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Despite the absence of responsiveness during anesthesia, conscious experience may persist. However, reliable, easily acquirable and interpretable neurophysiological markers of the presence of consciousness in unresponsive states are still missing. A promising marker is based on the decay-rate of the power spectral density (PSD) of the resting EEG. We acquired resting electroencephalogram (EEG) in three groups of healthy participants (n = 5 each), before and during anesthesia induced by either xenon, propofol or ketamine. Dosage of each anesthetic agent was tailored to yield unresponsiveness (Ramsay score = 6). Delayed subjective reports assessed whether conscious experience was present (‘Conscious report’) or absent/inaccessible to recall (‘No Report’). We estimated the decay of the PSD of the resting EEG—after removing oscillatory peaks—via the spectral exponent β, for a broad band (1–40 Hz) and narrower sub-bands (1–20 Hz, 20–40 Hz). Within-subject anesthetic changes in β were assessed. Furthermore, based on β, ‘Conscious report’ states were discriminated against ‘no report’ states. Finally, we evaluated the correlation of the resting spectral exponent with a recently proposed index of consciousness, the Perturbational Complexity Index (PCI), derived from a previous TMS-EEG study. The spectral exponent of the resting EEG discriminated states in which consciousness was present (wakefulness, ketamine) from states where consciousness was reduced or abolished (xenon, propofol). Loss of consciousness substantially decreased the (negative) broad-band spectral exponent in each subject undergoing xenon or propofol anesthesia—indexing an overall steeper PSD decay. Conversely, ketamine displayed an overall PSD decay similar to that of wakefulness—consistent with the preservation of consciousness—yet it showed a flattening of the decay in the high-frequencies (20–40 Hz)—consistent with its specific mechanism of action. The spectral exponent was highly correlated to PCI, corroborating its interpretation as a marker of the presence of consciousness. A steeper PSD of the resting EEG reliably indexed unconsciousness in anesthesia, beyond sheer unresponsiveness. •Unconsciousness does not imply unresponsiveness.•Consciousness is abolished during xenon and propofol, yet preserved during ketamine.•EEG Spectral exponent indexes the 1/f-like decay of non-oscillatory PSD background.•Xenon and propofol steepen broad-band decay; ketamine flattens high-frequency decay.•Spectral exponent separates un/consciousness in anesthesia-induced unresponsiveness.

In a randomized trial, 5400 patients scheduled to undergo CABG were assigned either to an anesthetic regimen that included a volatile anesthetic or to total intravenous anesthesia. At 1 year, there was no significant difference between the two groups in the number of deaths from any cause.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

To compare the clinical efficacy of co-induction with propofol-midazolam-ketamine with etomidate as the sole induction agent. Prospective, double-blinded, randomized controlled trial. Operating room of a university hospital. 60 ASA physical status 1 and 2 patients scheduled for limited elective surgery requiring general anesthesia. Patients were randomized to two groups to receive etomidate 0.3 mg/kg (single-drug group) or propofol 0.6 mg/kg + ketamine 0.8 mg/kg + midazolam 0.06 mg/kg (three-drug group). Hemodynamic responses (systolic and diastolic blood pressure, and mean arterial pressure) were examined at baseline and at one, three, and 5 minutes after tracheal intubation. Plasma catecholamine levels were measured at baseline, one, and 5 minutes after tracheal intubation. Heart rate (HR) changes differed significantly between the two groups at three minutes (P = 0.01) and 5 minutes (P = 0.00) after tracheal intubation. However, the HR increase in the three-drug group was in the acceptable range. Percentage changes of epinephrine level differed between the two groups at 5 minutes after tracheal intubation (P = 0.03). The higher norepinephrine/epinephrine ratio noted in the single-drug group may be implicated in lower adrenal sympathetic activity. Propofol-midazolam-ketamine co-induction may be used instead of etomidate for anesthesia induction in patients with hemodynamic instability. •Co-induction with propofol-midazolam-ketamine was compared with etomidate as the sole induction agent.•Etomidate is more expensive and less available than the propofol-midazolam-ketamine combination.•In hemodynamically unstable patients, etomidate is less desirable owing to a higher NE/E ratio, which may account for the noted lower adrenal sympathetic activity.•Propofol-midazolam-ketamine co-induction may be preferred anesthesia induction in some patients.

For the past five decades, there has been little progress in the development of oral anticoagulants, with the choices being limited to the vitamin K antagonists (VKAs). The situation is changing with the development of orally active small molecules that directly target thrombin or activated factor X (FXa). The two agents in the most advanced stages of development are dabigatran etexilate and rivaroxaban, which inhibit thrombin and FXa, respectively. Both are approved in the EU and Canada for venous thromboprophylaxis in patients undergoing elective hip- or knee-replacement surgery. Other agents in the early stages of development include several FXa inhibitors (apixaban, DU 176b, LY 517717, YM 150, betrixaban, eribaxaban [PD 0348292] and TAK 442) and one thrombin inhibitor (AZD 0837). With a predictable anticoagulant response and low potential for drug-drug interactions, these new agents can be given in fixed doses without coagulation monitoring. This renders them more convenient than VKAs. While the anticoagulant effect of the new thrombin and FXa inhibitors is similar, differences in the pharmacokinetic and pharmacodynamic parameters may influence their use in clinical practice. Here, we compare the pharmacokinetic and pharmacodynamic features of these new oral agents.

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2–4 h after tablet intake. Oral bioavailability is high (80–100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30–40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5–9 h in healthy young subjects and 11–13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.

Ginkgo biloba is among the most favourite and best explored herbal drugs. Standardized extracts of Ginkgo biloba represent the only herbal alternative to synthetic antidementia drugs in the therapy of cognitive decline and Alzheimer’s diseases. The clinical efficiency of such standardized Ginkgo biloba extracts (GBE) is still controversial, but authors of numerous international clinical studies recommended the use of GBE in the described therapies. Extracts of Ginkgo biloba are a mixture of substances with a wide variety of physical and chemical properties and activities. Numerous pharmacological investigations lead to the conclusion that the terpene trilactones (TTL) and the flavonoids of GBE are responsible for the main pharmacological effects of the extract in the therapy of cognitive decline. Therefore, the quality of GBE products must be oriented on a defined quantity of TTL and flavonoids. Furthermore, because of their toxic potential the amount of ginkgolic acid should be less than 5 ppm. However, data on pharmacokinetics and bioavailability, especially related to the central nervous system (CNS), which is the target tissue, are relatively rare. A few investigations characterize the TTL and flavonoids of Ginkgo biloba pharmacokinetically in plasma and in the brain. Recent investigations show that significant levels of TTL and Ginkgo biloba flavonoids cross the blood–brain barrier and enter the CNS of rats after oral application of GBE. Knowledge about the pharmacokinetic behaviour of these substances is necessary to discuss the pharmacological results on a more realistic basis.

Background Images evoked immediately before the induction of anesthesia with the help of suggestions may influence dreaming during anesthesia.The aim of the study was to assess the incidence of evoked dreams and dream recalls by employing suggestions before induction of anesthesia while administering different general anesthetic combinations. Methods This is a single center, prospective randomized including 270 adult patients scheduled for maxillofacial surgical interventions. Patients were assigned to control, suggestion and dreamfilm groups according to the psychological method used. According to the anesthetic protocol there were also three subgroups: etomidate & sevoflurane, propofol & sevoflurane, propofol & propofol groups. Primary outcome measure was the incidence of postoperative dreams in the non-intervention group and in the three groups receiving different psychological interventions. Secondary endpoint was to test the effect of perioperative suggestions and dreamfilm-formation training on the occurrance of dreams and recallable dreams in different general anesthesiological techniques. Results Dream incidence rates measured in the control group did not differ significantly (etomidate & sevoflurane: 40%, propofol & sevoflurane: 26%, propofol & propofol: 39%). A significant increase could be observed in the incidence rate of dreams between the control and suggestion groups in the propofol & sevoflurane (26%-52%) group (p = 0.023). There was a significant difference in the incidence of dreams between the control and dreamfilm subgroup in the propofol & sevoflurane (26% vs. 57%), and in the propofol & propofol group (39% vs.70%) (p = 0.010, and p = 0.009, respectively). Similar to this, there was a significant difference in dream incidence between the dreamfilm and the suggestion subgroups (44% vs. 70%) in the propofol & propofol group (p = 0.019). Propofol as an induction agent contributed most to dream formation and recalls (χ2-test p value: 0.005). The content of images and dreams evoked using suggestions showed great agreement using all three anesthetic protocols. Conclusion The psychological method influenced dreaming during anesthesia. The increase of the incidence rate of dreams was dependent on the anesthetic agent used, especially the induction agent. The study was registered in ClinicalTrials.gov. Identifier: NCT01839201 .

Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and pharmacodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum plasma concentrations attained within 3–4 hours. Orally administered gabapentin exhibits saturable absorption — a nonlinear (zero-order) process — making its pharmacokinetics less predictable. Plasma concentrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at <-90% irrespective ofthe dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs. Both drugs are excreted renally, with elimination half-lives of approximately 6 hours. Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In conclusion, pregabalin appearsto have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect.

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.