Nonblended poly(l-lactide) (PLLA) films having different molecular weights and nonblended poly(lactide) (PLA) films, enantiomeric blend films from PLLA and poly(d-lactide) (PDLA), and ...diastereoisomeric blend films of poly(dl-lactide) (PDLLA) with either PLLA or PDLA, having different l-lactide (LLA) contents (X LLAs) in the range of 0−0.99, were amorphous made by melt-quenching. The effects of molecular weight, X LLA, and average l- and d-lactyl unit sequence length (l L and l D, respectively) on the enzymatic hydrolysis of the films were investigated in the presence of proteinase K. The enzymatic hydrolysis rate (R EH) of PLLA estimated by gravimetry increased monotonically with the inverse of number-average molecular weight (M n). The extrapolation of R EH of PLLA to M n -1 = 0, where no exo-chain-scission takes place, gave a positive R EH value (1.75 μg/(mm2·h)), meaning that the enzymatic hydrolysis of PLLA proceeds via both endo- and exo-chain-scission. The R EH of the nonblended films as well as the enantiomeric and diastereoisomeric blend films decreased monotonically with the decease in X LLA and finally became zero for X LLA below 0.3. The R EH values of the blend films of PLLA and PDLLA with PDLA (l D = ∞) were lower than expected, while the R EH values of the blend films of PLLA with PDLLA (l D = 4) agreed completely with the expected values. These results reveal that the nonblended PLA films are enzymatically hydrolyzable when X LLA and l L are higher than 0.3 and 3, respectively, and l D is lower than 10 and that the presence of long d-lactyl unit sequences (l D > 4) as in PDLA hinders the enzymatic hydrolysis of long l-lactyl unit sequences even when long d- and l-lactyl unit sequences are present in the different molecules.
Background and Purpose
AMG 139 is a human anti‐IL‐23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo ...studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody.
Experimental Approach
The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys.
Key Results
AMG 139 bound with high affinity to both human and cynomolgus monkey IL‐23 and specifically neutralized the biological activity of IL‐23 without binding or blocking IL‐12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half‐life of 8.4–13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose‐proportionally from 30 to 300 mg·kg−1 and mean accumulation between the first and last dose ranged from 2‐ to 3.5‐fold. Peripheral blood immunophenotyping, T‐cell‐dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg−1 s.c. or i.v.).
Conclusions and Implications
The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.
To examine current BMI and various aspects of BMI history as pre-screening tools for undiagnosed diabetes in Japanese individuals.
This cross-sectional study included 16 226 men and 7026 women aged ...30-75 years without a self-reported history of clinician-diagnosed diabetes. We estimated the probability of having undiagnosed diabetes (fasting glucose ≥ 7.0 mmol/l and/or HbA1c ≥ 48 mmol⁄mol (≥ 6.5%) for the following variables: current BMI, BMI in the early 20s (BMI(20y)), lifetime maximum BMI (BMI(max)), change between BMI in the early 20s and current BMI (ΔBMI(20y-cur)), change between BMI in the early 20s and maximum BMI (ΔBMI(20y-max)), and change between lifetime maximum and current BMI (ΔBMI(max-cur)).
The prevalence of undiagnosed diabetes was 3.3% (771/23252) among participants. BMI(max) , ΔBMI(20y-max) and current BMI (1-sd increments) were more strongly associated with diabetes than the other factors (multivariate odds ratio 1.58 95% CI 1.47-1.70 in men and 1.65 95% CI 1.43-1.90 in women for BMI(max) ; multivariate odds ratio 1.47 95% CI 1.37-1.58 in men and 1.61 95% CI 1.41-1.84 in women for ΔBMI(20y-max) ; multivariate odds ratio 1.47 95% CI 1.36-1.58 in men and 1.63 95% CI 1.40-1.89 in women for current BMI). The probability of having diabetes was markedly higher in those with both the highest tertile of BMI(max) and greatest ΔBMI(20y-max) ; however, a substantially lower likelihood of diabetes was observed among individuals with the lowest and middle tertiles of current BMI (< 24.62 kg/m² in men and < 22.54 kg/m² in women).
Lifetime maximum BMI and BMI changes from early adulthood were strongly associated with undiagnosed diabetes. Adding BMI history to people's current BMI would improve the identification of individuals with a markedly higher probability of having undiagnosed diabetes.
We investigated the effect of long-term ingestion of dietary medium-chain triacylglycerols (MCT) on body weight and fat in humans. Using a double-blind, controlled protocol, we assessed the potential ...health benefits of MCT compared with long-chain triacylglycerols (LCT) in 78 healthy men and women body mass index (BMI) ≥ 23 kg/m2: n = 26 (MCT), n = 30 (LCT); BMI < 23 kg/m2: n = 15 (MCT), n = 7 (LCT). Changes in anthropometric variables, body weight and body fat during the 12-wk MCT treatment period were compared with those in subjects consuming the LCT diet. The subjects were asked to consume 9218 kJ/d and 60 g/d of total fat. The energy, fat, protein and carbohydrate intakes did not differ significantly between the groups. Body weight and body fat in both groups had decreased by wk 4, 8 and 12 of the study. However, in the subjects with BMI ≥ 23 kg/m2, the extent of the decrease in body weight was significantly greater in the MCT group than in the LCT group. In subjects with BMI ≥ 23 kg/m2, the loss of body fat in the MCT group (−3.86 ± 0.3 kg) was significantly greater than that in the LCT group (−2.75 ± 0.2 kg) at 8 wk. In addition, in subjects with BMI ≥ 23 kg/m2, the decrease in the area of subcutaneous fat in the MCT group was significantly greater than that in the LCT group at wk 4, 8 and 12. These results suggest that the MCT diet may reduce body weight and fat in individuals (BMI ≥ 23 kg/m2) more than the LCT diet.
Serial changes in trunk muscle performance were prospectively studied in 20 patients who underwent posterior lumbar surgery.
To evaluate the influence of back muscle injury on postoperative trunk ...muscle performance and low back pain, to clarify the significance of minimization of back muscle injury during surgery.
The current investigators have reported examination of iatrogenic back muscle injury in an animal model and in humans. However, definite impairment caused by such back muscle injury has not been clarified.
The patients were divided into a short-retraction-time group (< 80 minutes; n = 12) and a long-retraction-time group (> or = 80 minutes; n = 8). Before surgery and 3 and 6 months after surgery, the degree of back muscle injury was estimated by magnetic resonance imaging, and trunk muscle strength was measured. In addition, the incidence and severity of low back pain were serially analyzed.
Back muscle injury was directly related to the muscle retraction time during surgery. The damage to the multifidus muscle was more severe, and the recovery of extensor muscle strength was delayed in the long-retraction-time group. In addition, the incidence of postoperative low back pain was significantly higher in the long-retraction-time group.
Postoperative trunk muscle performance is dependent on the muscle retraction time. Thus, it is beneficial to shorten the retraction time to minimize back muscle injury and subsequent postoperative low back pain.
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