Synthesis of Branch-Type 3-Allylindoles from N-Alkyl-N-cinnamyl-2-ethynylaniline Derivatives Using π-Allylpalladium Chloride Complex as a Catalyst.

The reaction of N-alkyl-N-cinnamyl-2-ethynylaniline derivatives 1 via annulation and aza-Claisen-type rearrangement easily afforded corresponding branch-type 3-allylindoles 2 with high regioselectivities in good yields using π-allylpalladium chloride complex as a catalyst.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Utility of a Score for Predicting Glomerular Filtration Rate Overestimation in Patients with Cardiovascular and Renal Diseases and Their Risk Factors.

Objective We recently reported a novel score for the detection of glomerular filtration rate (GFR) overestimation using a creatinine-based equation. We examined the utility of this score in patients with cardiovascular/renal diseases and diabetes mellitus. Methods We enrolled 1,425 patients (65±15 years old; 37% women) who were admitted to our hospital for the management of cardiovascular and renal diseases and their risk factors. Overestimation of the GFR (OE) was defined as a creatinine-based GFR (eGFRcre) ≥120% of the cystatin C-based estimated GFR. The OE score was calculated as the sum of the scores for the body weight, hemoglobin concentration, and blood urea nitrogen (BUN)/serum creatinine (Scr), totaling 1 point if the body weight was <63.0 kg in men or <42.0 kg in women, 1 point if the hemoglobin concentration was <12.4 g/dL in men or <11.0 g/dL in women, and 1 point if the BUN/Scr was >26.5. Results The proportion of patients with OE was 14.2%. The score predicted OE with a sensitivity of 70.8% and a specificity of 99.6%, and the sensitivity was increased in patients ≥75 years old (88.3%) and decreased in diabetics (58.6%). When patients were divided into subgroups by the total score, the frequencies of OE were 8% (59/754), 14% (72/502), 38% (58/151), and 72% (13/18) in patients with scores of 0, 1, 2, and 3, respectively. Conclusion The OE score is useful for detecting elderly cases of cardiovascular and renal diseases in which eGFRcre overestimates the GFR, although its utility is limited in diabetics.

[Efficacy and Safety of Linaclotide in Elderly Patients].

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.

[Association Suvorexant and Ramelteon Use with the Risk of Falling: A Retrospective Case-control Study].

Sedative hypnotics are among the classes of drugs reported to influence falls. However, the effects of the sedative hypnotic drugs, suvorexant and ramelteon, on falls are not well known. Therefore, we conducted this retrospective case-control study to examine the association of the use of these two sedative hypnotics with the risk of falls. Conducted at the Sapporo Medical University Hospital in Japan, our study included 360 patients with fall incidents and 819 randomly selected control patients. Patients in the fall group were significantly older with a lower body mass index, and had a history of falls, disabilities in activities of daily living, cognitive impairment, and delirium. Monovariate analysis revealed that patients in the fall group frequently used ramelteon [odds ratio (OR) 2.38, 95% confidence interval (CI): 1.49-3.81, p<0.001], but rarely used suvorexant (OR 0.66, 95% CI: 0.29-1.39, p=0.317), compared with control patients. Furthermore, multivariate analysis revealed that ramelteon use did not increase the risk of falls (adjusted OR 1.43, 95% CI: 0.82-2.48, p=0.207), whereas suvorexant use significantly decreased the risk of falls (adjusted OR 0.32, 95% CI: 0.13-0.76, p=0.009). Although ramelteon tends to be used in patients at a high risk of falls, it may not increase the risk of falls. In contrast, the use of suvorexant may reduce the risk of falls.

Overestimation of glomerular filtration rate by creatinine-based equation in heart failure patients is predicted by a novel scoring system.

AIMS: Creatinine-based estimated glomerular filtration rate (eGFRcre) has been shown to overestimate the glomerular filtration rate (GFR) when it is compared with cystatin C-based estimated GFR (eGFRcys) in older people. We investigated clinical determinants of GFR overestimation by eGFRcre and developed a score for prediction of GFR overestimation (OE) in heart failure patients. METHODS: We retrospectively examined 244 Japanese heart failure patients (aged 72.2 ± 13.1 years; 48% women) who had no known extrarenal factors that affect serum cystatin C concentration. eGFR OE by eGFRcre was defined as eGFRcre being ≥120% of cystatin C-based eGFR. RESULTS: The proportion of heart failure patients with OE was 14.3%. Patients with OE were older, had lower body weight and total skeletal muscle mass than those in patients without OE. Laboratory examinations showed that hemoglobin concentration was lower, and the ratio of blood urea nitrogen-to-creatinine was higher in patients with OE than in patients without OE. In multivariate regression analysis, body weight (<63.0 kg in men and <42.0 kg in women), hemoglobin level (<12.4 g/dL in men and <11.0 g/dL in women) and ratio of blood urea nitrogen-to-creatinine (>26.5) in addition to skeletal muscle mass were independently associated with OE. A score calculated by using cut-off levels of body weight, hemoglobin concentration and ratio of blood urea nitrogen-to-creatinine predicted OE with a sensitivity of 97.1% and a specificity of 98.1%. CONCLUSION: Overestimation of GFR by eGFRcre is predictable by a novel scoring system, which might be useful for the detection of patients who require cystatin C-based eGFR measurement for accurate assessment of renal function. Geriatr Gerontol Int 2020; 20: 752-758.

Systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia and hyperbaric oxygen treatment for non-small cell lung cancer with multiple pulmonary metastases: preliminary results.

PURPOSE: The purpose of this retrospective case series was to evaluate the toxicity and efficacy of systemic chemotherapy using paclitaxel and carboplatin plus regional hyperthermia (HT) and hyperbaric oxygen treatment (HBO) for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Twenty-two patients with NSCLC with multiple pulmonary metastases intravenously received paclitaxel (50 mg/m(2)), carboplatin (area under the curve of 1.0-1.5) and 10% glucose weekly for 3 out of 4 weeks. Hyperthermia (HT) of the whole thoracic region was also administered weekly during intravenous infusion of carboplatin in all patients. In addition, 16 (72%) of 22 patients received hyperbaric oxygen (HBO) treatment immediately after weekly chemotherapy. A total of 107 cycles were performed in 16 patients with HBO, and 27 cycles in 6 patients without HBO. The toxicity and efficacy of these patients were retrospectively analyzed. RESULTS: Both the hematologic and non-hematologic toxicities were mild and leucopenia/neutropenia of > or = grade 3 was seen in one patient, while pneumonitis of > or = grade 3 occurred in one patient. Fourteen (64%) of 22 patients had an objective response. The median time to progression of disease in all patients was 8 months and in 16 patients with HBO was 9 months. Four (44%) of 9 patients with prior chemotherapy including paclitaxel and carboplatin obtained objective responses. CONCLUSIONS: The novel combined therapy of paclitaxel and carboplatin with HT and HBO may therefore be a feasible and promising modality for treating NSCLC with multiple pulmonary metastases, and the results justify further evaluation to clarify the benefits of this treatment regimen.

Concurrent chemoradiotherapy with gemcitabine plus regional hyperthermia for locally advanced pancreatic carcinoma: initial experience.

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy (CRT) with gemcitabine plus regional hyperthermia (HT) for locally advanced pancreatic carcinoma (LAPC). MATERIALS AND METHODS: A total of 29 patients with LAPC treated with concurrent CRT using gemcitabine were retrospectively analyzed. Radiotherapy was administered with a median total dose of 61.2 Gy. Of the 29 patients, 20 (69%) also underwent regional HT during CRT (CRHT group). The remaining 9 patients did not receive regional HT (CRT group) because of a common bile duct stent placement, patient refusal, older age, or obesity. The efficacy and toxicity of the treatments and the predictors of good outcome were evaluated. RESULTS: The median disease progression-free and overall survival times were significantly better for the CRHT group than for the CRT group (8.8 vs. 4.9 months, P = 0.02, and 18.6 vs. 9.6 months, P = 0.01), respectively. Grade 3-4 hematological toxicities for the CRHT group were detected in eight patients (40%) and grade 3 nonhematologic toxicity in one (diarrhea). CONCLUSION: Concurrent CRT using gemcitabine with regional HT may be a feasible and promising regimen for LAPC, and the results justified further evaluation in a large number of patients to confirm its definite benefit.

Effect of prophylactic hyperbaric oxygen treatment for radiation-induced brain injury after stereotactic radiosurgery of brain metastases.

PURPOSE: The purpose of the present study was to evaluate the prophylactic effect of hyperbaric oxygen (HBO) therapy for radiation-induced brain injury in patients with brain metastasis treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: The data of 78 patients presenting with 101 brain metastases treated with SRS between October 1994 and September 2003 were retrospectively analyzed. A total of 32 patients with 47 brain metastases were treated with prophylactic HBO (HBO group), which included all 21 patients who underwent subsequent or prior radiotherapy and 11 patients with common predictors of longer survival, such as inactive extracranial tumors and younger age. The other 46 patients with 54 brain metastases did not undergo HBO (non-HBO group). The radiation-induced brain injuries were divided into two categories, white matter injury (WMI) and radiation necrosis (RN), on the basis of imaging findings. RESULTS: The radiation-induced brain injury occurred in 5 lesions (11%) in the HBO group (2 WMIs and 3 RNs) and in 11 (20%) in the non-HBO group (9 WMIs and 2 RNs). The WMI was less frequent for the HBO group than for the non-HBO group (p = 0.05), although multivariate analysis by logistic regression showed that WMI was not significantly correlated with HBO (p = 0.07). The 1-year actuarial probability of WMI was significantly better for the HBO group (2%) than for the non-HBO group (36%) (p < 0.05). CONCLUSIONS: The present study showed a potential value of prophylactic HBO for the radiation-induced WMIs, which justifies further evaluation to confirm its definite benefit.

Pressure stress reduces inducible NO synthase expression by interleukin-1ß stimulation in cultured rat vascular smooth muscle cells.

Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling. We investigated the effect of pulsatile pressure stress on nitric oxide (NO) production and inducible NO synthase (iNOS) expression by interleukin-1ß (IL-1ß) stimulation in rat vascular smooth muscle cells (VSMCs). VSMCs were enzymatically isolated from aortic media of Wistar rats. Pulsatile pressure applied to VSMCs was repeatedly given between 80 and 160 mm Hg at a frequency of 4 cycles per min using an original apparatus. Protein expression and activation were evaluated by Western blot analysis. mRNA expression was evaluated by real-time reverse transcription-polymerase chain reaction. The pulsatile pressure reduced IL-1ß-induced NO production, iNOS protein, and mRNA expression. The pressure also reduced GTP cyclohydrolase I mRNA expression. Furthermore, the pressure reduced phosphorylation of IL-1ß-induced extracellular signal-regulated kinase (ERK), nuclear factor-κB (NF-κB) p65, and I-κBα. The pressure had no effect on I-κBß degradation by IL-1ß stimulation. The present study shows for the first time that pressure stress reduces IL-1ß-induced iNOS expression via a mechanism involving the ERK-NF-κB signaling pathway.

Radiotherapy with 8-MHz radiofrequency-capacitive regional hyperthermia for stage III non-small-cell lung cancer: the radiofrequency-output power correlates with the intraesophageal temperature and clinical outcomes.

PURPOSE: To assess the efficacy of radiotherapy (RT) combined with regional hyperthermia (HT) guided by radiofrequency (RF)-output power and intraesophageal temperature and evaluate the potential contribution of HT to clinical outcomes in patients with Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Thirty-five patients with Stage III NSCLC treated with RT plus regional HT were retrospectively analyzed. Twenty-two of the 35 patients underwent intraesophageal temperature measurements. Patients with subcutaneous fat of 2.5 cm or greater, older age, or other serious complications did not undergo this therapy. The 8-MHz RF-capacitive heating device was applied, and in all patients, both the upper and lower electrodes were 30 cm in diameter, placed on opposite sides of the whole thoracic region, and treatment posture was the prone position. The HT was applied within 15 minutes after RT once or twice a week. RESULTS: All thermal parameters, minimum, maximum, and mean of the four intraesophageal temperature measurements at the end of each session and the proportion of the time during which at least one of the four intraesophageal measurements was 41 degrees C or higher in the total period of each session of HT, of the intraesophageal temperature significantly correlated with median RF-output power. Median RF-output power (>/=1,200 W) was a statistically significant prognostic factor for overall, local recurrence-free, and distant metastasis-free survival. CONCLUSIONS: The RT combined with regional HT using a higher RF-output power could contribute to better clinical outcomes in patients with Stage III NSCLC. The RF-output power thus may be used as a promising parameter to assess the treatment of deep regional HT if deep heating using this device is performed with the same size electrodes and in the same body posture.

Concurrent hyperfractionated radiotherapy and carboplatin with transoral debulking microsurgery for T2N0 glottic cancer.

BACKGROUND: Our aim was to evaluate the efficacy and toxicity of chemoradiotherapy (CRT) with transoral debulking microsurgery for T2N0 glottic cancer. METHODS: Thirty patients with T2N0 glottic cancer treated with concurrent hyperfractionated radiotherapy (RT) and carboplatin were retrospectively analyzed. Median total dose of RT was 72 Gy. Nineteen of 30 patients also received transoral debulking microsurgery during or before CRT. The remaining 11 patients who demonstrated complete response or good partial response at 36 to 45.6 Gy were not treated with transoral debulking microsurgery. RESULTS: Local recurrence developed in 5 patients; 4 of these patients did not undergo transoral debulking microsurgery. The 3-year local control rate was significantly better for CRT with transoral debulking microsurgery (95%) than for CRT alone (61%) (p = .02). CONCLUSION: CRT with transoral debulking microsurgery may have a positive impact on the local control of T2N0 glottic cancer, which justifies further evaluation to confirm its definite benefit.