Kei Kawada, T Ishida, T Yoshioka, H Fukuda, T Hayashi, Mitsuhiro Goda and Keisuke Ishizawa : Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases., Die Pharmazie, Vol.79, No.6, 118-123, 2024.
(Summary)
Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, 80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the 80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.
(Keyword)
Adolescent / Adult / Aged / Aged, 80 and over / Child / Female / Humans / Male / Middle Aged / Young Adult / Adverse Drug Reaction Reporting Systems / Anti-Inflammatory Agents, Non-Steroidal / Brain Diseases / Databases, Factual / Japan / Phenylpropionates / United States / United States Food and Drug Administration
Kei Kawada, Tomoaki Ishida, Hitoshi Fukuda, Yuki Hyohdoh, Toru Kubo, Tomoyuki Hamada, Yuichi Baba, Toshinobu Hayashi, Fuka Aizawa, Kenta Yagi, Yuki Izawa-Ishizawa, Takahiro Niimura, Shinji Abe, Mitsuhiro Goda, Hiroaki Kitaoka and Keisuke Ishizawa : Effects of renin-angiotensin system inhibitor and beta-blocker use on mortality in older patients with heart failure with reduced ejection fraction in Japan., Frontiers in Cardiovascular Medicine, Vol.11, 2024.
(Summary)
RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.
Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression. In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents. ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured , and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses. Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of , and in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, , and also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide. Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent.
Toshinobu Hayashi, Mototsugu Shimokawa, Koichi Matsuo, Kei Kawada, Takafumi Nakano and Takashi Egawa : Efficacy of 3-day versus 5-day aprepitant regimens for long-delayed chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy., Expert Opinion on Pharmacotherapy, Vol.24, No.18, 2221-2226, 2024.
(Summary)
A 5-day regimen triplet antiemetic prophylaxis with APR decreased long-delayed vomiting compared with a 3-day regimen in patients receiving CDDP-based chemotherapy. However, the 5-day regimen showed no advantage over the 3-day regimen against long-delayed nausea.
Tomoaki Ishida, Kei Kawada, Kohei Jobu, Shumpei Morisawa, Tetsushi Kawazoe, Satomi Nishimura, Keita Akagaki, Saburo Yoshioka and Mitsuhiko Miyamura : Exosome-like nanoparticles derived from Allium tuberosum prevent neuroinflammation in microglia-like cells., The Journal of Pharmacy and Pharmacology, Vol.75, No.10, 1322-1331, 2023.
(Summary)
A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation.
Aberrant melanin overproduction can significantly impact an individual's appearance and cause mental and psychological distress. Current inhibitors of melanin production exert harmful side effects due to inadequate selectivity; thus a need to develop more selective melanin synthesis inhibitors is necessary. Extracellular vesicles are important agents of intercellular signalling in prokaryotes and eukaryotes. Recently, plant-derived nanoparticles, similar to mammalian exosomes, have attracted attention for their use in health research. In this study, to investigate the potential of plant-derived exosome-like nanoparticles (ELNs) as inhibitors of melanin production, we used hot water to extract ELNs from the rhizome of (A-ELNs). The size of A-ENLs ranged from 34 to 401 nm and carried three microRNA: ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p. These A-ENLs were applied to B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). After A-ELNs were taken up by B16-F10 cells, their melanin levels were significantly reduced. Furthermore, A-ELNs significantly reduced tyrosinase activity in B16-F10 cells and mRNA expression of microphthalmia-associated transcription factor (), tyrosinase, tyrosinase-related protein 1, and DOPA chrome tautomerase. These results suggest that A-ELN suppresses melanogenic enzymes expression by downregulating , thereby inhibiting melanin synthesis. Hence, A-ELN can be developed into a novel topical drug after additional studies and optimization.
Toshinobu Hayashi, Mototsugu Shimokawa, Koichi Matsuo, Masanobu Uchiyama, Kei Kawada, Takafumi Nakano and Takashi Egawa : Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy., Oncology, Vol.101, No.9, 584-590, 2023.
(Summary)
Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.
T Kawazoe, T Ishida, K Jobu, Kei Kawada, S Yoshioka and M Miyamura : Analysis of Urinary Retention Caused by Selective β 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER)., Die Pharmazie, Vol.78, No.5, 56-62, 2023.
(Summary)
Overactive bladder (OAB) is a frequent chronic disorder which impairs quality of life by frequent, uncontrollable urination. Newly developed selectiveβ 3-adrenoceptor agonists (sβ 3-agonists) have the same efficacy in treating OAB but significantly fewer side effects than the traditionally used anti-muscarinics. However, safety data on these compounds are scarce. In this study, we analysed the occurrence of adverse effects in patients taking sβ 3-agonists and their characteristics using the JADER database. The most frequently reported adverse effect associated with the use of sβ 3-agonists was urinary retention [mirabegron; crude reporting odds ratios (ROR): 62.1, 95% confidence interval (CI): 52.0-73.6, P<0.001, vibegron; crude ROR: 250, 95% CI : 134-483, P<0.001]. Data from patients with urinary retention were stratified by sex. In both men and women, the rate of urinary retention was higher when using the mirabegron/anti-muscarinic drug when compared to mirabegron monotherapy; its occurrence was higher in men with a history of benign prostatic hypertrophy than in those without. Weibull analysis showed that approximately 50% of sβ 3 agonist-induced urinary retention occurred within 15 days after initiation of treatment, and then gradually decreased. Although sβ 3-agonists are useful against OAB, they may induce several side effects, especially urinary retention, which can further evolve into more severe conditions. Urinary retention occurs more frequently in patients concomitantly taking medication that either increases urethral resistance or has organic factors that block the urethra. When using sβ 3-agonists, the concomitantly used medications and underlying diseases should be thoroughly reviewed, and safety monitoring should be instituted early during the treatment.
(Keyword)
Male / Humans / Female / Urinary Retention / Muscarinic Antagonists / Quality of Life / East Asian People / Adrenergic beta-3 Receptor Agonists / Urinary Bladder, Overactive / Drug-Related Side Effects and Adverse Reactions / Receptors, Adrenergic / Treatment Outcome
Kei Kawada, Tomoaki Ishida, Kohei Jobu, Shumpei Morisawa, Motoki Nishida, Naohisa Tamura, Saburo Yoshioka and Mitsuhiko Miyamura : Glycyrrhizae Radix suppresses lipopolysaccharide- and diazepam-induced nerve inflammation in the hippocampus, and contracts the duration of pentobarbital- induced loss of righting reflex in a mouse model., Journal of Natural Medicines, Vol.77, No.3, 561-571, 2023.
(Summary)
Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1β, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.
Naohisa Tamura, Tomoaki Ishida, Kei Kawada, Kohei Jobu, Shumpei Morisawa, Saburo Yoshioka and Mitsuhiko Miyamura : Risk Factors for Anticancer Drug-Induced Hyponatremia: An Analysis Using the Japanese Adverse Drug Report (JADER) Database., Medicina, Vol.59, No.1, 2023.
(Summary)
Hyponatremia has been reported in women and patients with lung cancer receiving cisplatin, with a growing trend in the number of elderly patients receiving cisplatin. Furthermore, since the onset of hyponatremia during cisplatin administration is frequently reported within 10 days, patient information should be thoroughly examined before and monitored throughout the administration, which can contribute to the early detection and prevention of hyponatremia.
Keita Akagaki, Aki Kadota, Tomoaki Ishida, Takaya Sagawa, Yoko Kagaya, Kei Kawada, Naohisa Tamura, Hisashi Shiraishi, Kohei Jobu, Saburo Yoshioka, Masaki Yamamoto, Mikiya Fujieda and Mitsuhiko Miyamura : [Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets]., Journal of the Pharmaceutical Society of Japan, Vol.143, No.12, 1039-1046, 2023.
(Summary)
are expected to improve the adherence and quality of life of patients who require selenium supplementation.
(Keyword)
Humans / Selenium / Quality of Life / Mannitol / Tablets / Drug Packaging / Administration, Oral / Solubility / Drug Compounding
Kei Kawada, Tomoaki Ishida, Kohei Jobu, Shumpei Morisawa, Naohisa Tamura, Shouhei Sugimoto, Masafumi Okazaki, Saburo Yoshioka and Mitsuhiko Miyamura : Adverse Reaction Profiles Related to Gastrointestinal Bleeding Events Associated with BCR-ABL Tyrosine Kinase Inhibitors., Medicina, Vol.58, No.10, 2022.
(Summary)
: Specific TKIs and patient characteristics were associated with gastrointestinal bleeding. Our results aid the prompt identification and treatment of TKI-related gastrointestinal bleeding.
Kei Kawada, Toru Kubo, Tomoaki Ishida, Kohei Jobu, Shumpei Morisawa, Tomoyuki Hamada, Yuiti Baba, Kazuya Kawai, Yoko Nakaoka, Toshikazu Yabe, Takashi Furuno, Eisuke Yamada, Hitoshi Fukuda, Tsuyoshi Ohta, Toshinobu Hayashi, Hiroaki Kitaoka and Mitsuhiko Miyamura : Assisted Living and Medication Adherence in Super-aged Patients With Heart Failure in the Japanese Population., Journal of Cardiovascular Pharmacology, Vol.79, No.4, 467-471, 2022.
(Summary)
Poor adherence to medication in patients with heart failure (HF) is associated with poor clinical outcomes. Although social support has been reported to improve medication adherence in patients with HF, the detailed underlying mechanism of this association is unclear. This study investigated appropriate social support types to ensure medication adherence, as well as patient characteristics that benefit from such social support in patients with HF. This was a retrospective observational study investigating the association of social support with medication adherence in 824 patients with HF who were registered in a prospective multicenter database. First, we analyzed the association between social support types and poor medication adherence leading to hospitalization. An interaction analysis was performed to detect patients' characteristics that benefited most from social support in terms of medical adherence. Fifty patients (6.1%) were hospitalized for poor adherence to medications. Multivariable analysis revealed that not receiving assisted living, which was defined as having supporting individuals at least once a week, was independently associated with poor medication adherence-related hospitalization. An interaction analysis revealed that patients with dementia benefited from assisted living significantly, whereas male patients or current smokers did not. Summarily, assisted living at least once a week was appropriate for improving medication adherence in patients with HF and was particularly effective in patients with dementia. Performed in a super-aging region in Japan, this study may also suggest the relevance of social support in preventing HF exacerbation in other developed countries that will experience an aging society in the near future.
(Keyword)
Aged / Dementia / Heart Failure / Humans / Japan / Male / Medication Adherence / Prospective Studies
Kei Kawada, Tomoaki Ishida, Kohei Jobu, Shumpei Morisawa, Tetsushi Kawazoe, Motoki Nishida, Satomi Nishimura, Naohisa Tamura, Saburo Yoshioka and Mitsuhiko Miyamura : Yokukansan suppresses neuroinflammation in the hippocampus of mice and decreases the duration of lipopolysaccharide- and diazepam-mediated loss of righting reflex induced by pentobarbital., Journal of Natural Medicines, Vol.76, No.3, 634-644, 2022.
(Summary)
Neuroinflammation is associated with the development of hypoactive delirium, which results in poor clinical outcomes. Drugs effective against hypoactive sur have not yet been established. Yokukansan has an anti-neuroinflammatory effect, making it potentially effective against hypoactive delirium. This study aimed to examine the effect of Yokukansan on the pentobarbital-induced loss of righting reflex duration extended with lipopolysaccharide (LPS)-induced neuroinflammation and diazepam-induced gamma-aminobutyric acid receptor stimulation in a mouse model. The active ingredients in Yokukansan and its anti-neuroinflammatory effect on the hippocampus were also investigated. Furthermore, we examined the in vitro anti-inflammatory effects of Yokukansan on LPS-stimulated BV2 cells, a murine microglial cell line. Findings revealed that treatment with Yokukansan significantly decreased the duration of pentobarbital-induced loss of righting reflex by attenuating the LPS-induced increase in interleukin-6 and tumor necrosis factor-alpha levels in the hippocampus. Moreover, treatment with Yokukansan significantly decreased the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus after 24 h of LPS administration. In addition, glycyrrhizic acid, an active ingredient in Yokukansan, partially decreased the duration of pentobarbital-induced loss of righting reflex. Treatment with Yokukansan also suppressed the expression of inducible nitric oxide, interleukin-6, and tumor necrosis factor mRNA in LPS-stimulated BV2 cells. Thus, these findings suggest that Yokukansan and glycyrrhizic acid may be effective therapeutic agents for treating neuroinflammation-induced hypoactive delirium.
Sarcopenic obesity is associated with increased visceral fat and decreased muscle mass, resulting in decreased insulin sensitivity, increased production of inflammatory cytokines, and oxidative stress. In this study, we first evaluated the effects of herbal medicines on the transcriptional activity of the Sirtuin 1 (sirt1) promoter in vitro as an indicator of their therapeutic effect. Our data suggested that hot water Saikokeishikankyoto (SKK) extracts increased sirt1 transcriptional activity in vitro, identifying it as a candidate therapeutic for evaluation in the KKAy type 2 diabetic obesity mouse model. These in vivo evaluations revealed that SKK treatment increased the wet weight and muscle fiber content in cross sections of the gastrocnemius muscle (GA) and restored motor function in these animals. In addition, SKK treatment reduced tumor necrosis factor-α (TNFα) expression in the sera and suppressed Atrogin1 and MuRF1 transcription in the GA samples. This treatment also increased sirt1 expression in these tissues. These results suggest that SKK inhibits skeletal muscle atrophy and improves motor function in KKAy mice by suppressing inflammation. In actual clinical practice, SKK is expected to inhibit muscle atrophy and improve motor dysfunction in sarcopenic obesity.
Tomoaki Ishida, Kohei Jobu, Kei Kawada, Shumpei Morisawa, Tetsushi Kawazoe, Hisashi Shiraishi, Hiroko Fujita, Satomi Nishimura, Hitomi Kanno, Mitsue Nishiyama, Kazuo Ogawa, Yasuyo Morita, Kazuhiro Hanazaki and Mitsuhiko Miyamura : Impact of Gut Microbiota on the Pharmacokinetics of Glycyrrhizic Acid in Yokukansan, a Kampo Medicine., Biological & Pharmaceutical Bulletin, Vol.45, No.1, 104-113, 2022.
(Summary)
Individual differences in gut microbiota can affect the pharmacokinetics of drugs. Yokukansan is a traditional Japanese kampo medicine used to treat peripheral symptoms of dementia and delirium. A study examining the pharmacokinetics of the components of yokukansan reported large individual differences in the pharmacokinetics of glycyrrhizic acid (GL). It is known that GL is metabolized by intestinal bacteria to glycyrrhetinic acid (GA), which is absorbed in the gastrointestinal tract. Thus, the gut microbiota may affect GL pharmacokinetics. We aimed to clarify the relationship between the gut microbiota composition and pharmacokinetics of GL in yokukansan. Mice were orally administered yokukansan, following the administration of various antibiotics, and the plasma concentration of GA and composition of gut microbiota were measured. The GA plasma concentration was low in mice treated with amoxicillin and vancomycin. The composition of gut microbiota revealed a different pattern from that of the control group. Mice with low plasma levels of GA had lower levels of the phylum Bacteroides and Firmicutes. Additionally, bacteria, such as those belonging to the genera Parabaceroides, Bacteroides, Ruminococcus and an unknown genus in families Lachnospiraceae and Ruminococcaceae, exerted positive correlations between the gene copies and plasma GA levels. These bacteria may contribute to the absorption of GA in the gastrointestinal tract, and multiple bacteria may be involved in GL pharmacokinetics. The pharmacokinetics of GL may be predicted by evaluating the composition of gut bacteria, rather than by evaluating the amount of a single bacterium.
Shohei Sugimoto, Tomoaki Ishida, Kei Kawada, Kohei Jobu, Shumpei Morisawa, Naohisa Tamura, Daisuke Takuma, Saburo Yoshioka and Mitsuhiko Miyamura : Central Nervous System Ischemia Associated with Bevacizumab: An Analysis of the Japanese Adverse Drug Event Report Database., Biological & Pharmaceutical Bulletin, Vol.45, No.12, 1805-1811, 2022.
(Summary)
Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.
(Keyword)
Aged / Humans / Middle Aged / Pharmaceutical Preparations / Bevacizumab / Japan / Vascular Endothelial Growth Factor A / Drug-Related Side Effects and Adverse Reactions / central nervous system / ischemia / Glioma
Kei Kawada, Tomoaki Ishida, Kohei Jobu, Tsuyoshi Ohta, Hitoshi Fukuda, Shumpei Morisawa, Tetsushi Kawazoe, Naohisa Tamura and Mitsuhiko Miyamura : Association of Aggression and Antiepileptic Drugs: Analysis Using the Japanese Adverse Drug Event Report (JADER) Database., Biological & Pharmaceutical Bulletin, Vol.45, No.6, 720-723, 2022.
(Summary)
Aggression is the most common adverse effect of antiepileptic drugs (AEDs). This study aimed to investigate the association of aggression with AED use. The reporting odds ratio (ROR) from adverse event reports, submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, was used to calculate and investigate the association between AEDs and aggression. We also analyzed the association of aggression with the combined use of AEDs and the relationship between AED-associated aggression and patient characteristics. A total of 433 patients developed aggression. Significant aggression signals were detected for perampanel (crude ROR: 325.04, 95% confidence interval (CI): 118.48-752.58, p < 0.01), levetiracetam (crude ROR: 17.14, 95% CI: 10.33-26.90, p < 0.01), lacosamide (crude ROR: 16.90, 95% CI: 2.02-62.51, p < 0.01), lamotrigine (crude ROR: 15.98, 95% CI: 9.99-24.39, p < 0.01), valproate (crude ROR: 6.68, 95% CI: 4.27-10.02, p < 0.01), and carbamazepine (crude ROR: 2.47, 95% CI: 1.17-4.59, p < 0.01). The combined therapy with perampanel and levetiracetam had a significant aggression signal (adjusted ROR: 25.90, 95% CI: 1.14-59.10, p < 0.01). In addition, we found that aggression frequently occurred in patients <60 year (adjusted ROR: 2.88, 95% CI: 1.49-5.56, p < 0.01) treated with levetiracetam. These results may be useful for minimizing the risk of aggression during the treatment of AEDs.
(Keyword)
Adverse Drug Reaction Reporting Systems / Aggression / Anticonvulsants / Drug-Related Side Effects and Adverse Reactions / Humans / Japan / Levetiracetam
In obese patients with type 2 diabetes, reduced insulin sensitivity, increased production of inflammatory cytokines, and increased oxidative stress were observed, which lead to decreased protein synthesis and increased proteolysis in the skeletal muscles. Juzentaihoto (JTT) is herbal medicine and we have previously reported that the administration of JTT hot water extract alleviates skeletal muscle atrophy in a mouse model with streptozotocin-induced type 1 diabetes. In this study, we evaluated the inhibitory effects of JTT on muscle atrophy in a mouse model with obesity and type 2 diabetes. JTT was administered to KKAy mice with type 2 diabetic obesity and its effects on the skeletal muscles were evaluated. After JTT administration in KKAy mice, the wet weight and muscle fibre cross-sectional area of gastrocnemius increased and the time duration of exercise in the rotarod test improved. In addition, the serum levels of tumour necrosis factor-α and interleukin-6 decreased, adiponectin levels increased, and homeostasis model assessment for insulin resistance improved. Furthermore, JTT administration decreased the mRNA levels of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1), increased the mRNA levels of Sirtuin1 in gastrocnemius. Our results suggest that JTT improves insulin resistance, suppresses inflammation, and reduces oxidative stress in KKAy mice, thereby suppressing skeletal muscle atrophy. JTT administration in clinical practice is expected to improve muscle atrophy in patients with obesity and type 2 diabetes.
Shumpei Morisawa, Kohei Jobu, Tomoaki Ishida, Kei Kawada, Hitoshi Fukuda, Yu Kawanishi, Taku Nakayama, Shinkuro Yamamoto, Naohisa Tamura, Mitsuhiro Takemura, Nao Kagimoto, Tsuyoshi Ohta, Noritaka Masahira, Hideo Fukuhara, Shun-Ichiro Ogura, Tetsuya Ueba, Keiji Inoue and Mitsuhiko Miyamura : Association of 5-aminolevulinic acid with intraoperative hypotension in malignant glioma surgery., Photodiagnosis and Photodynamic Therapy, Vol.37, 2021.
(Summary)
5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells.
Kei Kawada, Hitoshi Fukuda, Toru Kubo, Tsuyoshi Ohta, Tomoaki Ishida, Shumpei Morisawa, Tetushi Kawazoe, Manami Okamoto, Hiroko Fujita, Kohei Jobu, Yasuyo Morita, Tetsuya Ueba, Hiroaki Kitaoka and Mitsuhiko Miyamura : Added value of anxiolytic benzodiazepines in predictive models on severe delirium in patients with acute decompensated heart failure: A retrospective analysis., PLoS ONE, Vol.16, No.4, 2021.
(Summary)
The use of anxiolytic benzodiazepines was independently correlated with severe delirium, and their use in models based on conventional risk factors had an additive value for predicting delirium in patients with ADHF.
(Keyword)
Acute Disease / Age Factors / Aged / Aged, 80 and over / Anti-Anxiety Agents / Benzodiazepines / Critical Care / Delirium / female / heart failure / Humans / Incidence / female / Middle Aged / Patient Admission / Respiration, Artificial / Retrospective Studies / Risk Factors / Severity of Illness Index / Sex Factors / Treatment Outcome
Toshinobu Hayashi, Mototsugu Shimokawa, Fumitaka Mizuki, Koichi Matsuo, Kei Kawada, Takafumi Nakano and Takashi Egawa : Efficacy of one-day versus multiple-day dexamethasone for chemotherapy-induced nausea and vomiting in lung cancer patients receiving carboplatin-based chemotherapy: a propensity score-matched analysis., Supportive Care in Cancer, Vol.29, No.9, 5029-5035, 2021.
(Summary)
RA and APR concerning CINV incidence in lung cancer patients receiving CBDCA-based chemotherapy. Antiemetic regimens of one-day DEX result in poor control of delayed nausea; therefore, we recommend the application of the DEX-sparing strategy only after careful patient selection while considering the development of nausea.
Toshinobu Hayashi, Mototsugu Shimokawa, Koichi Matsuo, Hirotoshi Iihara, Kei Kawada, Takafumi Nakano and Takashi Egawa : Chemotherapy-induced nausea and vomiting (CINV) with carboplatin plus pemetrexed or carboplatin plus paclitaxel in patients with lung cancer: a propensity score-matched analysis., BMC Cancer, Vol.21, No.1, 2021.
(Summary)
The CBDCA + PEM regimen has a higher risk of causing delayed nausea than the CBDCA + PTX regimen, and aggressive antiemetic prophylaxis should be offered to patients treated with CBDCA + PEM.
Kei Kawada, Tsuyoshi Ohta, Hitoshi Fukuda, Toshinobu Hayashi, Koudai Tanaka, Toshi Imai, Yasuyo Morita and Mitsuhiko Miyamura : Effect of lubiprostone on vinca alkaloid-induced constipation in patients with hematological malignancies: a propensity score-matched analysis., Annals of Hematology, Vol.99, No.10, 2429-2436, 2020.
(Summary)
Patients receiving vinca alkaloids for hematological malignancies frequently experience constipation that is unresponsive to laxatives. Research on treatment of vinca alkaloid-induced constipation is limited. This study aimed to determine whether the chloride channel activator lubiprostone ameliorates vinca alkaloid-induced constipation in patients with hematological malignancies. In this retrospective cohort study, vinca alkaloid-induced constipation (grade ≥ 3 using the Common Terminology Criteria for Adverse Events) was investigated in patients treated for hematological malignancies between July 2014 and June 2019 who had already been prescribed osmotic laxatives and additionally received either a stimulant laxative or lubiprostone. Univariate and multivariate analyses were performed to identify the risk factors for persistent constipation after introduction of the second laxative. A propensity score model was used to match 67 patients taking a stimulant laxative and 67 treated with lubiprostone, and the occurrence of intractable constipation was compared between groups. Overall, 203 patients were included, among whom 50 (25%) had constipation. On multivariate analysis, body mass index, opioid use, and addition of lubiprostone were independently associated with constipation. Patients treated with lubiprostone were significantly less likely to experience intractable constipation than did those treated with stimulant laxatives (10% vs. 34%, P = 0.002). Moreover, post-constipation diarrhea was significantly less frequent among patients treated with lubiprostone (42% vs. 63%, P = 0.024). Lubiprostone was more effective than stimulant laxatives at treating vinca alkaloid-induced intractable constipation in patients with hematological malignancies, and its use could enable safe vinca alkaloid chemotherapy.
Tomoaki Ishida, Kei Kawada, Shumpei Morisawa, Kohei Jobu, Yasuyo Morita and Mitsuhiko Miyamura : Risk Factors for Pseudoaldosteronism with Yokukansan Use: Analysis Using the Japanese Adverse Drug Report (JADER) Database., Biological & Pharmaceutical Bulletin, Vol.43, No.10, 1570-1576, 2020.
(Summary)
Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.
(Keyword)
Adolescent / adult / Adverse Drug Reaction Reporting Systems / Age Factors / Aged / data analysis / Databases, Factual / Drugs, Chinese Herbal / female / Humans / Japan / Liddle Syndrome / female / Middle Aged / Risk Factors / Young Adult
Kei Kawada, 太田 剛史, 田中 聡 and 宮村 充彦 : ベンゾジアゼピン系・非ベンゾジアゼピン系睡眠導入薬を慢性的に服用している急性期脳卒中発症患者における安全な睡眠薬選択の検討, Japanese Journal of Pharmaceutical Health Care and Sciences, Vol.45, No.4, 175-181, 2019.
31.
Kei Kawada, Tsuyoshi Ohta, Koudai Tanaka, Mitsuhiko Miyamura and Satoshi Tanaka : Addition of Suvorexant to Ramelteon Therapy for Improved Sleep Quality with Reduced Delirium Risk in Acute Stroke Patients., Journal of Stroke & Cerebrovascular Diseases, Vol.28, No.1, 142-148, 2018.
(Summary)
Addition of suvorexant to ramelteon therapy, rather than a GABA receptor agonist, can improve subjective sleep quality without inducing delirium in acute stroke patients.
Kei Kawada, Tsuyoshi Ohta, Koudai Tanaka and Norifumi Miyamoto : Reduction of Nicardipine-Related Phlebitis in Patients with Acute Stroke by Diluting Its Concentration., Journal of Stroke & Cerebrovascular Diseases, Vol.27, No.7, 1783-1788, 2018.
(Summary)
The simple and appropriate proposition about nicardipine administration lowered maximum nicardipine concentration and reduced the incidence of nicardipine-related phlebitis in patients with acute stroke.
門口 直仁, 田中 聡, Kei Kawada, 高平 豊 and 服部 暁昌 : 救命救急・集中治療領域におけるバンコマイシン血中濃度予測性の検討, Journal of Japanese Society for Emergency Medicine, Vol.15, No.2, 212, 2012.
42.
門口 直仁, 田中 聡, Kei Kawada, 高平 豊 and 服部 暁昌 : 救命救急・集中治療領域におけるバンコマイシン血中濃度予測性の検討, Journal of Japanese Society for Emergency Medicine, Vol.15, No.2, 212, 2012.
43.
Kei Kawada, 長崎 大武, 田中 聡, 服部 暁昌 and 田中 照夫 : 救命救急センターにおける医薬品安全管理への薬剤師の貢献, Journal of Japnese Society of Hospital Pharmacists, Vol.48, No.2, 181-184, 2012.
岡崎 由紀, 田中 聡, Kei Kawada, 長崎 大武 and 服部 暁昌 : 手術室における医薬品管理体制の評価, The Journal of Japan Society for Health Care Management, Vol.12, 193, 2011.
46.
田中 聡, 村田 厚夫, 長崎 大武, Kei Kawada and 服部 暁昌 : 救急医療における認定薬剤師の誕生と未来 高知医療センターにおける薬剤師による救急医療支援業務, Journal of Japanese Society for Emergency Medicine, Vol.14, No.2, 220, 2011.
47.
Kei Kawada, 長崎 大武, 田中 聡, 服部 暁昌 and 寺岡 美千代 : 命救急センターにおける医薬品関連インシデントの発生状況, The Journal of Japan Society for Health Care Management, Vol.11, 213, 2010.
Kei Kawada, 田中 聡, 小笠原 恵子, 寺岡 美代子 and 石原 潤子 : 救命救急センターにおける医薬品安全管理への薬剤師の取り組み, Journal of Japanese Society for Emergency Medicine, Vol.11, No.2, 255, 2008.
51.
Yusuke Fujiwara, Kei Kawada, Daiki Takano, Susumu Tanimura, Kei-ichi Ozaki and Michiaki Kohno : Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner., Biochemical and Biophysical Research Communications, Vol.340, No.2, 560-566, 2005.
(Summary)
Constitutive activation of the PI3 kinase/Akt pathway is associated with the neoplastic phenotype of a large number of human tumor cells. As the anti-apoptotic role of the PI3 kinase/Akt pathway has been established, we have examined whether specific blockade of this pathway sensitizes tumor cells to DNA-damaging agent-induced cytotoxicity by enhancing apoptotic cell death. Although a PI3 kinase inhibitor, LY294002, by itself does not induce apoptotic cell death, LY294002 selectively and markedly enhances the apoptosis-inducing efficacy of doxorubicin: such an enhanced cell death is only detected in tumor cells in which the PI3 kinase/Akt pathway is constitutively activated, and it is totally dependent on the functional p53 pathway. These results suggest that the combination of a PI3 kinase/Akt pathway inhibitor and doxorubicin provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the PI3 kinase/Akt pathway is constitutively activated and the p53 pathway is functional.