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Purpose: This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients., Methods: Surgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0-2.5 mg/kg until LoC followed by 4-10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety., Results: Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (- 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p ≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam., Conclusions: This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia., Clinical Trial Registration: This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973.

AQP4 (aquaporin-4), a water channel protein that is predominantly expressed in astrocyte end-feet, plays an important role in the brain oedema formation, and is thereby considered to be a potential therapeutic target. Using a stopped-flow analysis, we showed that propofol (2,6-diisopropylphenol), a general anaesthetic drug, profoundly inhibited the osmotic water permeability of AQP4 proteoliposomes in the presence of Zn²⁺. This propofol inhibition was not observed in AQP1, suggesting the specificity for AQP4. In addition, the inhibitory effects of propofol could be reversed by the removal of Zn²⁺. Other lipid membrane fluidizers also similarly inhibited AQP4, suggesting that the modulation of protein-lipid interactions plays an essential role in the propofol-induced inhibition of AQP4. Accordingly, we used Blue native PAGE and showed that the profound inhibition caused by propofol in the presence of Zn²⁺ is coupled with the reversible clustering of AQP4 tetramers. Site-directed mutagenesis identified that Cys²⁵³, located at the membrane interface connecting to the C-terminal tail, is responsible for Zn²⁺-mediated propofol inhibition. Overall, we discovered that propofol specifically and reversibly inhibits AQP4 through the interaction between Zn²⁺ and Cys²⁵³. The findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors.

1. Propofol (2,6-diisopropylphenol) is an intravenous anaesthetic used for the induction and maintenance of general anaesthesia; it also potently and dose-dependently depresses respiration. The aim of the present study was to analyse propofol-induced changes in spatiotemporal patterns of inspiratory-related neural activity and to investigate the involvement of the GABAA receptor by using an optical imaging technique. 2. The brain stems and spinal cords of 0-1-day-old Wistar rats were isolated and stained using a fluorescent voltage-sensitive dye. Neuronal activity in the preparation was detected using an optical recording apparatus containing a charge-coupled device (CCD)-based camera. 3. Bath-applied propofol (7.5 μmol/L) decreased the C4 burst rate to 45.9% of baseline. Although optical signals corresponding to membrane depolarization during the pre-inspiratory phase in the parafacial region of the ventral medulla decreased to 28.7% of baseline following propofol application, those during the inspiratory phase in the caudal part of the rostral ventrolateral medulla did not. 4. The inhibitory effect of bath-applied propofol was reversed by 2 μmol/L bicuculline. 5. Changes in optical signals corresponding to the population activity of pre-inspiratory neurons were parallel to changes in the C4 burst rate. 6. The results suggest that propofol decreases the inspiratory burst rate by reducing the activity of pre-inspiratory neurons and that GABAA receptor activation plays a role in propofol-induced central respiratory depression. These results are consistent with those of previous electrophysiological studies., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

Background: The purpose of this study was to investigate the interaction of anesthetic agents with Org 9426 (rocuronium bromide) infused continuously. The effect of intubation dose of Org 9426 on its infusion rate was also investigated., Methods: Total of 38 Japanese patients were randomly allocated either to receive intubation dose of 0.6 or 0.9 mg x kg(-1) of Org 9426. These patient groups were anesthetized with either sevoflurane or propofol. Infusion of Org 9426 was started with the initial infusion rate of 7 microg x kg(-1) x min(-1) when T1 reappeared after the intubation dose. The infusion rate was adjusted to keep the height of T1 between 3-10% of the control value., Results: The rates of infusion 90 min after the start of infusion were 3.4, 7.5, 3.9 and 7.7 microg x kg(-1) x min(-1) for the 0.6 mg x kg(-1)-sevoflurane, 0.6 mg x kg(-1) propofol, 0.9 mg x kg(-1)-sevoflurane and 0.9 mg x kg(-1) propofol groups, respectively. Sevoflurane significantly reduced the infusion rate with both intubation doses. The mean infusion rates of 0.9 mg x kg(-1) groups were slower than those of 0.6 mg x kg(-1) groups up to 60 min after the start of infusion. Mean clearance of Org 9426 during infusion was not different between sevoflurane and propofol anesthesia., Conclusions: Patients receiving sevoflurane anesthesia required a markedly lower Org9426 infusion rate compared with patients receiving propofol anesthesia.

Background: The purpose of this randomized, multi-center phase III trial was to investigate the influence of sevoflurane and propofol on the neuromuscular blocking effects and pharmacokinetic parameters of Org 9426 (rocuronium bromide) in Japanese population., Methods: Thirty-nine adult Japanese patients participated in this randomized, multi-center study. Neuromuscular function was monitored continuously with TOF-Watch SX (Organon NV, Netherlands) after anesthetic induction with propofol. These subjects randomly received either 0.6 mg x kg(-1) or 0.9 mg x kg(-1) of rocuronium for endotracheal intubation. These two groups were further divided to two anesthetic regiments : sevoflurane group and propofol group. The difference in onset and recovery of rocuronium-induced neuromuscular block was statistically analyzed with two-way ANOVA., Results: Mean duration for maximal block was 76 seconds and 66 seconds, respectively. The duration between Org 9426 administration and 25% recovery of first twitch response was significantly prolonged in patients given 0.9 mg x kg(-1) of Org 9426. Sevoflurane also significantly increased this duration. However, the serum concentration of Org 9426 was not statistically different between the four study groups., Conclusions: The duration of Org 9426-induced neuromuscular blockade was significantly increased under sevoflurane anesthesia compared to propofol anesthesia. This difference may be attributed to pharmacodynamic change.

Purpose: Propofol reduces the cerebral metabolic rate for oxygen (CMRO2), regional CMRO2 (rCMRO2), cerebral blood flow (CBF), and regional CBF (rCBF), but maintains the coupling of cerebral metabolism and blood flow. Under mild to moderate hypothermia, the coupling is maintained, while rCBF is reduced, but no direct measurement of rCMRO2 has yet been reported. This study aimed to evaluate the effects of propofol under normothermic and mild hypothermic temperatures upon rCMRO2, rCBF, and their regional coupling, through direct measurement by positron emission tomography., Methods: Rhesus monkeys were anesthetized with 65% nitrous oxide and propofol. Then rCBF and rCMRO2 were measured under four sets of conditions: infusion of a low-propofol dose (12 mg.kg(-1) x h(-1)) at normothermic temperatures (38 degrees C), a high dose (25 mg x kg(-1) x h(-1)) at normothermic temperatures, a low dose under mild hypothermia (35 degrees C), and a high dose under mild hypothermia. The ratio of rCBF/rCMRO(2) was calculated from these data., Results: Reductions in CMRO2 and rCMRO2 in most regions were associated with two factors: the higher propofol dose and the induction of hypothermia, but there was no interaction between these factors. Concerning blood flow, no significant reduction was observed, except for CBF by the induction of hypothermia. The ratio of rCBF/rCMRO2 was constant in this study setting., Conclusion: During propofol anesthesia, it is possible to reduce cerebral metabolism throughout the entire brain as well as in any brain region by increasing the propofol dose or inducing hypothermia. The concurrent use of these two interventions has an additive effect on metabolism, and can be considered as safe, as their combination does not impair the coupling of cerebral metabolism and blood flow.

The neural mechanisms of propofol-induced central respiratory depression remain poorly understood. In the present study, we studied these mechanisms and the involvement of gamma-aminobutyric acid (GABA)A receptors in propofol-induced central respiratory depression. The brainstem and the cervical spinal cord of 1- to 4-day-old rats were isolated, and preparations were maintained in vitro with oxygenated artificial cerebrospinal fluid. Rhythmic inspiratory burst activity was recorded from the C4 spinal ventral root. The activity of respiratory neurons in the ventrolateral medulla was recorded using a perforated patch-clamp technique. We found that bath-applied propofol decreased C4 inspiratory burst rate, which could be reversed by the administration of a GABAA antagonist, bicuculline. Propofol caused resting membrane potentials to hyperpolarize and suppressed the firing of action potentials in preinspiratory and expiratory neurons. In contrast, propofol had little effect on resting membrane potentials and action potential firing in inspiratory neurons. Our findings suggest that the depressive effects of propofol are, at least in part, mediated by the agonistic action of propofol on GABAA receptors. It is likely that the GABAA receptor-mediated hyperpolarization of preinspiratory neurons serves as the neuronal basis of propofol-induced respiratory depression in the newborn rat.

AQP4 (aquaporin-4), a water channel protein that is predominantly expressed in astrocyte end-feet, plays an important role in the brain oedema formation, and is thereby considered to be a potential therapeutic target. Using a stopped-flow analysis, we showed that propofol (2,6-diisopropylphenol), a general anaesthetic drug, profoundly inhibited the osmotic water permeability of AQP4 proteoliposomes in the presence of Zn2+ . This propofol inhibition was not observed in AQP1, suggesting the specificity for AQP4. In addition, the inhibitory effects of propofol could be reversed by the removal of Zn2+ . Other lipid membrane fluidizers also similarly inhibited AQP4, suggesting that themodulation of protein-lipid interactions plays an essential role in the propofol-induced inhibition of AQP4. Accordingly, we used Blue native PAGE and showed that the profound inhibition caused by propofol in the presence of Zn2+ is coupled with the reversible clustering of AQP4 tetramers. Site-directed mutagenesis identified that Cys253, located at the membrane interface connecting to the C-terminal tail, is responsible for Zn2+ -mediated propofol inhibition. Overall, we discovered that propofol specifically and reversibly inhibits AQP4 through the interaction between Zn2+ and Cys253. The findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors. [ABSTRACT FROM AUTHOR]

AQP4 (aquaporin-4), a water channel protein that is predominantly expressed in astrocyte end-feet, plays an important role in the brain oedema formation, and is thereby considered to be a potential therapeutic target. Using a stopped-flow analysis, we showed that propofol (2,6-diisopropylphenol), a general anaesthetic drug, profoundly inhibited the osmotic water permeability of AQP4 proteoliposomes in the presence of Zn2+ . This propofol inhibition was not observed in AQP1, suggesting the specificity for AQP4. In addition, the inhibitory effects of propofol could be reversed by the removal of Zn2+ . Other lipid membrane fluidizers also similarly inhibited AQP4, suggesting that themodulation of protein-lipid interactions plays an essential role in the propofol-induced inhibition of AQP4. Accordingly, we used Blue native PAGE and showed that the profound inhibition caused by propofol in the presence of Zn2+ is coupled with the reversible clustering of AQP4 tetramers. Site-directed mutagenesis identified that Cys253, located at the membrane interface connecting to the C-terminal tail, is responsible for Zn2+ -mediated propofol inhibition. Overall, we discovered that propofol specifically and reversibly inhibits AQP4 through the interaction between Zn2+ and Cys253. The findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors. [ABSTRACT FROM AUTHOR]