The delivery of nanoparticles improves the pharmacokinetic properties of celecoxib to open a therapeutic window for oral administration of insoluble drugs.

A sensitive and reliable LC-MS/MS method is established and validated to determine the concentration of celecoxib, in the serum of cynomolgus monkey, using celecoxib-D7 as an internal standard. The pharmacokinetic process was investigated after giving Celebrex, celecoxib nanoparticles (CXB-NPs) and hyaluronic acid celecoxib nanoparticles (HA-CXB-NPs) by intragastric (i.g.) administration. Chromatographic separation was performed with a C18 column (2.1 × 100 mm, 2.6 µm) at 40°C with a mobile phase of 2‰ HCOOH in water and acetonitrile. The mass spectral acquisition was then performed in the multiple reaction monitoring mode, with negative ESI ion at m/z 380.0 → 316.0 and m/z 387.1 → 323.1 for celecoxib and celecoxib-D7, respectively. Good linearity was observed over the concentration range from 3 to 2,000 ng/ml (R2 = 0.9954). The intra- and inter-day precision and accuracy, matrix effect and extraction recovery, as well as stability, all met the determination requirements of biological samples. The pharmacokinetic parameters of Celebrex, CXB-NPs and HA-CXB-NPs were determined as: area under the curve, 1,855.98 ± 346.59, 1,908.00 ± 1,130.24 and 2,164.48 ± 657.47 h·ng/ml; peak concentration, 261.08 ± 113.26, 261.12 ± 94.67 and 263.34 ± 151.78 µg/L; time to peak concentration, 2.00 ± 1.22, 4.00 ± 0.00 and 3.60 ± 0.89 h; half-life, 4.39 ± 1.26, 2.33 ± 0.94 and 4.92 ± 3.13 h; relative bioavailability, 102.80 ± 49.62 and 116.63 ± 25.55%. The validated method was successfully applied to the pharmacokinetic study of celecoxib in cynomolgus monkey, after i.g. administration. The preparation of the nanoparticles of celecoxib and the modification of hyaluronic acid on the surface of nanoparticles could improve the bioavailability and prolong the circulation of celecoxib in vivo, which could lay the foundation for further development of celecoxib nanoparticles.

Sirt1 mediates improvement of isoflurane-induced memory impairment following hyperbaric oxygen preconditioning in middle-aged mice.

Hyperbaric oxygen (HBO) preconditioning (PC) has been suggested as a feasible method to provide neuroprotection from postoperative cognitive dysfunction (POCD). However, whether HBO-PC can ameliorate cognitive deficits induced by isoflurane, and the possible mechanism by which it may exert its effect, has not yet been clarified. In the present study, middle-aged mice were exposed to isoflurane anesthesia (1.5 minimal alveolar concentration [MAC]) for 2 h to establish a POCD model. After HBO preconditioning, cognitive function and expression of hippocampal sirtuin 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were evaluated 24 h following isoflurane treatment, in the presence or absence of Sirt1 knockdown by short hairpin RNA (shRNA). HBO preconditioning increased the expression of Sirt1, Nrf2, and HO-1 and ameliorated memory dysfunction. Meanwhile, Sirt1 knockdown inhibited the expression of Nrf2 and HO-1 and attenuated the HBO preconditioning-associated memory improvement. Our results suggest that the application of HBO preconditioning is a useful treatment for POCD, and that Sirt1 may be a potential molecular target for POCD therapy.