Efficacy of combined use of Suvorexant and Ramelteon in preventing postoperative delirium: a retrospective comparative study.

BACKGROUND: Suvorexant and ramelteon have been presented as useful for preventing postoperative delirium. Previous studies reported on the comparison with benzodiazepine hypnotics which have been known for the risk for inducing delirium, but the comparison with patients not taking any hypnotics has not been reported yet. Therefore, we assessed the incidence rates for postoperative delirium comparing cancer patients who received preoperative combined administration with suvorexant and ramelteon and those not taking any hypnotics. METHODS: Among 110 cancer patients who underwent surgeries at the Division of Hepato-Biliary-Pancreatic Surgery at the Shizuoka Cancer Center between April 1, 2017 and June 30, 2020, 50 patients who received combined administration with suvorexant and ramelteon from 7 days prior to their surgeries and 60 patients who did not take any hypnotics including suvorexant and ramelteon were classified. They were retrospectively observed during the 7 days from their surgeries onward to compare the cumulative incidence rates for postoperative delirium. RESULTS: The cumulative incidence rate for postoperative delirium during the 7 days in the combined-administration group was 14.0% (7/50), while that for the no-hypnotic group was 36.7% (22/60), which proved that the incidence rate for the former was significantly low (OR: 0.28, 95%CI: 0.11-0.73, P = 0.009). CONCLUSIONS: The present study suggests that the preventive combined administration with suvorexant and ramelteon starting from the preoperative period for cancer patients can be effective in lowering the incidence rate for postoperative delirium. TRIAL REGISTRATION: Retrospectively registered.

Effects of Opioids, Steroids, Benzodiazepines, Anticholinergics, and Antihistamines on the Efficacy of Antipsychotics for Treating Delirium in End-of-Life Adult Patients Undergoing Palliative Care.

The purpose of the study was to determine the effect of combination therapy involving opioids, steroids, benzodiazepines, anticholinergics, and antihistamines on antipsychotics efficacy for delirium. The study included adult inpatients receiving end-of-life palliative care and diagnosed with hyperactive delirium. Changes in delirium symptoms were assessed using the Intensive Care Delirium Screening Checklist (ICDSC). A retrospective analysis was conducted on 97 patients with ICDSC scores of ≥4, comparing the scores before and after antipsychotic administration. A mean score <4 sustained for 3 days after antipsychotics administration was considered effective. The mean days with ICDSC <4 within a 3-day period were evaluated as well. The efficacy of antipsychotics was compared between cases with and without the use of opioids, steroids, benzodiazepines, anticholinergics, and antihistamines. The results revealed no significant differences in the efficacy of antipsychotics for delirium when used in conjunction with opioids (odds ratio 0.614, 95% CI [0.179-2.105]), benzodiazepines (0.387, [0.108-1.390]), steroids (1.258, [0.276-5.746]), or anticholinergics (2.085, [0. 148-29.458]). Additionally, no significant differences were observed in the mean days with ICDSC <4 within 3-day period. Although opioids, benzodiazepines, steroids, anticholinergics, and antihistamines are recognized as delirium risk factors, their use for symptom relief in patients with delirium may not affect antipsychotic efficacy.

Phylogeny analysis of whole protein-coding genes in metagenomic data detected an environmental gradient for the microbiota.

Environmental factors affect the growth of microorganisms and therefore alter the composition of microbiota. Correlative analysis of the relationship between metagenomic composition and the environmental gradient can help elucidate key environmental factors and establishment principles for microbial communities. However, a reasonable method to quantitatively compare whole metagenomic data and identify the primary environmental factors for the establishment of microbiota has not been reported so far. In this study, we developed a method to compare whole proteomes deduced from metagenomic shotgun sequencing data, and quantitatively display their phylogenetic relationships as metagenomic trees. We called this method Metagenomic Phylogeny by Average Sequence Similarity (MPASS). We also compared one of the metagenomic trees with dendrograms of environmental factors using a comparison tool for phylogenetic trees. The MPASS method correctly constructed metagenomic trees of simulated metagenomes and soil and water samples. The topology of the metagenomic tree of samples from the Kirishima hot springs area in Japan was highly similarity to that of the dendrograms based on previously reported environmental factors for this area. The topology of the metagenomic tree also reflected the dynamics of microbiota at the taxonomic and functional levels. Our results strongly suggest that MPASS can successfully classify metagenomic shotgun sequencing data based on the similarity of whole protein-coding sequences, and will be useful for the identification of principal environmental factors for the establishment of microbial communities. Custom Perl script for the MPASS pipeline is available at https://github.com/s0sat/MPASS.

Chemotherapy-induced neutropenia as a prognostic factor in patients with extensive-stage small cell lung cancer.

PURPOSE: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. RESULTS: No significant difference was found between grades 0-3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0-3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28-0.87, P = 0.015). CONCLUSION: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS.

Japanese Nationwide Comparative Survey of Medication Guidance Provided by Certified and Uncertified Palliative Care Pharmacists.

BACKGROUND: As members of a medical team, pharmacists are expected to provide optimal patient-centered, evidence-based pharmacotherapy. In Japan, in consideration of the importance of palliative care, a system was initiated for certifying palliative care pharmacists in 2010. However, no studies have evaluated the usefulness of board certification in palliative pharmacy. Therefore, we surveyed the status of medication guidance for the physical and psychological symptoms of patients receiving palliative care and compared the medication guidance provided by certified and uncertified pharmacists. METHODS: The survey was conducted in February and March 2022. Pharmacists registered as members of the Japanese Society of Pharmaceutical Palliative Care and Sciences were surveyed by using a web-based questionnaire and 209 pharmacists responded: the certified pharmacist group comprised 123 (58.9%) pharmacists and the uncertified pharmacist group comprised 86 (41.1%) pharmacists. RESULTS: The certified pharmacist group provided better and more frequent medication guidance, according to responses to four of the six items related to pain relief. Three items were related to non-pain symptom relief, and one of the four items was related to psychiatric symptom relief (P < 0.05). The study showed that the certified pharmacist group received a better rating than the uncertified pharmacist group for involvement in palliative pharmacotherapy leading to improvement of patient quality of life (P < 0.05). CONCLUSION: As compared with uncertified pharmacists, certified pharmacists intervened more proactively and provided a broader range of palliative care.

Hyponatremia timing, incidence, and associated risk factors in patients treated with cisplatin for lung cancer: a retrospective study.

The incidence of cisplatin-derived hyponatremia remains unknown, although nausea, vomiting, and renal dysfunction are common adverse events of cisplatin, a platinum-based preparation. The factor contributing to hyponatremia is described but not well known. This study aimed to retrospectively investigate the incidence of hyponatremia, timing, and associated risk factors. This study surveyed patients with lung cancer who received cisplatin chemotherapy from August 2013 to July 2019 at Shizuoka Cancer Center. The severity of hyponatremia was evaluated based on Common Terminology Criteria for Adverse Events. A total of 814 patients were included in this study. 682 (83.7%) patients had hyponatremia of any grade: grade 1 (<135-130 mmol/L), grade 3 (<130-120 mmol/L), and grade 4 (<120 mmol/L) hyponatremia were observed in 619 (76.0%), 51 (6.3%), and 12 (1.5%) patients, respectively. Of 63 patients with grade 3-4 hyponatremia, 43 (68.3%) developed it in the first treatment cycle. In multivariate analysis, the short hydration regimen (<3000 mL/day) has a lower incidence of grade 3-4 hyponatremia than a normal (>3000 mL) hydration regimen (OR: 0.35 [0.16-0.80], p = 0.013). In addition, if the Na+ value before the start of administration is < 135mmol/L, the incidence of grade3 and 4 hyponatremia is higher (OR:0.14 [0.07-0.28], p < 0.001). Hyponatremia due to cisplatin is likely to occur in patients with low Na levels before administration, such as the elderly. Since short hydration might avoid diuretics, hydration methods might need to be reconsidered to prevent hyponatremia.

Prevention of Acne-Like Eruption Caused by Panitumumab Treatment through Oral Administration of Non-steroidal Anti-inflammatory Drugs.

Acne-like eruption caused by anti-epidermal growth factor receptor (EGFR) antibodies such as panitumumab reduces treatment adherence and patient QOL; an alternative therapy is desired. Meanwhile, the usefulness of oral Non-steroidal Anti-inflammatory Drugs (NSAIDs) for acne-like eruptions caused by low-molecular-weight EGFR inhibitors such as erlotinib has been reported in the treatment of lung cancer. This study aimed to investigate whether the combined use of oral NSAIDs and panitumumab for colorectal cancer patients helps prevent acne-like eruption. We retrospectively investigated 167 colorectal cancer patients who had been treated with panitumumab for three cycles or more. The observation period was set from the start of panitumumab treatment to the end of three cycles. Within this period, the incidence and severity of acne-like eruptions were compared. A total of 59 and 108 patients were in the NSAIDs use and non-use groups, respectively, showing differences in the incidence of acne-like eruption rates (78.0 vs. 90.7%, respectively; p = 0.033). In the use group, eruption severity grades 0, 1, 2, and 3 were observed in 13, 33, 13, and 0 patients, respectively; the corresponding values in the non-use group were 10, 60, 36, and 2, respectively (p = 0.007). Oral NSAIDs may help prevent acne-like eruptions caused by panitumumab.

Pharmacists' Adherence Support System FollowNavi for Patients with Type 2 Diabetes.

In Japan, the Pharmaceutical and Medical Device Act was amended in December 2019 and now requires pharmacists to follow-up patients continuously during treatment to ensure proper use of medicines. According to some reports on patients with type 2 diabetes mellitus (T2DM), follow-up by doctors is effective for improving treatment. Enhanced face-to-face medication counseling by pharmacists leads to good glycemic control in patients with diabetes. However, the effects of information and communication technology (ICT)-based follow-up during the medication period are not well-understood. We determined the efficacy of pharmacists' follow-up using FollowNavi, a patient compliance instruction support system, and using our developed LINE tool for patients with T2DM. Through a before-after study, changes in glycemic control and medication adherence after 6 months of follow-up were investigated, and multiple regression analysis was performed to investigate the factors associated with changes in hemoglobin A1c (HbA1c) levels. Questionnaire surveys related to usability were completed by patients and pharmacists. In the 35 patients with T2DM, HbA1c levels decreased significantly after 6 months, although fasting blood glucose levels and medication adherence showed no significant differences. Changes in HbA1c levels were significantly associated with age (p = 0.044), baseline HbA1c levels (p < 0.001), and diabetes duration (p = 0.004). In the questionnaire, 81.8% of patients responded that they would prefer to continue using FollowNavi. These results suggest that follow-up using FollowNavi is useful for glycemic control in patients with T2DM.

A retrospective comparison of haloperidol and hydroxyzine combination therapy with haloperidol alone in the treatment of overactive delirium.

BACKGROUND: For the treatment of delirium, antipsychotics such as haloperidol are used as standard treatments. However, haloperidol has a little sedative effect and may not be sufficiently effective in controlling overactive delirium. Hydroxyzine, an antihistamine, may be used in combination with haloperidol to supplement its sedative effect. The aim of this study was to investigate the effect of haloperidol alone or in combination with hydroxyzine on the improvement of overactive delirium retrospectively. METHOD: Delirium was assessed from medical records using the Intensive Care Delirium Screening Checklist (ICDSC). The number of patients and days with an ICDSC score of < 4, indicating an absence of delirium after haloperidol alone or haloperidol and hydroxyzine was surveyed for 6 days. RESULTS: A total of 157 patients were diagnosed with delirium from April 2019 to July 2021, of which 18 patients received haloperidol alone, and 21 patients received the combination of haloperidol and hydroxyzine for overactive delirium. The number of patients with a mean ICDSC score of < 4 on days 1-6 was two patients (11%) in the haloperidol groups and two patients (10%) in the combination of haloperidol and hydroxyzine group (P = 0.999). The days within < 4 of the ICDSC score on days 1-6 were 0.8 (1.3) and 0.8 (1.5), respectively (P = 0.848). CONCLUSION: Haloperidol alone and haloperidol plus hydroxyzine are both effective in the treatment of overactive delirium. However, the concomitant use of hydroxyzine with haloperidol may not improve the efficacy of treatment of overactive delirium compared to haloperidol alone.

Incidence of Delirium With Different Oral Opioids in Previously Opioid-Naive Patients.

BACKGROUND: Opioids are known to induce delirium, but few studies have closely investigated differences in incidence of delirium among different opioids. OBJECTIVES: To determine whether there is a clinically significant difference in the incidence of delirium between oral opioids in previously opioid-naive patients. METHODS: Subjects were 259 opioid-naive in-patients with cancer who were started on morphine sulfate, oxycodone hydrochloride, or tapentadol hydrochloride extended-release tablets at our hospital between August 1, 2014, and September 30, 2018. The incidence of delirium during the first week of treatment was compared between the drugs. RESULTS: The incidence of delirium was 4.8% (n = 83) for morphine sulfate, 6.9% (n = 131) for oxycodone hydrochloride, and 6.7% (n = 45) for tapentadol hydrochloride. The incidence did not significantly differ between oxycodone hydrochloride (OR = .69, 95% CI = .20-2.30, P [Fisher's exact test] = .77) or tapentadol hydrochloride (OR = .71, 95% CI = .15-3.32, P [Fisher's exact test] = .70) and morphine sulfate (reference group). Moreover, the incidence did not significantly differ between tapentadol hydrochloride (OR = 1.03, 95% CI = .27-3.00, P [Fisher's exact test] = 1.00) and oxycodone hydrochloride (reference group). CONCLUSION: The incidence of delirium in previously opioid-naive patients did not differ significantly among morphine sulfate, oxycodone hydrochloride, and tapentadol hydrochloride extended-release tablets, suggesting similar risk of delirium in opioid-naive patients among these oral opioids.

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer: A STROBE-compliant observational study.

ABSTRACT: Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid µ receptor 1 (OPRM1) (rs1799971), opioid δ receptor 1 (rs2234918), opioid κ receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0-0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4-18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.

[Effects of Oral Magnesium and Antacid Administration on Serum Magnesium Levels and Renal Function in Patients Receiving Cisplatin].

The efficacy of magnesium oxide(MgO)when taken daily as a laxative for hypomagnesemia and renal dysfunction due to cisplatin(CDDP)administration is not clear. It is known that the efficacy of MgO is suppressed when used in combination with antacids, such as proton pump inhibitors. Therefore, we conducted a retrospective analysis of the effects of MgO and antacid administration on serum Mg levels and renal function(estimated glomerular filtration rate: eGFR)in CDDP-treated patients. In the analysis of up to 6 cycles of CDDP administration, the serum Mg levels and eGFR of CDDP-treated patients (n=614)were significantly reduced(p<0.001 and p=0.002, respectively, ANOVA). Patients who used MgO had higher serum Mg levels than patients who did not use MgO(p<0.001, ANOVA). However, no effect of MgO administration was observed on eGFR(p=0.832, ANOVA). There was no effect of antacid combination on serum Mg levels and eGFR in patients receiving MgO. MgO use may have contributed to a reduction in hypomagnesemia. However, it was considered that the decrease in eGFR could not be suppressed as the improvement in hypomagnesemia was slight. Intravenous Mg supplementation is required when CDDP is administered. Furthermore, it is expected that oral Mg supplementation will improve Mg absorption.

Effectiveness of a pharmaceutical instruction video for adherence to dermatopathy treatment in patients with cancer receiving the anti-epidermal growth factor receptor antibody.

BACKGROUND: Dermatopathy develops as a side effect in patients receiving anti-epidermal growth factor receptor antibody treatment. Topical moisturizers are used for the prevention and treatment of this dermatopathy. Active participation of patients in their own treatment is important for the appropriate application of topical preparations. We prepared a pharmaceutical instructional video for adhering to the topical application protocol. In this study, we investigated the effectiveness of this pharmaceutical instructional video on treatment adherence. METHODS: Study participants were patients with cancer receiving the anti-epidermal growth factor receptor antibody for the first time. A pharmacist instructed the patients on how to use the pharmaceutical instruction video. Daily topical preparation use following the video demonstration was assessed. The effectiveness of the pharmaceutical instruction video was evaluated by assessing the adherence of patients who did not use the pharmaceutical instruction video for the past 2 periods (26 months; controls 1 and 2). The incidence of side effects was compared between the two control groups and the group of patients who received the pharmaceutical instruction video. RESULTS: The amount of topical preparation consumed (median, g/day) by patients who received patient compliance instructions using the pharmaceutical instruction video was 9.8 g/day, as compared with control group 1 (4.5 g/day) and control group 2 (5.5 g/day) (p < 0.001). There was no difference in the incidence of side effects during the three periods. CONCLUSION: The use of visual instructional media for patient compliance by pharmacists may be effective in maintaining and improving treatment adherence.

A preliminary study of the effect of naldemedine tosylate on opioid-induced nausea and vomiting.

BACKGROUND: Opioid-induced nausea and vomiting (OINV) is induced by opioid receptor stimulation of chemoreceptor trigger zones and vestibular apparatus by opioids. Naldemedine tosylate (NALD) is a peripherally acting non-selective opioid receptor antagonist, used for opioid-induced constipation (OIC). However, the effect of NALD on OINV had not yet been investigated. In this retrospective study, we investigated the secondary effects of NALD on OINV. METHOD: Patients who received sustained-release oral morphine or oxycodone preparation were enrolled in the study. Patients who used NALD (0.2 mg) within 2 days of opioid initiation were included in the analysis. The use of rescue antiemetics within 7 days from opioid initiation was defined as OINV expression. Patients who received antiemetics before opioid initiation or those who received chemotherapy around 4 days from opioid initiation were excluded from the analysis. The incidence of OINV was compared between patients who used and did not use NALD. RESULTS: In total, 982 patients were included in the study. Among them, 89 patients who received NALD and 614 patients who did not receive NALD were analyzed. The incidence of OINV in patients who used NALD was significantly lower than that of patients who did not use NALD (36.0% vs. 47.2%, p = 0.046). CONCLUSION: For patients with constipation, using NALD at an early stage of opioid initiation might have secondary benefits, such as relief from OINV, besides improvement of OIC. To confirm the effectiveness of NALD for OINV, the symptom grade and intensity during concomitant use of NALD should be observed in a future study.

Measurement of the leak rate of masks used for anticancer drug handling using a mask fitting tester.

BACKGROUND: Exposure to inhalation of anticancer drugs is frequent in anticancer drug handling. Using an activated carbon mask with the ability to remove particulates and vapors of anticancer drugs may be effective. Mask fitting performance is important, because low fitting performance leads to inhalation via bypassing the mask filter (leak). This study evaluated the leak rate of multiple-shaped masks. METHODS: Activated carbon and nonactivated carbon masks of the pleated-type (like surgical mask) and cup-type were used. Four pharmacists wore the masks and a fitting tester was employed. The particle reduction rate of particles in ambient air was calculated using: particle count (outside - inside)/outside × 100 (%). Leak rate was calculated as the difference in the particle reduction rate due to the presence or the absence of a seal in the mask surroundings. RESULTS: Reduction rates of the pleated-type nonactivated carbon mask and the pleated-type activated carbon mask were 14.8% and 34.8% (mean). These values significantly increased to 85.6% and 83.3% upon sealing the mask surroundings. Particle reduction rates of the cup-type nonactivated carbon mask and activated carbon mask were 99.3% and 33.6%. When mask surroundings were sealed, these values were 99.6% and 39.2%. Leak rates of pleated-type nonactivated carbon mask, pleated-type activated carbon mask, cup-type nonactivated carbon mask, and cup-type activated carbon mask were 70.8%, 48.5%, 0.3%, and 5.6%, respectively. CONCLUSION: A difference was found in the leak rate between masks used in anticancer drug handling. Based on the low leak rate, the cup-type activated carbon mask was thought to be effective.

Influence of oral magnesium-containing supplement and antacid administration on hypomagnesemia induced by panitumumab.

PURPOSE: Hypomagnesemia is a common side effect of panitumumab. The effect of magnesium-containing supplement as a laxative and concomitant antacid (proton pump inhibitor and histamine H2 antagonist) administration on panitumumab-induced hypomagnesemia was retrospectively investigated. METHODS: Patients with advanced or recurrent colorectal cancer who received panitumumab were included in this study. Serum magnesium levels were extracted from the electronic medical records of 1753 administrations in 221 patients who received panitumumab. Serum magnesium levels in patients with or without oral magnesium-containing supplement and antacid treatment were compared using analysis of covariance as the number of panitumumab administration up to 16 times for covariates. RESULTS: The mean serum magnesium levels were significantly decreased with increasing number of panitumumab administrations (2.13 mg/dL at 1st vs. 1.55 mg/dL at 16th, p < 0.001). The use of oral magnesium-containing supplement significantly inhibited the decline in mean serum magnesium level (1.98 mg/dL vs. 1.78 mg/dL, p < 0.001). However, antacid use in patients receiving oral magnesium-containing supplement significantly decreased the effectiveness of the magnesium supplement on serum magnesium level (2.02 mg/dL vs. 1.93 mg/dL, p < 0.05). CONCLUSION: The use of oral magnesium-containing supplement might function as magnesium supplement based on the finding that use of oral magnesium-containing supplement during panitumumab administration decreased hypomagnesemia. However, combination of antacid decreased the supplemental effect of oral magnesium on hypomagnesemia. These results suggest the possibility that use of antacids during anti-EGFR antibody administration may promote hypomagnesemia.

Safety profile of prophylactic rescue dosing of immediate-release oral opioids in cancer patients.

BACKGROUND: Appropriate prophylactic rescue dosing of opioids is considered effective for cancer pain relief, but no study has reported the safety of such prophylactic rescue. We compared the safety of prophylactic rescue dosing of immediate-release oral opioids with that of regular rescue dosing. METHODS: The study included 103 cancer patients who used either immediate-release morphine syrup or immediate-release oxycodone powder at Shizuoka Cancer Center between January and December 2016. Patients were divided into those who mostly used (prophylactic group) and those who never used (regular group) prophylactic rescue doses of opioids and compared the incidence of adverse events (AEs). We also investigated whether the prophylactic rescue dose negatively interfered with its objective activity, such as meals. RESULTS: Incidence of each AE in the prophylactic versus regular groups was as follows: somnolence, 20.6% versus 14.3%; nausea, 22.1% versus 17.1%; constipation, 19.1% versus 20.0%; urinary retention, 1.5% versus 2.9%; delirium, 4.4% versus 8.6%; and pruritus, 0% versus 2.9%. No serious AE associated with prophylactic rescue dosing was observed. No significant difference was observed in the incidence of any AE between the two groups (p > 0.05, Fisher's exact test). No AE interfered with the objective activity of the prophylactic rescue dose. CONCLUSION: Incidence of AEs associated with prophylactic rescue dosing is not different from that associated with regular rescue dosing. In addition, the prophylactic rescue dose did not adversely affect its objective activity, suggesting the safety of appropriate prophylactic rescue dosing was similar to that of regular rescue dosing. TRIAL REGISTRATION: The study approval number in the institution; H29-J30-29-1-3. Registered June 5, 2017.

Safe and rapid development of capillary electrophoresis for ultratrace uranyl ions in radioactive samples by way of fluorescent probe selection for actinide ions from a chemical library.

After the serious nuclear accident at the Fukushima Daiichi Nuclear Power Plant caused by the Great East Japan Earthquake in 2011, the development of feasible, safe, and highly sensitive analytical methods (in terms of low levels of radiation exposure and radioactive waste generation) for radioactive samples, especially actinide (An) ions, represents an important challenge. Here we propose a methodology for selecting appropriate emissive probes for An ions with very low consumption and emission of radioactivity by capillary electrophoresis-laser-induced fluorescence detection (CE-LIF), using a small chemical library of probes with eight different chelating moieties. It was found that the emissive probe L1, which possesses the tetradentate chelating moiety 1,10-phenanthroline-2,9-dicarboxylic acid (PDA), was suitable for detecting uranyl ions. The detection limit for the uranyl-L1 complex using CE-LIF combined with dynamic ternary complexation and on-capillary concentration techniques was determined to be 2.9 × 10-12 M (0.7 ppt). No interference from the large excess of matrix metal ions was observed. This method was successfully applied to real radioactive liquid samples collected from nuclear facilities, including the Fukushima Daiichi Nuclear Power Plant. This strategy not only permitted the development of a safe and rapid analytical method but also provided insight into the coordination chemistry of An ion complexes. Specifically, the PDA structure provided substantial kinetic inertness to its uranyl complex; the formation of a ternary complex between uranyl-L1 and carbonate was revealed; and unusual interactions were observed between the π-electron systems of uranyl and the phenanthroline ring, which stabilized the uranyl-PDA interaction.

A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes.

Skin inflammation is caused by excessive production of cytokines and chemokines in response to an external stimulus, such as radiation, but the mechanisms involved are not completely understood. Here, we report a novel mechanism of γ-irradiation-induced interleukin-6 (IL-6) production mediated by P2Y11 receptors in epidermal cells. After irradiation of HaCaT cells derived from human epidermal keratinocytes with 5 Gy of γ-rays (137Cs: 0.78 Gy/min), IL-6 production was unchanged at 24 h after γ-irradiation, but was increased at 48 h. IL-6 mRNA was increased at 30 h, and IL-6 production was increased at 33 h after irradiation. The production of IL-6 was sustained at least for 4 d after irradiation. P2Y11 receptor antagonist NF157 inhibited IL-6 production in irradiated cells. Treatment with ATP, a ligand of P2Y11 receptor caused IL-6 production within 24 h. ATP-induced IL-6 production was also suppressed by NF157. Extracellular ATP level was increased after irradiation. The p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling was involved in the production of IL-6 at the downstream of P2Y11 receptor activation. In addition, the cell cycle was arrested at the G2/M phase, and DNA repair foci were not disappeared at 48 h after γ-irradiation. The protein level of histone methylation enzyme G9a, which inhibits IL-6 production, was decreased after γ-irradiation. In conclusion, we suggest that γ-irradiation induces sustained IL-6 production in HaCaT cells from 33 h after irradiation, which is mediated through P2Y11 receptor-p38 MAPK-NF-κB signaling pathway and G9a degradation. This is a novel mechanism of cytokine production in γ-irradiated cells.

Synthesis of Mg-Al Mixed Oxides with Markedly High Surface Areas from Layered Double Hydroxides with Organic Sulfonates.

Mg-Al mixed oxides with record-high surface areas and basic site concentrations were synthesized from Mg-Al layered double hydroxides with interlayer isethionate (Ise) or 3-hydroxy-1-propanesulfonate (HPS). Anion exchange of interlayer CO3 2- in synthetic hydrotalcites with the organic sulfonates induces disorders in layer stacking as characterized by powder X-ray diffraction and enables facile delamination in water. Thermal treatment of materials anion-exchanged by Ise (MgAl-Ise) and HPS (MgAl-HPS) in N2 and H2 resulted in the formation of Mg-Al mixed oxides with marked enhancement in Brunauer-Emmett-Teller (BET) surface area relative to those treated in air. Treatment in a flow of H2 is particularly effective, doubling the surface area of mixed oxides derived from MgAl-Ise relative to those obtained in a flow of N2. A higher degree of disorder in layer stacking in MgAl-HPS than MgAl-Ise resulted in the formation of Mg-Al mixed oxides with higher surface areas than those from MgAl-Ise. As a result, thermal activation of MgAl-HPS in a flow of H2 yielded Mg-Al mixed oxides with the highest BET surface area (410 m2 g-1) and CO2 uptake (1.6 mmol g-1 at 25 °C and 100 kPa) in all samples. These values are significantly higher than those obtained from the initial hydrotalcites as well as those reported in the literature with similar Mg-Al ratios. Investigation of the thermal activation steps by thermogravimetric analysis and mass spectrometry indicates that the key factors to achieve high surface area and CO2 uptake are to weaken interactions between layers by inducing stacking disorders and to facilitate the removal of interlayer sulfonates by preventing the formation of sulfates from them via thermal activation under a reducing environment.