action based on PTP1B inhibition. Thus, we propose the Kampo formulations identified in this study as strong PTP1B inhibitors, which could be developed as clinical therapeutic agents to treat IR-T2DM.

A new flavonoid glycoside and other chemical constituents from leaves of Rosa davurica and their antioxidant activity.

A 70% ethanol extract from the leaves of Rosa davurica showed significant antioxidant activity in both superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assays. Phytochemical study of this extract resulted in the isolation of eight compounds, including a new flavonoid glycoside. The chemical structure was determined by various spectroscopic analyses. The isolated compounds and their structurally related compounds, belonging to two classes: quercetin 3-O-glycosides and gallic acid derivates, were evaluated for their superoxide anion- and DPPH free radical-scavenging activities. These compounds showed significant superoxide anion-scavenging activity with the EC50 values ranging from 1.68 to 18.09 µM, and DPPH free radical-scavenging activity with the EC50 values ranging from 7.18 to 67.62 µM. The structure-activity relationship was also reported.