As a novel and effective approach, response surface model is used in the study of drug-drug interactions. When two drugs are used simultaneously, this model can be applied to estimate the key characters of the response surface, to find the desired response region by optimal drugs combination, to explore the mechanism of drug-drug interactions, and thus to guide sound clinical application and reduce the risk and cost. In this article, the model's basic mathematical and pharmacological concepts are introduced, and its research progresses are reviewed.
Alfentanil ; pharmacology ; Anesthetics ; pharmacology ; Computer Simulation ; Drug Interactions ; Drug Synergism ; Humans ; Midazolam ; pharmacology ; Models, Statistical ; Propofol ; pharmacology

The effects of halothane or isoflurane, alone and in combination with propofol or thiopental were investigated for their effects on intracranial pressure (ICP) in the rabbit, with inducing artificially-increased ICP with an intracranial balloon. The higher the end-tidal concentrations of either halothane or isoflurane, the lower the mean arterial pressures (MAP) and cerebral perfusion pressures (CPP). However, the ICP was not influenced by the depth of anesthesia for either inhalation anesthetics. The mean ICPs at 1.5 MAC of halothane and isoflurane were 14 +/- 2 and 20 +/- 2 mmHg, respectively. With the increase of intracranial volume using a 0.7 ml-saline balloon, the ICPs were increased to 193 and 205% in halothane and isoflurane anesthesia, respectively. The ICPs were returned to the levels prior to balloon inflation by the injection of thiopental or propofol. The authors conclude that propofol could be used to reduce ICP under halothane or isoflurane anesthesia if it is ascertained to have the characteristics of a balanced coupling between cerebral metabolism and blood flow like barbiturates do and that either halothane or isoflurane with increased concentrations may decrease MAP without significant change of ICP.
*Anesthesia ; Animal ; Female ; *Halothane ; Intracranial Pressure/*drug effects ; *Isoflurane ; Male ; Propofol/*pharmacology ; Rabbits ; Thiopental/*pharmacology

OBJECTIVE: To examine the predicted effect-site concentration of propofol at two clinical end-points: loss of verbal contact (LVC) and loss of consciousness (LOC), and to explore the relationship between bispectral index (BIS) values, cerebral state index (CSI) values and the predicted effect-site concentration during the target-controlled infusion of propofol. METHODS: In 20 patients during the target-controlled infusion of propofol, the propofol infusion was set at an initial effect-site concentration of 0.5 mg/L, and increased by 0.5 mg/L every 5 min until 5 min after the modified observer's assessment of alertness/sedation scale (OAA/S) values reached zero. The predicted effect-site concentration of propofol, the values of CSI and BIS were recorded, and the sedation level was examined by the modified OAA/S every 20s. The predicted effect-site concentrations of propofol in target-controlled infusion (TCI) system were recorded when they increased by more than 0.1 mg/L. The predicted effect-site concentrations of propofol and the values of BIS and CSI at LVC and LOC in 5%, 50% and 95% of the patients were calculated. RESULTS: There was good linearity between BIS and the predicted effect-site concentration of propofol (R(2)=0.787), as well as between CSI and the predicted effect-site concentration of propofol (R(2)=0.792). The predicted effect-site concentrations of propofol at LVC in 5%, 50% and 95% of the patients were 1.1,1.8 and 2.4 mg/L, respectively. The values of BIS and CSI at LVC in 5%, 50% and 95% of the patients were 79.2, 69.2 and 59.2; 74.9, 65.9 and 56.8, respectively. The predicted effect-site concentrations of propofol at LOC in 5%, 50% and 95% of the patients were 1.5, 2.5 and 3.4 mg/L, respectively. At LOC, the values of BIS and CSI in 5%, 50% and 95% of the patient were 73.6, 57.1 and 40.6; 65.2, 54.8 and 44.3, respectively. CONCLUSION During target-controlled infusion of propofol, LVC and LOC occur within a definite range of predicted effect-site concentrations. There is the good linearity between BIS, CSI and the predicted effect-site concentrations of propofol. CSI may be more useful than BIS in predicting LVC and LOC.
Adult ; Anesthetics, Intravenous ; administration & dosage ; pharmacology ; Electroencephalography ; Female ; Humans ; Male ; Monitoring, Intraoperative ; Propofol ; administration & dosage ; pharmacology

OBJECTIVE: To explore the regulatory effects of GABAergic neurons in the zona incerta (ZI) on sevoflurane and propofol anesthesia. METHODS: Forty-eight male C57BL/6J mice divided into 8 groups (n=6) were used in this study. In the study of sevoflurane anesthesia, chemogenetic experiment was performed in 2 groups of mice with injection of either adeno-associated virus carrying hM3Dq (hM3Dq group) or a virus carrying only mCherry (mCherry group). The optogenetic experiment was performed in another two groups of mice injected with an adeno-associated virus carrying ChR2 (ChR2 group) or GFP only (GFP group). The same experiments were also performed in mice for studying propofol anesthesia. Chemogenetics or optogenetics were used to induce the activation of GABAergic neurons in the ZI, and their regulatory effects on anesthesia induction and arousal with sevoflurane and propofol were observed; EEG monitoring was used to observe the changes in sevoflurane anesthesia maintenance after activation of the GABAergic neurons. RESULTS: In sevoflurane anesthesia, the induction time of anesthesia was significantly shorter in hM3Dq group than in mCherry group (P < 0.05), and also shorter in ChR2 group than in GFP group (P < 0.01), but no significant difference was found in the awakening time between the two groups in either chemogenetic or optogenetic tests. Similar results were observed in chemogenetic and optogenetic experiments with propofol (P < 0.05 or 0.01). Photogenetic activation of the GABAergic neurons in the ZI did not cause significant changes in EEG spectrum during sevoflurane anesthesia maintenance. CONCLUSION Activation of the GABAergic neurons in the ZI promotes anesthesia induction of sevoflurane and propofol but does not affect anesthesia maintenance or awakening.
Male ; Animals ; Mice ; Mice, Inbred C57BL ; Propofol/pharmacology* ; Sevoflurane/pharmacology* ; Zona Incerta ; Anesthesia, General ; GABAergic Neurons

The deficiency of aquaporin-4 (AQP4) has been reported to alter release of neurotransmitters in the mouse brain. However, the functional relevance of AQP4 in mediating essential components of the general anaesthetic state is unknown. The aim of the present study was to investigate the role of AQP4 in general anaesthesia in mice lacking AQP4. The hypnotic effects of propofol, ketamine, and pentobarbital in AQP4 knockout (KO) and CD1 control mice were evaluated using the behavioural endpoint of loss of righting reflex (LORR). The effects of propofol on extracellular levels of amino acids in prefrontal cortex of freely moving mice were investigated using microdialysis coupled to high performance liquid chromatography with fluorescent detection. The result showed that, after receiving ketamine or pentobarbital, LORR occurred at earlier time in KO mice than that in control animals. Intraperitoneal injection of ketamine or pentobarbital increased the duration of LORR. After the administration of propofol, the duration of LORR was significantly reduced in KO mice compared with that in controls. Propofol increased the extracellular levels of aspartate, glutamate, and GABA, but not taurine, in prefrontal cortex. There were significant differences of increase patterns of the three kinds of neurotransmitters between KO and WT mice. Notably, the duration of GABA level increase correlated with the duration of LORR in two genotypes of mice. These results provide in vivo evidence of different responses in time-dependent release of excitatory and inhibitory neurotransmitters in prefrontal cortex of the two genotypes of mice. It is suggested that changes in anaesthetic reactions in mice with AQP4 loss may be related to neurotransmitter regulation, and that normal functioning of AQP4 plays an important role in the maintenance of anaesthetic hypnosis.
Anesthetics, Intravenous ; pharmacology ; Animals ; Aquaporin 4 ; deficiency ; genetics ; Hypnotics and Sedatives ; pharmacology ; Ketamine ; pharmacology ; Mice ; Mice, Knockout ; Neurotransmitter Agents ; metabolism ; Pentobarbital ; pharmacology ; Prefrontal Cortex ; drug effects ; metabolism ; Propofol ; pharmacology

Sedation allows patients to tolerate unpleasant endoscopic procedures by relieving anxiety, discomfort, or pain. It also reduces a patient's risk of physical injury during endoscopic procedures, while providing the endoscopist with an adequate setting for a detailed examination. Sedation is therefore considered by many endoscopists to be an essential component of gastrointestinal endoscopy. Endoscopic sedation by nonanesthesiologists is a worldwide practice and has been proven effective and safe. Moderate sedation/analgesia is generally accepted as an appropriate target for sedation by nonanesthesiologists. This focused review describes the general principles of endoscopic sedation, the detailed pharmacology of sedatives and analgesics (focused on midazolam, propofol, meperidine, and fentanyl), and the multiple regimens available for use in actual practice.
Analgesia ; Analgesics ; Anxiety ; Endoscopy ; Endoscopy, Gastrointestinal* ; Humans ; Hypnotics and Sedatives ; Meperidine ; Midazolam ; Pharmacology ; Propofol

Four major factors affecting anesthetic choices in surgery include the requirements of surgery (including type and location), anesthesiologist's experience and expertise, patient's preference, and the surgeon's preference. Especially, the type and location of surgical procedure may limit anesthetic techniques and choice of anesthetic agents. Available anesthetic techniques consist of three basic options: regional anesthesia, monitored anesthesia care (MAC), and general anesthesia. Recent advances in nerve stimulators and ultrasound guidance devices help to make regional blocks more successful with less complications. MAC is increasingly used with given advantages of supplying sedation, anxiolysis, additive analgesia, and improved safety to patients. Remarkable advances in general anesthesia include total intravenous anesthesia (TIVA) and fast-track anesthesia to use drugs with rapid action and short duration including propofol, desflurane, and sevoflurane, and advanced equipments such as target-controlled infusion pumps and monitoring devices of anesthetic depth. Advances in medical technology and pharmacology will continue to develop newer anesthetic agents, techniques, and patterns.
Analgesia ; Anesthesia ; Anesthesia, Conduction ; Anesthesia, General ; Anesthesia, Intravenous ; Anesthetics ; Humans ; Infusion Pumps ; Pharmacology ; Propofol ; Ultrasonography

OBJECTIVETo observe the effects of different concentrations of propofol on brain regions activated by mechanical stimuli, and then to investigate the analgesic effect of propofol.

METHODSTwenty healthy male volunteers were randomly divided into two groups: light anesthesia group (group L) (BIS 60-80) and deep anesthesia group (group D)(BIS 40-60). Propofol was administrated by target controlled infusion system in pilot study. The target effect site concentration (ESC) of propofol was defined as the average of the ESC from BIS 80 to 60 or BIS 60 to 40 in group L or group D respectively. Mechanical stimuli were applied using von Frey filaments at the center of the left foot, and the pain threshold and VAS scores were evaluated. fMRI examinations were taken 1 week after pilot study with the following sequences: structure imaging+ functional imaging: functional imaging=stimulus sequence+propofol sequence, in which the stimulus sequence was 6 × (20 s on + 20 s off). This sequence was repeated after propofol sequence.

RESULTSAs shown by fMRI, in group L, active brain regions of (the second stimulation-the first stimulation, P2-P1) were seen in cingulate gyrus, thalamus, and cerebellum, while active brain regions of (P1-P2) were seen in temporal lobe, frontal gyrus, and occipital lobe. In group D, the active brain region of (P2-P1) was only seen in cerebellum, while active brain regions of (P1-P2) were seen in cingulate gyrus and thalamus. Active brain regions of (deep-low) with propofol infusion in response to vFFs stimulation were observed in cerebellum.

CONCLUSIONSPropofol at different concentrations has different effect on the activation of brain regions. It may exert its analgesic effect via different mechanisms.

Adult ; Brain ; physiology ; Humans ; Magnetic Resonance Imaging ; Male ; Propofol ; pharmacology ; Stress, Mechanical ; Young Adult

OBJECTIVETo investigate the effect of propofol on brain regions at different sedation levels and the association between changes in brain region activity and loss of consciousness using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) and bispectral index (BIS) monitoring.

METHODSForty-eight participants were enrolled at Peking Union Medical College Hospital from October 2011 to March 2012 and randomly assigned to a mild or a deep sedation group using computer- generated random numbers. Preliminary tests were performed a week prior to scanning to determine target effect site concentrations based on BIS and concomitant Observer's Assessment of Alertness/Sedation scores while under propofol. Within one week of the preliminary tests where propofol dose-response was established, BOLD-fMRI was conducted to examine brain activation with the subject awake, and with propofol infusion at the sedation level.

RESULTSMild propofol sedation inhibited left inferior parietal lobe activation. Deep sedation inhibited activation of the left insula, left superior temporal gyrus, and right middle temporal gyrus. Compared with mild sedation, deep propofol sedation inhibited activation of the left thalamus, precentral gyrus, anterior cingulate, and right basal nuclei.

CONCLUSIONMild and deep propofol sedation are associated with inhibition of different brain regions, possibly explaining differences in the respective loss of consciousness processes.

Adult ; Brain ; drug effects ; Consciousness Monitors ; Deep Sedation ; Dose-Response Relationship, Drug ; Humans ; Hypnotics and Sedatives ; pharmacology ; Male ; Propofol ; pharmacology

BACKGROUNDSome patients still suffer from implicit memory of intraoperative events under adequate depth of anaesthesia. The elimination of implicit memory should be a necessary aim of clinical general anaesthesia. However, implicit memory cannot be tested during anaesthesia yet. We propose bispectral index (BIS) and auditory evoked potential index (AEPI), as predictors of implicit memory during anaesthesia.

METHODSThirty-six patients were equally divided into 3 groups according to the Observer's Assessment of Alertness/Sedation Score: A, level 3; B, level 2; and C, level 1. Every patient was given the first auditory stimulus before sedation. Then every patient received the second auditory stimulus after the target level of sedation had been reached. BIS and AEPI were monitored before and after the second auditory stimulus presentation. Four hours later, the inclusion test and exclusion test were performed on the ward using process dissociation procedure and the scores of implicit memory estimated.

RESULTSIn groups A and B but not C, implicit memory estimates were statistically greater than zero (P < 0.05). The implicit memory scores in group A did not differ significantly from those in group B (P > 0.05). Implicit memory scores correlated with BIS and AEPI (P < 0.01). The area under ROC curve is BIS > AEPI. The 95% cutoff points of BIS and AEPI for predicting implicit memory are 47 and 28, respectively.

CONCLUSIONSImplicit memory does not disappear until the depth of sedation increases to level 1 of OAA/S score. Implicit memory scores correlate well with BIS and AEPI during sedation. BIS is a better index for predicting implicit memory than AEPI during propofol induced sedation.

Adolescent ; Adult ; Electroencephalography ; Evoked Potentials, Auditory ; Humans ; Hypnotics and Sedatives ; pharmacology ; Memory ; drug effects ; Middle Aged ; Propofol ; pharmacology ; ROC Curve