Effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from thermoresponsive poly(N-isopropylacrylamide) hydrogels
JOURNAL OF CONTROLLED RELEASE
Authors: Coughlan, DC; Quilty, FP; Corrigan, OI
The effect of drug physicochemical properties on swelling/deswelling kinetics and pulsatile drug release from a thermoresponsive hydrogel was examined. Hydrogels were loaded with drug and thermally triggered swelling/deswelling and release experiments were performed. Two series of drugs of contrasting hydrophilicity and varying physicochemical properties were examined. Benzoic acid (BA), its methyl and propyl esters, and diltiazem base were used as model hydrophobic drugs. Sodium benzoate (NaB), diltiazem HCl (DHCl), vitamin B12 (VB12) and various dextrans (MW 4300, 10,200, 42,000, 68,800) were used as model hydrophilic agents of increasing size. The hydrogel swelling rate was slowed by the presence of the hydrophobic drugs and this decreased rate was solubility dependant for the benzoates. The hydrophilic series increased the rate of swelling compared to the unloaded system. In all cases, the magnitude and rate of hydrogel contraction were proportional to the extent of swelling prior to temperature switch. Drug release was by diffusion below the lower critical solution temperature (LCST), while a solubility-dependent drug pulse release on temperature switch was observed for the hydrophobic series. Effectiveness of thermal control of hydrophobic drug release increased with increasing solubility. The hydrophilic series produced a molecular size-dependent drug pulse on temperature switch above the LCST. Pulsatile on-off drug release was shown with DHCl, VB12 and the various dextrans. Drug solubility, size and chemical nature were shown to be of particular importance in the control of hydrogel swelling and drug release from thermosensitive hydrogels. (C) 2004 Elsevier B.V. All rights reserved.
Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
Authors: Zhao, Guangchao; Deng, Jiao; Shen, Yuan; Zhang, Peng; Dong, Hailong; Xie, Zhongcong; Xiong, Lize
Background Postoperative neurocognitive disorder (PND) is a severe postoperative complication with no effective therapy that affects up to 19-52% of senior patients. Age and surgery type have been identified as risk factors. However, what caused the increased risk in the elderly is poorly understood. Methods We utilized a PND model in aged mice undergoing experimental laparotomy with general anesthesia to evaluate the causal relationship between hyperhomocysteinemia and increased PND susceptibility. PND was assessed by Novel Object Tasks, Fear Conditioning Tests, and Barnes Maze Tests. Serum homocysteine (Hcy) as well as vitamin B12 and folate acid levels were tested before, immediately after surgery and from day 1 to day 29 after surgery by ELISA. The effectiveness of preventative strategy including diet supplementation of vitamin B12 + folic acid (Vit B12 + FA) and S-adenosylmethionine (SAM) injection targeting hyperhomocysteinemia were also tested. Results PND in aged mice lasted for at least 2 weeks after experimental laparotomy, which was not observed in young adult mice. Serum Hcy results indicated a significant correlation between postoperative cognitive performance and perioperative Hcy level. Preoperative supplementation with VB12 and folic acid (FA) in the diet or S-adenosylmethionine (SAM) injection reduced perioperative serum Hcy level and inhibited the development of PND in aged mice. Conclusions Serum homocysteine accumulation is a fundamental cause for increased susceptibility of PND in aged mice. Preoperative diet supplementation of VitB12 + FA can effectively reduce PND in aged mice, which may be a promising prophylaxis treatment in clinical settings.