Effect of melatonin on attenuating the isoflurane-induced oxidative damage is related to PKCα/Nrf2 signaling pathway in developing rats.

Isoflurane, an inhalational anesthesia, has frequently been used in pediatric anesthesia. However, research indicates that isoflurane can induce oxidative stress and affect neural and cognitive development. Melatonin, an endogenous hormone that exhibits antioxidant functions, can play a neuroprotective role by activating the PKCα/Nrf2 signaling pathway in response to oxidative stress. This study aims to determine whether the effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. Rat pups at postnatal day 7 were treated with control or 1.5% isoflurane for 4 h after pretreatment for 15 min with either melatonin (10 mg/kg i.p.) or 1% ethanol. The hematoxylin and eosin staining and transmission electron microscopic examination were used for observation of histopathology. The oxidative stress-related indicators were detected by using assay kits. The western blotting, immunohistochemistry and immunofluorescence were used to detect the activation of PKCα/Nrf2 signaling pathway. Results showed that isoflurane induced nerve damage in the hippocampus, and melatonin could reduce this injury. Oxidative stress-related indicators suggested that isoflurane can significantly increase reactive oxygen species and malondialdehyde levels, and decrease superoxide dismutase and glutathione activity compared with the control group, whereas melatonin ameliorated these indices. Expression of proteins associated with the PKCα/Nrf2 signaling pathway indicated that the neuroprotective effect of melatonin is related to activation of the PKCα/Nrf2 signaling pathway. These results suggest that the attenuating effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. These findings promote further research into underlying mechanisms and effective treatments to attenuate anesthesia neurotoxicity.

Behavioral and cardiopulmonary effects of dexmedetomidine-midazolam and dexmedetomidine-midazolam-butorphanol in the silver fox (Vulpes vulpes).

OBJECTIVE: To evaluate the behavior and some cardiopulmonary variables of dexmedetomidine-midazolam or dexmedetomidine-midazolam-butor-phanol in the silver fox (Vulpes vulpes). STUDY DESIGN: Blinded, randomized design. ANIMALS: Sixteen adult silver foxes, aged 7-9 months, weighting 6.0-9.2 kg. METHODS: Animals were randomly assigned to dexmedetomidine (50 µg kg-1) and midazolam (0.45 mg kg-1) (group DM) or to dexmedetomidine (30 µg kg-1), midazolam (0.45 mg kg-1) and butorphanol (0.25 mg kg-1) (group DMB), administered intramuscularly. Pulse rate (PR), respiratory rate (fR), noninvasive arterial pressures, oxygen saturation (SpO2), rectal temperature (T) and behavioral scores (posture, sedation, antinociception, jaw relaxation and auditory response) were measured at 5, 10, 20, 30, 40, 50 and 60 minutes after injection. Time from drug injection to recumbency with no response to stimuli (IT) and time from administration of atipamezole (0.2 mg kg-1) to standing with coordination (RT) were recorded. The occurrences of adverse events were recorded. Data were analyzed by two-tailed unpaired t-tests and Bonferroni post hoc tests. Significant differences were accepted at p<0.05. RESULTS: There were no statistically significant differences between the groups for IT or RT. Arterial pressures were higher in DMB at each time point except at 5 minutes. PR was lower in DM at each time point except at 10 and 60 minutes. No significant difference was found between the groups for fR, SpO2 and T. The behavioral scores were significantly lower (lower quality immobilization) in DMB at 5,10 and 60 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: IT and RT were not different between the groups. Both protocols provided immobilization for 30-40 minutes with excellent muscle relaxation and analgesia adequate for clinical examinations and some simple surgical procedures.

[Pharmacokinetics and Bioequiavailability of Asparaginase in Asparaginase Nanospheres].

OBJECTIVE: To determine the pharmacokinetics and bioequivalence of self-assembled hyaluronic acid-graft-poly (ethylene glycol)/hydroxypropyl-beta-cyclodextrin hollow nanospheres loaded with asparaginase (AHHPs) in SD rats. METHODS: AHHPs were prepared and observed under transmission electron microscopy. Its size, Zeta potential and entrapment efficiency were detected. Asparaginase (AAS) activities were measured after intravenous injection of AHHPs or free AAS in rats. The pharmacokinetic parameters were calculated using software DAS 2.1.1 for bioequivalence assessment. RESULTS: The self-prepared AHHPs had an average particle size of (367.43 ± 2.72) nm, Zeta potential of (-15. 70 ± 1.25) mV, and average entrapment efficiency of (66.03 ± 3.81)%. The intravenous injection of AHHPs and free AAS produced an area under concentration-time Curve (AUC)(0-48 h) of (162.06 ± 4.01) U/mL · h and (46.38 ± 1.98) U/mL · h, AUC(0-∞) of (203.74 ± 12.91) U/mL · h and (51.44 ± 3.01) U/mL · h, mean residence time (MRT) (0-72h) of (4.35 ± 0.06) h and (1.76 ± 0.06) h, MRT(0-∞) of (7.53 ± 1.05) h and (2.44 ± 0.29) h, peak concentration (Cmax) of (30.37 ± 0.43) U/mL and (26.06 ± 0.88) U/mL, and time to peak concentration (Tmax) of (0.75 ± 0.00) h and (0.08 ± 0.00) h, respectively. Compared with free AAS, the AUC(0-48 h), AUC(0-∞), MRT(0-72 h), MRT(0-∞),Cmax and Tmax of AHHPs increased by 3.5, 4.0, 2.5, 3.1, 1.2 and 9.4 times, respectively. The 90% confidential intervals of AUC(0-48 h), AUC(0.∞) and Cmax of the tested formulation were 72.6%-74.0%, 72.3%-73.7%, 94.7%-96.3%, respectively. CONCLUSION: AHHPs can improve the bioavailability of AAS, extending its biological half-life in rats. AHHPs and free AAS are not bioequivalent.

[Pharmacokinetics Study on Curcumin Hydroxypropyl-ß-Cyclodextrin Phospholipid Complex in Rats].

OBJECTIVE: To compare the in vivo pharmacokinetics of curcumin hydroxypropyl-ß-cyclodextrin phospholipid complex, curcumin hydroxypropyl-ß-cyclodextrin and curcumin phospholipid complex, and to discuss the advantage of hydroxypropyl-ß-cyclodextrin phospholipid complex as carrier. METHODS: Drawing blood after SD rats were oral administered with the above preparations and free drug at 50 mg/kg( corresponding to curcumin) , and the blood concentration were determined by HPLC. RESULTS: The AUC0-∞ of curcumin hydroxypropyl-ß-cyclodextrin phospholipid complex was(1 126. 20 ± 323. 24) g/(L . h), which was 5. 89, 1. 49 and 1. 17 times as curcumin (191. 08 ± 43. 27) µg/( L . h), curcumin phospholipid complex(754. 93 ± 55. 33) µg/(L . h), curcumin hydroxypropyl-ß- cyclodextrin(961. 21 ± 253. 65) µg/(L . h). CONCLUSION: The curcumin hydroxypropyl-ß-cyclodextrin phospholipid complex has a better absorption property than curcumin phospholipid complex and curcumin hydroxypropyl-ß-cyclodextrin, which is more beneficial to improve the bioavailability.

[Pharmacokinetics and Intestinal Absorption of Curcumin Chitosan Hydrochloride Coated Liposome in Rats].

OBJECTIVE: To investigate the pharmacokinetics and intestinal absorption characteristic of curcumin chitosan hydrochloride coated liposome(CCLP) in SD rats. METHODS: Blood samples were collected after oral administration. Pharmacokinetic parameters were analyzed by DAS program. Rat single pass intestinal perfusion method was employed to investigate the absorption mechanism. RESULTS: The AUC0-t, AUC0-∞, t1/2, and Cmax of CCLP were 1. 73-fold, 1. 95-fold, 1. 56-fold and 1. 91-fold of the free drug. The intestinal absorption rate constant (Ka) of CCLP in duodenum, jejunum, ileum and colon were 1. 48, 1. 28, 1. 17 , and 4. 01 times as much as the free drug and the effective permeability(Peff) of CCLP were 1. 58, 1.-33, 1. 30 and 4. 55 times of the free drug, respectively. CONCLUSION: The bioavailability of CCLP in rats is increased remarkably and Ka is increased in various intestinal segments by CCLP, especially in colon, as well as Peff.

[Study on pharmacokinetics of demethoxycurcumin phospholipid complex in rats].

OBJECTIVE: To study the pharmacokinetics of Demethoxycurcumin phospholipid complex in rats with oral administration. METHODS: Drawing blood from the SD rats after oral administration Demethoxycurcumin phospholipid complex and free demethoxycurcumin. The blood concentration were determined by HPLC. RESULTS: The pharmacokinetics parameter of Demethoxycurcumin phos- pholipid complex were calculated and the results were as follows: AUC0-t (693. 306 ± 128. 55) µg/(L . h),1. 96-fold increase in the area under the plasma concentration versus time curve (AUC0-t) than that of free demethoxycurcumin, and AUC0-∞ (716. 174 ± 123. 18) µg/(L - h), 1. 93-fold increase than that of free demethoxycurcumin. Cmax (95. 044 ± 6. 95) µg/L, Tmax (0. 17 ± 0) h. Conclusion:Demethoxycurcumin phospholipid complex have higher bioavailability than free demethoxycurcumin,and their preparations bioequivalence are unqualified.