Management of patients after total knee arthroplasty using mechanical prophylaxis and reduced doses of edoxaban: A retrospective cohort study.

OBJECTIVE: Edoxaban is given as pharmacologic prophylaxis alone or in combination with mechanical prophylaxis for venous thromboembolism after total knee arthroplasty. Several choices are made regarding edoxaban dosages when used in combination with mechanical prophylaxis. This study aimed to compare efficacy and safety in patients who received edoxaban with elastic stockings after total knee arthroplasty between those who received the standard dose, including those who received a reduced dose after meeting dose reduction criteria, and those who received reduced doses without dose reduction criteria. MATERIALS AND METHODS: This study included 143 patients in the standard-dose group (with 125 patients receiving dose-adjusted edoxaban 15 mg/day) and 110 patients in the low-dose group, and it compared the incidence of venous thromboembolism and bleeding events between groups. The impact of edoxaban administration on the occurrence of venous thromboembolism after total knee arthroplasty was also examined using multivariate regression analysis. RESULTS: Our results showed that rates of venous thromboembolism and bleeding events in patients wearing elastic stockings after total knee arthroplasty were similar in both standard- and low-dose groups. Multivariate regression analysis showed that use of reduced-dose edoxaban without dose adjustment did not correlate with the occurrence of venous thromboembolism, but edoxaban administration was significantly associated with older age and longer surgery time (odds ratio 1.84, 95% confidence interval 1.04 - 3.25, p = 0.036; odds ratio 1.69; 95% confidence interval 1.09 - 2.62, p = 0.019). CONCLUSION: These results suggest that reduced dose selection of edoxaban for patients who receive mechanical prophylaxis after total knee arthroplasty and post-administration pharmacological management may be useful.

Effects of reduced edoxaban administration on bleeding risk and D-dimer levels in patients wearing elastic stockings after total hip arthroplasty: A retrospective cohort study.

OBJECTIVE: Edoxaban is sometimes given at reduced doses when used concomitantly with physical prophylaxis to prevent symptomatic venous thromboembolism (VTE) after total hip arthroplasty (THA). This study aimed to evaluate the safety of reduced doses of edoxaban administered independent of the dose-reduction criteria and their effects on D-dimer levels after THA in Japanese patients. MATERIALS AND METHODS: This study enrolled 22 patients who received edoxaban 30 mg/day and 45 patients who received edoxaban 15 mg/day with dose adjustment as a standard-dose group, and 110 patients who received edoxaban 15 mg/day without dose adjustment as a low-dose group. The incidence of bleeding events was then compared between groups with patients wearing elastic stockings. Multivariate regression analysis was also performed to examine the effect of edoxaban administration on D-dimer levels after THA. RESULTS: The incidence of bleeding events after THA did not differ significantly between groups. In the multivariate model, dose reduction of edoxaban did not correlate with D-dimer levels on postoperative days 7 and 14, but higher D-dimer levels at postoperative days 7 and 14 correlated significantly with longer duration of surgery (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.20 - 2.29, p = 0.002; OR 1.63, 95% CI 1.17 - 2.29, p = 0.004, respectively). CONCLUSION: These results suggest that information on the duration of surgery may be useful in the pharmaceutical management in edoxaban drug prophylaxis combined with physical prophylaxis after THA in Japanese patients.

Validation of Self-Monitoring Devices Supporting Sodium Intake Reduction: An Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers.

INTRODUCTION: Although several approaches for approximating daily Na intake and the Na/K ratio using casual urine are available, the most useful method remains unclear during daily practice and at home. METHODS: Twenty-seven participants measured their casual urinary Na/K ratio repeatedly using a Na/K ratio monitor and also measured overnight urine once daily using a monitoring device which delivers on-site feedback to estimate their salt intake under unrestricted, low-salt (LS) (6 g/day), and high-salt (HS) (12 g/day) diets. RESULTS: The monitoring method utilizing overnight urine to estimate daily Na remained insensitive, resulting in significant overestimation during the LS diet and underestimation during the HS diet periods; estimated salt intake during the LS and HS diet periods plateaued at 7-8 g/day and 9-10 g/day within 3 day; mean estimated salt intake was 11.3 g/day, 7.9 g/day, and 9.8 g/day on the last day of the unrestricted, LS, and HS diets; the coefficient of variation (CV) of the estimated Na intake was 0.23 and 0.17 in the latter half of the low- and high-salt diet periods, respectively. The mean urinary Na/K molar ratio was 5.6, 2.5, and 5.3 on the last day of the unrestricted, LS, and HS diets; the CV of the daily mean Na/K ratio was 0.41 and 0.36 in the latter half of the LS and HS diet periods, respectively. The urinary Na/K ratio during the LS and HS diet periods plateaued within 2 days. The monitoring method based on the daily mean of the casual urinary Na/K ratio reflected the actual change in Na intake, and the estimated value tracked the actual changes in salt intake with smaller difference than the overnight urine estimates when using the estimation coefficient set at 2; estimated salt intake during the LS and HS diet periods plateaued at 5-6 g/day and 10-12 g/day within 2-3 day; mean estimated salt intake was 11.0 g/day, 5.7 g/day, and 10.7 g/day on the last day of the unrestricted, LS, and HS diets, respectively. DISCUSSION/CONCLUSION: Estimates of daily Na intake derived from overnight urine may remain insensitive during dietary interventions. The urinary Na/K ratio reflects the actual change in Na intake during dietary modification and may serve as a practical marker, particularly during short-term interventions. Conversion from the urinary Na/K ratio to estimated salt intake may be useful, if the coefficient was set appropriate by further investigations.

[Search for the subconsciousness of hospital pharmacists on their practices of blood drawing or injection, and etc].

The purpose of this study was to clarify the subconsciousness of hospital pharmacists regarding them practicing drip infusion or blood drawing for therapeutic drug monitoring (TDM), etc. We conducted a mail-in survey targeting 476 randomly-selected hospital pharmacists. In our survey sheet we presented our "hypothetical condition" i.e., "that medical practices such as drip infusion or blood drawing for TDM by hospital pharmacists be legally allowed" and we asked them 23 items about the pros and cons of this hypothetical condition and its influence on medical practice. Then, using factor analysis, we searched for the subconsciousness of hospital pharmacists from their answers to the 23 items. We then analyzed the causal association between the factors extracted from the survey and the pros and cons of the "hypothetical condition" using logistic regression analysis. 47.7% of respondents agreed to the "hypothetical condition". The results of this research provided 5 factors, consisting of "expectation of medical care and society", "temperament of pharmacists", "pharmacotherapy", "employment", and "medical team". We understood from the result of logistic regression analysis that hospital pharmacists subconsciously had two kinds of expectation, i.e., expectation about medical care and society, and about qualitative improvement of pharmacotherapy, as their background when they decided to agree to themselves practicing drip infusion or blood drawing for TDM, etc.

Distinct mechanism of cell death is responsible for tunicamycin-induced ER stress in SK-N-SH and SH-SY5Y cells.

In order to elucidate underlying mechanism of cell death pathways in neuronal cells in humans, we studied responsible pathways involved in the endoplasmic reticulum (ER) stress-induced cell death in neuroblastoma cells, SK-N-SH and its neuroblast-type subclone SH-SY5Y cells. A time-dependent induction of ER chaperons, glucose regulated protein (GRP)78 and GRP94, was observed after treatment with tunicamycin (TM), and cell death was also induced concomitantly in both cells. Although the pro-caspase-12-like protein was defined in both cells, a decrease in the protein was observed in only SH-SY5Y cells after exposure to TM. In contrast, pro-caspase-4 was detected in only SK-N-SH cells, and the cleaved-form was induced by the treatment with TM. A caspase-4 inhibitor, Z-LEVD-FMK attenuated TM-induced cell death in SK-N-SH cells. Calpain- and caspase-3-mediated proteolysis of alpha II-spectrin was also increased after the treatment with TM in both cells. A calpain inhibitor, calpeptin, repressed TM-induced cell death in only SK-N-SH cells. GADD153/C/EBP homologous protein (CHOP) was significantly induced after exposure to TM in only SH-SY5Y cells and RNA interference to GADD153/CHOP repressed TM-induced cell death. These results demonstrate that induction of GADD153/CHOP plays a pivotal role in mechanism of ER stress-induced cell death in SH-SY5Y cells, on the other hand, cleavage of pro-caspase-4 by activation of calpain play a crucial role in SK-N-SH cells. It is also suggested that the relevance of caspase-4 to ER stress is cell-specific even between human-origin cell lines.

Isobavachalcone, a chalcone constituent of Angelica keiskei, induces apoptosis in neuroblastoma.

Six chalcones from Angelica keiskei KOIDZUMI (Ashitaba in Japanese) and two chalcones from Humulus lupulus L. (hop) were examined for their cytotoxicity in two human neuroblastoma cell lines (IMR-32 and NB-39) and normal cells (primary culture of rat cerebellar granule cells) by [3-(4,5)-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. All chalcones exhibited cytotoxicity against neuroblastoma cells, and two of them (isobavachalcone and xanthoangelol H) had no effect on normal cells even at high concentration (10(-4) M) exposure. Typical morphologic features of apoptosis, including cell shrinkage, chromatin condensation, nuclear fragmentation and formation of apoptotic bodies, were observed in isobavachalcone-treated cells by Hoechst 33342 staining. Western blot analysis showed that isobavachalcone significantly reduced pro-caspase-3 and pro-caspase-9, and subsequently increased the level of cleaved caspase-3 and cleaved caspase-9 in both neuroblastoma cell lines. Moreover, Bax was markedly induced by isobavachalcone application. These results suggest that isobavachalcone induces apoptotic cell death in neuroblastoma via the mitochondrial pathway and has no cytotoxicity against normal cells. Therefore, isobavachalcone may be applicable as an efficacious and safe drug for the treatment of neuroblastoma.

N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology.

Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down's syndrome have been associated with several mitochondrial alterations. Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions, particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.

N-Acetylcysteine and ebselen but not nifedipine protected cerebellar granule neurons against 4-hydroxynonenal-induced neuronal death.

4-Hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, has been shown to induce neurotoxicity in various types of neurons. To clarify the mechanisms underlying HNE-induced neurotoxicity, the effects of antioxidants (N-acetylcysteine (NAC) and ebselen with or without NAC pretreatment) and Ca(2+)-related reagents were examined in cerebellar granule neurons. The decreases in neuronal survival and mitochondrial membrane potential induced by HNE were suppressed by pretreatment with NAC at concentrations of 500 and 1000 microM. HNE-induced protein modification and reactive oxygen species generation were also suppressed by pretreatment with NAC at 1000 microM. Although simultaneous application of ebselen (10 microM) did not protect against HNE-induced neurotoxicity, it completely suppressed HNE-induced injury after pretreatment with NAC at 300 microM. HNE increased [Ca(2+)](i) levels, and this increase was significantly attenuated by simultaneous application of nifedipine (10 microM) or EGTA (1000 microM), but not by MK-801 or CNQX. However, none of these Ca(2+)-related reagents was able to prevent HNE-induced neuronal death or mitochondrial injury. These results suggest that pretreatment with a low concentration of NAC dramatically potentiates the neuroprotective activity of ebselen, and that HNE-induced increase in [Ca(2+)](i) is not involved in HNE-induced neuronal death in cerebellar granule neurons.

N-acetylcysteine selectively protects cerebellar granule cells from 4-hydroxynonenal-induced cell death.

4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, has been shown to induce neurotoxicity accompanied by multiple events. To clarify mechanisms of neuroprotective compounds on HNE-induced toxicity, the protective effects of N-acetylcysteine (NAC), alpha-tocopherol (TOC), ebselen and S-allyl-L-cysteine (SAC) were compared in cerebellar granule neurons. The decrease in MTT reduction induced by HNE was significantly suppressed by pretreatment of the neurons with 1000 microM NAC or 10 and 100 microM TOC; however, lactate dehydrogenase (LDH) release and propidium iodide (PI) fluorescence studies revealed that neuronal death was suppressed by NAC but not by TOC. Treatment of these neurons with HNE resulted in a drastic reduction of mitochondrial membrane potential, and this reduction was also prevented by NAC but not by TOC. Ebselen and SAC, a garlic compound, were unable to protect these neurons against HNE-induced toxicity. Pretreatment with NAC also prevented HNE-induced depletion of intracellular glutathione (GSH) levels in these neurons. These results suggest that NAC, but not other antioxidants such as TOC, SAC and ebselen, exerts significant protective effects against HNE-induced neuronal death in cerebellar granule neurons, and that this neuroprotective effect is due, at least in part, to preservation of mitochondrial membrane potential and intracellular GSH levels.

Distinct nuclear factor-kappaB/Rel proteins have opposing modulatory effects in glutamate-induced cell death in HT22 cells.

Members of the nuclear factor-kappaB (NF-kappaB)/Rel family (p50, p52, p65 (RelA), RelB and c-Rel) is sequestered in the cytoplasm through its tight association with the inhibitor of NF-kappaB (IkappaB). NF-kappaB has been shown to function as key regulators of either cell death or survival in neurons after activation of the cells by various extracellular signals. In the study presented here, we investigated whether the selective activation of diverse NF-kappaB/Rel family members in HT22 cells might lead to distinct effects on glutamate-induced cell death. Exposing HT22 cells to glutamate, which blocks cystine uptake into the cells via inhibition of the glutamate-cystine antiporter, resulted in a transient activation of IkappaB and NF-kappaB/Rel and caused delayed cell death. Aspirin, which has been shown to block phosphorylation of the IkappaB component of the cytoplasmic NF-kappaB complex, significantly suppressed glutamate-induced cell death, whereas the NF-kappaB decoy oligonucleotide potentiated it. The inhibition of NF-kappaB/Rel protein expression by antisense oligonucleotides showed that p65 is involved in glutamate-mediated cell death, whereas p50 is involved in inhibitory pathways of the cell death. These findings suggest that in HT22 cells, the balance between promoting and presenting cell death to glutamate-induced oxidative stress relies on the activation of distinct NF-kappaB proteins.

Protective effect of S-allyl-L-cysteine, a garlic compound, on amyloid beta-protein-induced cell death in nerve growth factor-differentiated PC12 cells.

Aged garlic extract (AGE) contains several neuroactive compounds, including S-allyl-L-cysteine (SAC) and allixin. We characterized cell death induced by amyloid beta-protein (Abeta), 4-hydroxynonenal (HNE), tunicamycin, an endoplasmic reticulum (ER) stressor, or trophic factor deprivation, and investigated whether and how SAC could prevent this in nerve growth factor (NGF)-differentiated PC12 cells, a model of neuronal cells. Exposure of the cells to amyloid beta-protein(1-40) (Abeta(1-40)) decreased the extent of [3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction activity and loss of neuronal integrity, but these effects were not prevented by Ac-DEVD-CHO, a caspase-3 inhibitor. Simultaneously applied SAC protected the cells against Abeta-induced cell death in a concentration-dependent manner. It also protected them against tunicamycin-induced neuronal death. In contrast, it afforded no protection against cell death induced by HNE and trophic factor deprivation, which is mediated by a caspase-3-dependent pathway. These results suggest that SAC may selectively protect cell death induced by Abeta and tunicamycin, which may be triggered by ER dysfunction in NGF-differentiated PC12 cells.

Introduction of simple swallowing ability test for prevention of aspiration pneumonia in the elderly and investigation of factors of swallowing disorders.

Aspiration pneumonia is a major cause of death in the elderly. In this study, a water swallowing test was introduced as a method of evaluating the swallowing ability of patients, and a swallowing ability evaluation team investigated an appropriate procedure and evaluation method for the situation of our hospital. We also investigated the relationship between the swallowing ability of patients examined by the water swallowing test and underlying diseases, complications, and medicated drugs. In the water swallowing test, the water-drinking method was fixed, and evaluation was made based on the time required for drinking, profile, and episodes, by which patients suspected of swallowing disorder were detected, confirming the usefulness of this method. The frequency of developing swallowing disorder was significantly higher in patients with cerebrovascular disorders, Parkinson's syndrome (p < 0.01, respectively) and symptomatic epilepsy, hypertension (p < 0.05, respectively) as underlying disease/complication. Regarding medicated drugs, H2 blockers were related to swallowing disorder (p < 0.05). It was confirmed that patients who were judged as having swallowing disorder (including suspected cases) by the water swallowing test, and patients with underlying diseases and complication that may cause the disorder, and patients medicated with drugs that may affect the swallowing ability require appropriate management by medical care staff.