The Discovery and Development of Propofol Anesthesia

Glen, J. B.

doi:10.1001/jama.2018.12756

Cited by 18 publications

(8 citation statements)

References 10 publications

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“…Reviewing the discovery origins provided in Supporting Information 1 demonstrates that, contrary to the textbook procedure of drug discovery which has been the standard of the past few decades, a significant portion of the most important drugs used in the clinic have originated from approaches that many drug hunters nowadays would consider “otherworldly” and “taken place on another planet”. − Most of the approved drugs have originated from emphasizing and using highly predictive phenotypic models, like predictive animal models, ex vivo systems, or cultures of bacteria, fungi, and protozoa (about 700 drugs including most of the drugs in these categories: observing nonhuman or ex vivo phenotypes, mechanism of action-informed phenotypic observations, and observing phenotypic effects of endogenous molecules). This is evident in the discovery origins of many drugs including isoproterenol, propranolol, cimetidine, ethosuximide, purine analogs, cyclosporine, pentamidine, − omeprazole, , propofol, − paclitaxel, topotecan, , ivermectin, , topiramate, , leflunomide, sirolimus, ezetimibe, cinacalcet, and tecovirimat. , …”

Section: Resultsmentioning

confidence: 99%

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Sadri

2023

J. Med. Chem.

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Target-based drug discovery is the dominant paradigm of drug discovery; however, a comprehensive evaluation of its real-world efficiency is lacking. Here, a manual systematic review of about 32000 articles and patents dating back to 150 years ago demonstrates its apparent inefficiency. Analyzing the origins of all approved drugs reveals that, despite several decades of dominance, only 9.4% of small-molecule drugs have been discovered through "target-based" assays. Moreover, the therapeutic effects of even this minimal share cannot be solely attributed and reduced to their purported targets, as they depend on numerous off-target mechanisms unconsciously incorporated by phenotypic observations. The data suggest that reductionist targetbased drug discovery may be a cause of the productivity crisis in drug discovery. An evidence-based approach to enhance efficiency seems to be prioritizing, in selecting and optimizing molecules, higher-level phenotypic observations that are closer to the sought-after therapeutic effects using tools like artificial intelligence and machine learning.

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Section: Resultsmentioning

confidence: 99%

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Sadri

2023

J. Med. Chem.

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“…Propofol (2, 6-diisopropylphenol) is a widely used systemic anesthetic that acts on γ-aminobutyric acid type A (GABAA) receptors, glycine receptors, nicotinic acetylcholine receptors, and N-methyl-D-aspartate (NMDA) receptors [14][15][16]. Moreover, propofol can suppress locus coeruleus (LC) neuronal activity, which may contribute to the inhibition of norepinephrine (NE) release [17].…”

Section: Ivyspringmentioning

confidence: 99%

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain

et al. 2021

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“…To solve this problem, propofol can come in handy; it is an intravenous hypnotic drug used to induce and maintain sedation and general anesthesia, which works by enhancing the inhibitory neurotransmitter γ‐aminobutyric acid (GABA) on the GABAA receptor 2 . Its properties include rapid metabolism, multiple doses that do not markedly increase the risk of delayed recovery of consciousness, and a low incidence of postoperative nausea, which makes it widely used in clinical practice 3 . In 2018, Dr. John Glenn, a pioneer in the discovery and clinical development of propofol, was awarded the Lasker Clinical Medicine Research Award in the United States, which suggests that propofol exerts a crucial role in clinical anesthesia 4 .…”

Section: Introductionmentioning

confidence: 99%

Effects of different injection methods of propofol anesthesia on the behavior and electroencephalography recording in mice

Luo

Chen

2022

Ibrain

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Propofol is commonly used in mice studies on the mechanism of general anesthesia. The administration routes of propofol include intraperitoneal injection, single tail vein injection, and continuous tail vein pumping. The aim of this study is to compare the effects of the three injection methods on the behavior and electroencephalography (EEG) recording in mice. Mice were divided into an intraperitoneal injection group, a single tail vein injection group, and a continuous tail vein pumping group according to the propofol administration route. The indexes for observation were: time of loss of righting reflex (LORR), time of resumption of righting reflex (RORR), and change in the number of EEG spindle waves during anesthesia. The LORR and RORR were detected again after 1 week to determine the repeatability of the three administration routes. Death and behavioral change after anesthesia recovery in mice were recorded in the three groups. For propofol administration in mice, intraperitoneal injection induced long-duration anesthesia, but the depth of anesthesia was shallow and there was a risk of anesthesia accidents. A small dose of propofol administered through a single tail vein can induce loss of consciousness but the LORR time was not recorded, hence the metrics during induction of anesthesia were not investigated. Continuous tail vein pumping produced stable behavior and EEG recording during anesthesia induction and recovery in mice, and the individual difference was small. Continuous tail vein pumping is an ideal administration route for studying the mechanism of loss of consciousness of propofol anesthesia in mice, which could provide reference data for future mice experiments using propofol.

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The Discovery and Development of Propofol Anesthesia

Cited by 18 publications

References 10 publications

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain

Effects of different injection methods of propofol anesthesia on the behavior and electroencephalography recording in mice

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