Aim: Propofol-remifentanil-dexmedetomidine-based total intravenous anesthesia is widely used, but ensuring the safety of the sleep-wakefulness transition and hemodynamic stability remains a challenge. This study aimed to investigate the influence of orexinergic neuron gene polymorphisms on interindividual variability in the time to loss of consciousness (LOC), time to wake, and cardiovascular fluctuations. Methods: A total of 250 patients were included in the study. Gene polymorphisms were detected using the Agena Bioscience MassARRAY system. Anesthesia induction began with propofol and maintained with propofol and remifentanil. Dexmedetomidine was administered before anesthesia induction. The time to LOC, time to wake, heart rate (HR), and mean arterial pressure (MAP) were documented. Results: HCRTR2 rs2292040 and rs76380807 were significantly associated with the time to LOC, and HCRTR2 rs7774031 was correlated with the time to wake. HCRTR2 rs3122162, rs3122169, and rs74296544 were correlated with HR fluctuations, and HCRTR1 rs2176807, rs2271933, rs871634, and HCRTR2 rs74296544 were associated with MAP fluctuations. Multiple linear regression analysis revealed that a TCI concentration of propofol > 4 μg ml-1 at the time of LOC and dexmedetomidine were influencing factors for the time to LOC, whereas HCRTR2 rs7774031 influenced the time to wake. Baseline HR, baseline MAP, dexmedetomidine, HCRTR2 rs3122162, and HCRTR1 rs2176807 were predictive factors for cardiovascular susceptibility. The predictive models for the time to LOC, time to wake, HR, and MAP fluctuations accounted for 41.89%, 3.36%, 35.56%, and 47.41% of variations, respectively. Conclusion: Genetic variants of orexinergic neurons may affect sleep-wakefulness transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.

Aim: The aim of the research is to establish a population pharmacokinetic (PPK) model of Clindamycin hydrochloride capsules in Chinese health subjects and investigate the factors affecting the pharmacokinetic parameters to provide guidance for the individualized treatment of Clindamycin. Methods: Clindamycin concentrations were measured in 48 selective health subjects (30 males and 18 females aged 18-45 years). The subjects were assigned to two groups randomly. 150mg Clindamycin oral administration were given at fasting or postprandial, respectively. Blood samples were collected at specified time. A total of 1344 blood drug concentration data were analyzed using NONMEM. The Non-linear mixed effect model was conducted to establish the population pharmacokinetic model of Clindamycin in Chinese healthy patients. The model was verified and evaluated by Visual Prediction Test (VPC) and Bootstrap method. Results: This study established a one-compartment pharmacokinetic model of Clindamycin hydrochloride capsules in Chinese healthy subjects. The final population pharmacokinetic parameters were oral absorption coefficient (Ka=2.69 h-1), apparent volume of distribution (V/F=76.74 L) and apparent clearance (CL/F= 30.10 L·h-1). And the food was the only significant covariate in the model. The final model was stable and predictable, verified by VPC and Bootstrap. Conclusion: A robust and predictable population pharmacokinetic model of Clindamycin in Chinese healthy subjects was constructed successfully. The dietary state had a significant effect on the pharmacokinetics of Clindamycin which gave an important steer for dose adjustment or changing medication in clinical practice. Moreover, the model had great potential to guide the individualized medication of Clindamycin.

Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.

Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.