Phosphonic and phosphinic acids, especially α-heteroatom-substituted ones, possess unique structural and physical features which enable them to act as hydrotically stable analogs to biological phosphates in biological processes. They also act as mimetics in the transition state of the protease-induced hydrolysis of dipeptides. The first half of this review focuses on selected new synthetic methods developed by our research group for the stereoselective synthesis of α-heteroatom-substituted phosphonic and phosphinic acid derivatives, including modified nucleotide analogs and phosphinyl dipeptide isosteres. In the latter half, this review summarizes the utility of difluoromethylenephosphonic acids and phosphonic acid esters in the development of enzyme inhibitors against protein tyrosine phosphatases, sphingomyelinases, purine nucleoside phosphorylases and thrombin. The enzyme inhibitors developed were used as probes to elucidate signal transductions and the mechanisms of enzyme actions. The findings of the studies are briefly described.
An ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) avoids insoluble chelate formation with metal-containing drugs in the intestinal tract and is rapidly hydrolyzed to the parent drug. Furthermore, the minimum inhibitory concentration confirms that LVFX-EHE is less likely to cause pseudomembranous colitis because of less susceptibility to normal intestinal bacteria flora. Pemetrexed dimedoxomil, the prodrug of pemetrexed, was synthesized via reaction with medoxomil bromide after modification of L-glutamate with the tert-butyloxycarbonyl protecting group (BOC), followed by hydrolysis of the BOC moiety with trifluoroacetic acid (TFA) in CH2Cl2 at a temperature of 0°C for 2 h. A serum pemetrexed concentration of >2 μg/mL was observed after oral administration of pemetrexed dimedoxomil at a dose of 60 mg/kg to rats.
This article reviews our studies on the oxiranyl anion-based, [X+2+Y]-type convergent strategy for the synthesis of polycyclic ether natural products. The strategy is noteworthy for its flexibility, which allows for the generation of different-sized fused ring systems based on a ring expansion reaction. For a precise understanding of this key ring expansion, we first focused on the reaction mechanism, in which an equatorial attack of TMS-diazomethane was determined to be the crucial step. In the later part of this review, the application of our oxiranyl anion-based strategy to large fused ring systems is described. The advantageous flexibility is highlighted in the divergent synthesis of five octacyclic ethers involving the CDEFGHIJ-ring skeleton of yessotoxin and its ring-modified analogs. Total synthesis of gymnocin-A was achieved using the oxiranyl anion convergent strategy, which furnished its large system of fourteen contiguous ether rings.
The regulation of the development and function of the nervous system is not preprogramed but responds to environmental stimuli to change neural development and function flexibly. This neural plasticity is a characteristic property of the nervous system. For example, strong synaptic activation evoked by environmental stimuli leads to changes in synaptic functions (known as synaptic plasticity). Long-lasting synaptic plasticity is one of the molecular mechanisms underlying long-term learning and memory. Since discovering the role of the transcription factor cAMP-response element-binding protein in learning and memory, it has been widely accepted that gene regulation in neurons contributes to long-lasting changes in neural functions. However, it remains unclear how synaptic activation is converted into gene regulation that results in long-lasting neural functions like long-term memory. We continue to address this question. This review introduces our recent findings on the gene regulation of brain-derived neurotrophic factor and discusses how regulation of the gene participates in long-lasting changes in neural functions.
We conducted a meta-analysis to investigate the influence of antifungal spectrum on the effectiveness and adverse events of empirical antifungal therapy for febrile neutropenia. We searched PubMed and Cochrane Central Register of Controlled Trials (Central), and identified randomized controlled trials reporting mortality, efficacy, adverse events, and hepatic and renal dysfunction. Five trials assessed the efficacy and adverse events of agents with antifungal spectrum covering and those not covering Aspergillus. There were no differences in mortality [risk ratio (RR); 0.79, 95% confidence interval (Cl); 0.60-1.02], efficacy ratio (RR; 1.01, 95%Cl; 0.91-1.12), adverse event ratio (RR; 0.23, 95%Cl; 0.04-1.23), and hepatic dysfunction ratio (RR; 0.81, 95%Cl; 0.59-1.12) between two groups. Antifungals with no activity against Aspergillus were associated with lower renal dysfunction ratio (RR; 0.27, 95%Cl; 0.10-0.71). Five trials compared agents with antifungal spectrum covering versus those not covering Mucor. There were no difference in mortality (RR; 1.24, 95%Cl; 0.98-1.57), efficacy ratio (RR; 1.09, 95%Cl; 0.91-1.30), and hepatic dysfunction ratio (RR; 0.98, 95%Cl; 0.66-1.45) between two groups. Antifungals with no activity against Mucor were associated with lower adverse event ratio (RR; 0.60, 95%Cl; 0.47-0.77) and renal dysfunction ratio (RR; 0.25, 95%Cl; 0.13-0.49). Presence or absence of activity against Aspergillus or Mucor is not associated with mortality or efficacy ratio. Amphotericin B with activity against Aspergillus and Mucor has a higher adverse event ratio. Depending on the case, selection of antifungal drugs considering efficacy and side effects is necessary.
Tazobactam/piperacillin (TAZ/PIPC) is a combination antibiotic frequently used to treat pneumonia. It has recently been reported that TAZ/PIPC worsens renal function in patients with existing renal impairment. Creatinine clearance is generally between 10 and 40 mL/min in Japanese patients, so TAZ/PIPC is given at a dose of 2.25 g three times daily or 4.5 g twice daily. If pneumonia is severe or intractable, the dose frequency may be increased to 2.25 g four times daily and 4.5 g three times daily. We examined the effect of these different dosing regimens on renal function. We studied a cohort of 57 patients with impaired renal function hospitalized with pneumonia and treated with TAZ/PIPC between January 2015 and November 2016. Patients were classified into four groups according to TAZ/PIPC dose: 2.25 g three times daily (Group A); 2.25 g four times daily (B); 4.5 g twice daily (C) and 4.5 g three times daily (D). We examined the frequency of acute kidney injury (AKI) and treatment effectiveness. In Groups A, B, C and D, AKI occurred in 5.6%, 0.0%, 25.0% and 38.5% of patient. In groups C and D, hydration and dose reduction were required to address early signs of impending AKI. Our findings suggest that the higher TAZ/PIPC dose of 4.5 g was responsible for the decline in renal function, even if the dose frequency was reduced.
Cells have developed ingenious defense mechanisms in response to oxidative stress. Here, we evaluated changes in anti-oxidative capacity during differentiation of 3T3-L1 preadipocytes into adipocytes. When 3T3-L1 preadipocytes were treated with H2O2 (0.10-2.0 mM) for 21 h, cell viability decreased in response to H2O2 concentration, with an LD50 of approximately 0.35 mM H2O2. In the cells undergoing differentiation at 2 and 6 d, LD50 increased to 1.0 and >2.0 mM H2O2, respectively. These results indicate that resistance to oxidative stress dramatically increased with progression of differentiation of preadipocytes into adipocytes. Catalase activity and GSH content increased in the differentiated cells at 6 d, whereas superoxide dismutase and glutathione peroxidase activities were slightly lower in adipocytes than in preadipocytes. Moreover, knockdown of catalase or depletion of intracellular GSH enhanced the sensitivity to H2O2. When GSH was added to the cells depleted of intracellular GSH, the antioxidant capacity recovered. Autophagy was increased in differentiated adipocytes but was not affected by H2O2 treatment. Therefore, these results suggest that the increase in intracellular catalase activity and GSH content played a role in the increased anti-oxidative capacity of differentiated 3T3-L1 adipocytes.
Considering the pharmacological effects of chiral drugs, enantiopure drugs may differ from their racemic mixture formulation in efficacy, potency, or adverse effects. Levomethorphan (LVM) and Dextromethorphan (DXM) act on the central nervous system and exhibit different pharmacological features. LVM, the l-stereoisomer of methorphan, shows many similarities to opiates such as heroin, morphine and codeine, including the potential for addiction, while the d-stereoisomer, DXM, does not have the same opioid effect. In the present study, NMR-based metabolomics were performed on the urine of rats treated with these stereoisomers, and showed significant differences in metabolic profiles. In urine within 24 h after treatment of these samples, levels of citrate, 2-oxoglutarate, creatine, and dimethylglycine were higher in LVM-treated rats than in DXM-treated rats. While urinary levels of hippurate and creatinine gradually increased over 72 h in DXM-treated rats, these metabolites were decreased in the urine by 48-72 h after treatment with LVM. The levels of these changed metabolites may provide the first evidence for different cellular responses to the metabolism of stereoisomers.
Influence of water contents to the pharmaceutical tablet strength is known empirically, and participation of hydrogen bonding force among adsorbed water molecules has been presumed. However, the detailed mechanisms of hydrogen bonding phenomena have not been reported. In this study, the hydrogen bonds states of the surface adsorbed waters on the excipient particles of the tablets were focused upon, and the relationship to the interparticle binding force determined by the Rumpf equation was discussed using a near-infrared spectroscopy (NIR). As for the results, NIR peaks of OH groups of surface water were shifted by a humidity change, and the degrees of the peak shifts correlated to interparticle binding force.
Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may differ between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario-based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1%) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1%) of these patients [kappa 0.32 (95% confidence interval 0.15-0.50)]. Of 111 patients, 42 (37.8%) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7%) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08-0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an effort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk.
Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kg×2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner- nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy.
We analyzed impression data and the scale of communication skills of students using text mining method to clarify which area a student was conscious of in communication in practical training. The results revealed that students tended to be conscious of the difference between practical hospital training and practical pharmacy training. In practical hospital training, specific expressions denoting relationships were “patient-visit”, “counseling-conduct”, “patient-counseling”, and “patient-talk”. In practical pharmacy training, specific expressions denoting relationships were “patient counseling-conduct”, “story-listen”, “patient-many”, and “patient-visit”. In practical hospital training, the word “patient” was connected to many words suggesting that students were conscious of a patient-centered communication. In practical pharmacy training, words such as “patient counseling”, “patient”, and “explanation” were placed in center and connected with many other words and there was an independent relationship between “communication” and “accept”. In conclusion, it was suggested that students attempted active patient-centered communication in practical hospital training, while they were conscious of listening closely in patient counseling in practical pharmacy training.
Based on the predictive performance in our previous study, we switched the therapeutic drug monitoring (TDM) analysis software for dose setting of vancomycin (VCM) from “Vancomycin MEEK TDM analysis software Ver2.0” (MEEK) to “SHIONOGI-VCM-TDM ver.2009” (VCM-TDM) in January 2015. In the present study, our aim was to validate the effectiveness of the changing VCM TDM analysis software in initial dose setting of VCM. The enrolled patients were divided into two groups, each having 162 patients in total, who received VCM with the initial dose set using MEEK (MEEK group) or VCM-TDM (VCM-TDM group). We compared the rates of attaining the therapeutic range (trough value; 10-20 μg/mL) of serum VCM concentration between the groups. Multivariate logistic regression analysis was performed to confirm that changing the VCM TDM analysis software was an independent factor related to attaining the therapeutic range. Switching the VCM TDM analysis software from MEEK to VCM-TDM improved the rate of attaining the therapeutic range by 21.6% (MEEK group: 42.6% vs. VCM-TDM group: 64.2%, p<0.01). Patient age ≥65 years, concomitant medication (furosemide) and the TDM analysis software used VCM-TDM were considered to be independent factors for attaining the therapeutic range. These results demonstrated the effectiveness of switching the VCM TDM analysis software from MEEK to VCM-TDM for initial dose setting of VCM.