43 research outputs found
<Abstract of published report>C_2-Symmetric N-(ÎČ-Mercaptoethyl)pyrrolidine as a Chiral Catalyst Ligand in the Addition Reaction of Aldehydes and Diethylzinc.
Pharmacological approach for drug repositioning against cardiorenal diseases
New applications of approved clinically used drugs are being discovered. Drug repositioning is a proposed strategy for developing these drugs as therapeutic agents for different diseases. Currently, approximately 2000 drugs are used in Japan. However, the compound targets and pathways involved in the pharmacological actions of 70-80% of these drugs have not been adequately clarified. Pharmacological examination of approved drugs is an important task in drug repositioning and vital for improving drug development efficiency. This review reports that angiotensin II type 1 receptor blockers show receptor-independent effects against reactive oxygen species generation in renal cells. Additionally, nitrosonifedipine has an antioxidative effect and protects endothelial cells against oxidative stress, and pioglitazone has multiple effects that improve dysfunctions in vascular control regulated by adrenergic and calcitonin gene-related peptide-containing nerves in animal models of diabetes. These data suggest that some approved drugs could be useful for treating cardiorenal diseases. Since cardiorenal diseases are likely to have chronic pathological conditions and require chronic drug administration, highly safe drugs are needed. Compared to newly developed drugs, drug repositioning of approved drugs with safety information is considered a particularly useful technique for searching new treatments for cardiorenal diseases
Evolution of oropharyngeal patterning mechanisms involving Dlx and endothelins in vertebrates
AbstractIn jawed vertebrates, the Dlx code, or nested expression patterns of Dlx genes, specify the dorsoventral polarity of pharyngeal arches, downstream of endothelin-1 (Edn-1) and its effectors, Bapx1 (Nkx3.2) and dHand (Hand2). To elucidate the evolution of the specification mechanism of the oropharyngeal skeletal system, lamprey homologs of Dlx, Edn, endothelin receptor (Ednr), Bapx1, and dHand were identified. Our analysis suggested that the Edn gene family emerged at the advent of vertebrates, and that gene duplications leading to the different Edn gnathostome subtypes (Edn1â3) occurred before the cyclostomeâgnathostome split. This timing of gene duplications, giving rise to multiple subtypes, was also implied for Dlx, Ednr, Hand, and Bapx. In lamprey embryos, nested expressions of Dlx genes were not observed in pharyngeal arches, nor was any focal expression of Bapx1, known in gnathostomes to specify the jaw joint. The dHand homolog, however, was expressed more intensively ventrally, as in gnathostomes. Lamprey homologs of Edn-1 and EdnrA were also shown to be expressed as described in mice, indicating involvement of this signaling pathway in the craniofacial patterning early in vertebrate evolution. These results suggest that the last common ancestor of all the extant vertebrates would have possessed basic gene repertoires involved in oropharyngeal patterning in gnathostomes, but the elaborate genetic program leading to the Dlx code is likely to have been acquired uniquely in gnathostomes
Evaluation of pharmaceutical lifesaving skills training oriented pharmaceutical intervention
Background: Many pharmacists are participating in team-based medical care in emergency hospitals. Therefore, there is a desperate need to improve the education system. In the present study, we provided a âpharmaceutical lifesaving skills trainingâ to the students in their fifth and sixth year of the pharmaceutical school and evaluated the programâs impact on the studentsâ learning and confidence in their ability to perform pharmaceutical interventions for emergency patients.
Methods: We conducted a pharmaceutical lifesaving skills training program with 12 participants who were in their fifth and six year of pharmaceutical school. We prepared a fictional scenario in which a patient with cardiac arrest has been rushed into a hospital. We measured the participantsâ level of knowledge of pharmaceutical lifesaving procedures and participantsâ confidence to perform pharmaceutical interventions before and after the training session. Using the data obtained from type II quantification method, we examined what elements in the content of the pharmaceutical lifesaving skill training attended by pharmacy students will affect the studentsâ confidence to perform pharmaceutical interventions. In addition, using the correspondence structural analysis, we examined which sections of the content of the pharmaceutical lifesaving skill training should be improved in the future.
Results: When we evaluated the level of knowledge acquired in pharmaceutical lifesaving skills training, the post-training overall correct answer rate was significantly higher than the pre-training overall correct answer rate. And also, level of participants' confidence to perform pharmaceutical interventions similarly increased after pharmaceutical lifesaving skill training. The influence degree graph indicates that the items likely to have a major impact on the participantsâ confidence to perform pharmaceutical interventions was âSelecting medicineâ. According to the correspondence structural analysis graph based on the questionnaire survey, one item identified as an improvement required was âSelecting medicineâ.
Conclusions: Our high-performance patient simulator-based lifesaving skills training program not only increased the participantsâ understanding of the training content but also increased their confidence in their ability to perform pharmaceutical interventions. Therefore, the pharmaceutical lifesaving skills training program we developed will contribute to the education of emergency care pharmacists who can perform pharmaceutical interventions for emergency patients
Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCRâABL inhibitor use by using an adverse drug event reporting database
Breakpoint cluster regionâAbelson murine leukemia (BCRâABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCRâABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCRâABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited followâup durations. In particular, BCRâABL inhibitorâinduced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drugârelated adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCRâABL inhibitorâinduced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCRâABL inhibitors. Subgroup analyses showed a clearly increased nilotinibâassociated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERSâ and JADERâbased signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCRâABL inhibitors and provides useful information for the selection of appropriate BCRâABL inhibitors
Development of monitoring tool by pharmacists
Purpose: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor- and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels.
Methods: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings.
Results: The management tool reduced the pharmacistsâ effort in collecting information on patientsâ prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects.
Conclusion: The results suggested that regardless of pharmacistsâ experience or skill, the introduction of this tool enables centralization of side-effect monitoring and can contribute to proper drug use
Impact of Energetic Ion Driven Global Modes on Toroidal Plasma Confinements
Excitation of energetic-ion-driven Alfv6n eigenmodes (AEs) and their impact on energetic ion confinement are widely and intensively studied in helical devices such as CHS and LHD as well as major tokamaks. The excitation of AEs sensitively depends on the parameter space defined by the averaged beam beta and the velocity ratio V6nlV6 (V611 : injected beam ion velocity, Va: Alfv6n velocity). In LHD, these two relevant parameters are widely scanned without suffering from current disruptions. So far, toroidicity induced AE (TAE), global AE (GAE) and energetic particle mode (EPM) or resonant TAE (R-TAE) were identified during tangential neutral beam injection (NBI) in CHS and LHD. Moreover, a new coherent mode with the frequency by about 8 times higher than the TAE frequency was observed in NBI heated plasmas of LHD at low magnetic field (<0.6T). This mode may be induced by helical field components of the confinement field. Nonlinear phenomena of bursting amplitude modulation and fast frequency chirping are clearly seen for TAEs and EPMs in CHS and LHD. EPMs in CHS and bursting TAEs in LHD enhance radial transport of energetic ions in certain plasma conditions
Developmental genetic bases behind the independent origin of the tympanic membrane in mammals and diapsids
International audienceThe amniote middle ear is a classical example of the evolutionary novelty. Although paleontological evidence supports the view that mammals and diapsids (modern reptiles and birds) independently acquired the middle ear after divergence from their common ancestor, the developmental bases of these transformations remain unknown. Here we show that lower-to-upper jaw transformation induced by inactivation of the Endothelin1-Dlx5/6 cascade involving Goosecoid results in loss of the tympanic membrane in mouse, but causes duplication of the tympanic membrane in chicken. Detailed anatomical analysis indicates that the relative positions of the primary jaw joint and first pharyngeal pouch led to the coupling of tympanic membrane formation with the lower jaw in mammals, but with the upper jaw in diapsids. We propose that differences in connection and release by various pharyngeal skeletal elements resulted in structural diversity, leading to the acquisition of the tympanic membrane in two distinct manners during amniote evolution
Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice
Aims/hypothesis
Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes.
Methods
Conditional macrophage-specific H-ferritin knockout (LysM-Cre FthKO) mice were used and divided into 4 groups; Wild-type (WT) and LysM-Cre FthKO mice with normal diet (ND), and WT and LysM-Cre Fth-KO mice with high-fat diet (HFD).
Results
Iron concentration reduced, and mRNA expression of ferroportin increased in macrophages from LysM-Cre FthKO mice. HFD-induced obesity was lower in LysM-Cre FthKO mice than in WT mice at 12 weeks (body weight (g); KO 34.6 ± 5.6 vs. WT 40.1 ± 5.2). mRNA expression of inflammatory cytokines, infiltrated macrophages, and oxidative stress increased in the adipose tissue of WT mice with HFD, but was not elevated in LysM-Cre FthKO mice with HFD. However, WT mice with HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre FthKO mice with HFD (adipose (Όmol Fe/g protein); KO 1496 ± 479 vs. WT 2316 ± 866, spleen (Όmol Fe/g protein); KO 218 ± 54 vs. WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre FthKO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and LPS-induced TNF-α mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA.
Conclusions/interpretation
Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes
Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway
Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency