-
Clinical Pharmacokinetics Oct 2021Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric... (Review)
Review
Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11β-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.
Topics: Anesthesia; Etomidate; Humans; Hypnotics and Sedatives
PubMed: 34060021
DOI: 10.1007/s40262-021-01038-6 -
Nature Sep 2020Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity...
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity in the brain. 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 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 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 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.
Topics: Allosteric Regulation; Anesthetics, General; Barbiturates; Benzodiazepines; Bicuculline; Binding Sites; Binding, Competitive; Cryoelectron Microscopy; Diazepam; Electrophysiology; Etomidate; Flumazenil; GABA-A Receptor Antagonists; Humans; Ligands; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Phenobarbital; Picrotoxin; Propofol; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 32879488
DOI: 10.1038/s41586-020-2654-5 -
Critical Care (London, England) Jun 2020Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness.... (Review)
Review
Practice guidelines provide clear evidence-based recommendations for the use of drug therapy to manage pain, agitation, and delirium associated with critical illness. Dosing recommendations however are often based on strategies used in patients with normal body habitus. Recommendations specific to critically ill patients with extreme obesity are lacking. Nonetheless, clinicians must craft dosing regimens for this population. This paper is intended to help clinicians design initial dosing regimens for medications commonly used in the management of pain, agitation, and delirium in critically ill patients with extreme obesity. A detailed literature search was conducted with an emphasis on obesity, pharmacokinetics, and dosing. Relevant manuscripts were reviewed and strategies for dosing are provided.
Topics: Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Benzodiazepines; Critical Illness; Deep Sedation; Delirium; Dexmedetomidine; Dose-Response Relationship, Drug; Etomidate; Haloperidol; Humans; Ketamine; Obesity; Pain Management; Quetiapine Fumarate
PubMed: 32513237
DOI: 10.1186/s13054-020-03040-z -
JAMA Surgery Oct 2022Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical...
IMPORTANCE
Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity.
OBJECTIVE
To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle.
INTERVENTIONS
Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion.
MAIN OUTCOMES AND MEASURES
Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12.
RESULTS
A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] μg/dL vs 6.1 [3.4] μg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population.
CONCLUSIONS AND RELEVANCE
Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02910206.
Topics: Aged; Aldosterone; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Etomidate; Hospitals; Humans; Hydrocortisone; Male; Postoperative Complications; Propofol
PubMed: 35947398
DOI: 10.1001/jamasurg.2022.3338 -
Chemical Reviews Oct 2021In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on... (Review)
Review
In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting to π* conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.
Topics: Amides; Chemistry Techniques, Synthetic; Lactams; Molecular Conformation; Nitrogen
PubMed: 34406005
DOI: 10.1021/acs.chemrev.1c00225 -
Scientific Reports Apr 2023Patients with sepsis often require emergency intubation. In emergency departments (EDs), rapid-sequence intubation with a single-dose induction agent is standard... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with sepsis often require emergency intubation. In emergency departments (EDs), rapid-sequence intubation with a single-dose induction agent is standard practice, but the best choice of induction agent in sepsis remains controversial. We conducted a randomized, controlled, single-blind trial in the ED. We included septic patients who were aged at least 18 years and required sedation for emergency intubation. Patients were randomly assigned by a blocked randomization to receive 0.2-0.3 mg/kg of etomidate or 1-2 mg/kg of ketamine for intubation. The objectives were to compare the survival outcomes and adverse events after intubation between etomidate and ketamine. Two hundred and sixty septic patients were enrolled; 130 patients/drug arm whose baseline characteristics were well balanced at baseline. In the etomidate group, 105 patients (80.8%) were alive at 28 days, compared with 95 patients (73.1%) in the ketamine group (risk difference [RD], 7.7%; 95% confidence interval [CI], - 2.5 to 17.9%; P = 0.092). There was no significant difference in the proportion of patients who survived at 24 h (91.5% vs. 96.2%; P = 0.097) and survived at 7 days (87.7% vs. 87.7%; P = 0.574). A significantly higher proportion of the etomidate group needed a vasopressor within 24 h after intubation: 43.9% vs. 17.7%, RD, 26.2% (95% CI, 15.4 to 36.9%; P < 0.001). In conclusion, there were no differences in early and late survival rates between etomidate and ketamine. However, etomidate was associated with higher risks of early vasopressor use after intubation. Trial registration: The trial protocol was registered in the Thai Clinical Trials Registry (identification number: TCTR20210213001). Registered 13 February 2021-Retrospectively registered, https://www.thaiclinicaltrials.org/export/pdf/TCTR20210213001 .
Topics: Humans; Adolescent; Adult; Etomidate; Ketamine; Anesthetics, Intravenous; Single-Blind Method; Intubation, Intratracheal; Sepsis; Emergency Service, Hospital; Vasoconstrictor Agents
PubMed: 37076524
DOI: 10.1038/s41598-023-33679-x -
Journal of the American Chemical Society Feb 2016DNA catalysts (deoxyribozymes) for a variety of reactions have been identified by in vitro selection. However, for certain reactions this identification has not been...
DNA catalysts (deoxyribozymes) for a variety of reactions have been identified by in vitro selection. However, for certain reactions this identification has not been achieved. One important example is DNA-catalyzed amide hydrolysis, for which a previous selection experiment instead led to DNA-catalyzed DNA phosphodiester hydrolysis. Subsequent efforts in which the selection strategy deliberately avoided phosphodiester hydrolysis led to DNA-catalyzed ester and aromatic amide hydrolysis, but aliphatic amide hydrolysis has been elusive. In the present study, we show that including modified nucleotides that bear protein-like functional groups (any one of primary amino, carboxyl, or primary hydroxyl) enables identification of amide-hydrolyzing deoxyribozymes. In one case, the same deoxyribozyme sequence without the modifications still retains substantial catalytic activity. Overall, these findings establish the utility of introducing protein-like functional groups into deoxyribozymes for identifying new catalytic function. The results also suggest the longer-term feasibility of deoxyribozymes as artificial proteases.
Topics: Amides; Catalysis; DNA; Hydrolysis
PubMed: 26854515
DOI: 10.1021/jacs.5b12647 -
Critical Care (London, England) Feb 2024Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation.
METHODS
We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ).
RESULTS
We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79-1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes.
CONCLUSIONS
All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality.
Topics: Adult; Humans; Etomidate; Ketamine; Bayes Theorem; Critical Illness; Intubation, Intratracheal
PubMed: 38368326
DOI: 10.1186/s13054-024-04831-4 -
Molecules (Basel, Switzerland) Oct 2018Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide... (Review)
Review
Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their ability to form resonating structures, thus, they are highly stable and adopt particular three-dimensional structures, which, in turn, are responsible for their functions. The main focus of this review article is to report the methodologies for the activation of the unactivated amide bonds present in biomolecules, which includes the enzymatic approach, metal complexes, and non-metal based methods. This article also discusses some of the applications of amide bond activation approaches in the sequencing of proteins and the synthesis of peptide acids, esters, amides, and thioesters.
Topics: Acids; Amides; Biological Products; Esters; Molecular Conformation
PubMed: 30322008
DOI: 10.3390/molecules23102615 -
Angewandte Chemie (International Ed. in... Jul 2021Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme... (Review)
Review
Enzyme catalysis is gaining increasing importance in synthetic chemistry. Nowadays, the growing number of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis especially provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compound libraries. Particularly important and highly topical are enzyme-catalysed oxyfunctionalisations, halogenations, methylations, reductions, and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymatic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
Topics: Amides; Biocatalysis; Enzymes
PubMed: 33453143
DOI: 10.1002/anie.202014931