Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Preoperative scoring system for predicting early adjacent vertebral fractures after Balloon Kyphoplasty

BackgroundAdjacent vertebral fracture (AVF) is a major complication following Balloon Kyphoplasty (BKP). There is no scoring system for predicting AVF using only preoperative elements. The purposes of this study were to develop a scoring system for predicting early AVF after BKP based on preoperative factors and to investigate the appropriate surgical indication for BKP.MethodsOf 220 patients who underwent BKP at a single institution since 2011, 65 patients over the age of 60 who had undergone a standing whole spine X-ray preoperatively were enrolled. Factors affecting the occurrence of early AVF were examined. A scoring system was created consisting of the factors exhibiting significant differences, and the correlation between the total score and the incidence of early AVF was investigated.ResultsTwenty of the 65 patients (30.8%) had early AVF. In a univariate analysis, age, previous vertebral fracture, pelvic tilt, and Local kyphosis significantly influenced early AVF. In a multivariate logistic regression analysis, age had an odds ratio of 1.136 (95% CI 1.001–1.289), previous vertebral fractures 4.181 (1.01–17.309), and Local kyphosis 1.103 (1.021–1.191). The scoring system was set as follows: ①Age (<75 years: 0 points(P), 75years≦: 1P), ②The number of previous vertebral fractures (0: 0 P, 1: 1P, 2: 2P, 3 or more: 3P), and ③Local kyphosis (<10°: 0P, 10°≦: 1P). There was a correlation between the total score and the incidence of early AVF (r = 0.812, 1P = 0.05). The incidence of early AVF was 6.4% (2 cases/31 cases) for a score of ≦1P and 54.5% (18 cases/33 cases) for a score of ≧2P.ConclusionsThere was a correlation between the total score and the incidence of early AVF. A score of 1 point or less may represent the appropriate surgical indication for BKP.     

Direct Observation of a Cyclic Vinyl Polymer Prepared by Anionic Polymerization using N‐Heterocyclic Carbene and Subsequent Ring‐Closure without Highly Diluted Conditions

A 1:1 adduct of methyl sorbate (MS) and 1,3‐di‐tert‐butylimidazol‐2‐ylidene (NHCtBu) initiates anionic polymerization of a nonconjugated polar alkene, allyl methacrylate (AMA) in toluene at ?20 °C. After the monomer is consumed quantitatively using a bulky aluminum Lewis acid, methylaluminum bis(2,6‐di‐tert‐butyl‐4‐methylphenoxide) (MAD), as an additive, successive ring‐closure occurs without highly dilute conditions to give a cyclic poly(AMA) containing α‐terminal MS unit, and an M_n of 8.8 × 10³?58.5 × 10³ with a narrow molecular dispersity index (M_w/M_n = 1.1₄–1.3₇). The lack of a need for dilution is due to the fact that an α‐terminal NHCtBu group is acting as the counter cation for the propagating center in the polymerization. From ¹H NMR and matrix assisted laser desorption/ionization (MALDI‐TOF) mass spectra, combined with transmittance electron microscope (TEM) observation of a synthesized poly(AMA) with longer alkyl side chains prepared via a thiol‐ene click reaction, it is concluded that once the monomer is consumed, nucleophilic attack at the neighboring methine of the α‐terminal NHCtBu residue by the propagating anionic center causes ring‐closing to cyclic poly(AMA).     

Topically injected adrenocorticotropic hormone induces mechanical hypersensitivity on a full‐thickness cutaneous wound model in rats

Cutaneous wound pain causes physical and psychological stress for patients with wounds. Previous studies reported that stress induces hyperalgesia and deteriorates wound healing. However, the effect of the stress response such as in hypothalamic‐pituitary‐adrenal (HPA) axis on local wound area is unclear. We aimed to investigate the effects of a stress response on the mechanical withdrawal threshold in the local wound area and describe the identification of a wound pain exacerbation. We topically injected adrenocorticotropic hormone (ACTH) into the granulation tissue of full‐thickness cutaneous wound model rats on the fifth day postwounding and measured the mechanical withdrawal thresholds, cytochrome P450 2Bs levels and concentration of 5,6‐epoxyeicosatrienoic acid in wound exudate. We found that ACTH induced mechanical hypersensitivity at 4 and 6 hours after injection (P = .004 and .021, respectively), and increased gene expression of cytochrome P450 2B12 expression (P = .046). Concentration of 5,6‐EET in the wound exudate was moderately correlated with the mechanical withdrawal threshold (r = ?.630). Finally, the mechanical withdrawal threshold in the 5,6‐EET group was significantly lower than that in the control group at 2 hours after the injection (P = .015). We propose that 5,6‐EET is one of the most promising contributors to the wound pain exacerbation. These findings could guide clinical wound and pain management.