8 research outputs found
Etomidate and its derivatives: time to say goodbye?
No full textEtomidate, an intravenous hypnotic used for anaesthesia and critical care, is known for its undesirable side effects, including pain on injection, myoclonus, and adrenocortical depression. Despite its continued clinical use due to its hemodynamic stability and rapid onset and offset, alternatives like propofol, ketamine, and remimazolam offer fewer drawbacks. Recent efforts to improve etomidate through chemical modifications, such as methoxyethyl etomidate hydrochloride (ET-26), have shown limited success, with persistent issues like involuntary muscle movements and adrenocortical suppression. We suggest that it might be time to move on from etomidate and focus on developing new anaesthetic agents
What’s New in Intravenous Anaesthesia? New Hypnotics, New Models and New Applications
Full text linkNew anaesthetic drugs and new methods to administer anaesthetic drugs are continually becoming available, and the development of new PK-PD models furthers the possibilities of using arget controlled infusion (TCI) for anaesthesia. Additionally, new applications of existing anaesthetic drugs are being investigated. This review describes the current situation of anaesthetic drug development and methods of administration, and what can be expected in the near future
Pharmacological approaches for a novel GABAa receptor agonist:the long and winding road of drug development in anesthesia
Full text linkAlthough several intravenous anesthetic agents are used in daily clinical practice, the ideal anesthetic agent still does not exist (yet). In this PhD-thesis, various pharmacological approaches are used to investigate the novel anesthetic agent ABP-700 and to assess the extent to which it approaches the ideal anesthetic agent. In the first part of the thesis, its safety and clinical profile are assessed in a phase I clinical trial. ABP-700 seems to have various beneficial properties, as it provides hemodynamic and respiratory stability sometimes lacking in other anesthetic agents, and shows a fast on- and offset of clinical effect. However, one major side effect is the occurrence of involuntary muscle movements. The second part of the thesis zooms in on the origin of these muscle movements, which are seen in the use of other anesthetics as well. It could be concluded, that these movements are most likely not of an epileptic nature, but that they are more likely caused by a disequilibrium that occurs in the central nervous system during induction of anesthesia. This notion is supported by a pharmacokinetic-pharmacodynamic model that we developed, using the data that we gathered during the phase I trial. Also, it was observed that a certain intrinsic susceptibility for these muscle movements exists in certain subjects. In order to find out what this intrinsic susceptibility and the exact mechanism behind these movements are, further research is necessary
Etomidate and its analogs : a review of pharmacokinetics and pharmacodynamics
Full text linkEtomidate 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 gamma-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter gamma-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 11 beta-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
Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid
Full text linkEditor's PerspectiveWhat We Already Know about This Topic The investigational etomidate analog ABP-700 causes involuntary muscle movements in humans at anesthetic doses and seizures in dogs at 10-fold higher toxicologic doses The mechanism of seizures in dogs, and their relationship to involuntary muscle movements in humans, is unknown What This Article Tells Us That Is New Toxicologic studies in dogs using supratherapeutic ABP-700 doses caused involuntary muscle movements and seizures, but these were temporally and electroencephalographically distinct, suggesting different underlying mechanisms Events occurred at ABP-700 and metabolite concentrations one and two orders of magnitude higher, respectively, than those found in humans Electrophysiologic studies of the principal metabolite of ABP-700 in oocyte-expressed gamma-aminobutyric acid type A receptors showed inhibition at the high supratherapeutic concentrations achieved in the dogs, and such inhibition may explain seizure activity Proepileptiform effects of ABP-700 in dogs may not be relevant to humans at therapeutic doses Background: The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (similar to 10x clinical) ABP-700 doses. gamma-aminobutyric acid type A (GABA(A)) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. Methods: ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg center dot kg(-1) center dot min(-1), 1.5 mg center dot kg(-1) center dot min(-1), or 2.3 mg center dot kg(-1) center dot min(-1)). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed alpha(1)beta(3)gamma(2L) GABA(A) and alpha(1)beta glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. Results: ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 mu M, 45 mu M, and 102 mu M (ABP-700) and 282 mu M, 478 mu M, and 1,110 mu M (CPM-acid). ABP-700 and CPM-acid concentration-GABA(A) receptor response curves defined using 6 mu M gamma-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM gamma-aminobutyric acid were 770 mu M (95% CI, 590 to 1,010 mu M) and 1,450 mu M (95% CI, 1,340 to 1,560 mu M), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 mu M (95% CI, 1,240 to 1,330 mu M). Conclusions: High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms.CPM-acid inhibits both GABA(A) and glycine receptors at the high (similar to 100x clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.</p
The stripped fish : translation and culture in Mario Bellatin’s Japanese novellas
No full textFor Mario Bellatin, a major figure in the contemporary Spanish-speaking world, artistic activity is all-embracing. His project shows a dynamics that exceeds the literary field in order to create a body of work which is formed or performed as much through the textual and the visual medium as through public interventions.
The way in which this author positions himself vis-à-vis the global marketplace and the uneven distribution of cultural capital, notably the ideological agendas that determine which works are recognized as 'World Literature' (Casanova, Apter), is paradoxical. Although he refuses to go along with the streamlined system of a World Republic of Letters, he has managed to secure a niche in the contemporary transnational canon with his experimental work (Hoyos). How did he achieve this?
To understand how the global and the local relate to each other in Bellatin's work, I will focus on the figure of the translator in two of his "oriental stories", El jardín de la señora Murakami and Shiki Nagaoka, una nariz de ficción (translated into English: Shiki Nagaoka, A Nose for Fiction). The first novella is a fictional translation of an inexistent literary text, the second one a fake biography of a non-existent writer-translator.
In my analysis of El jardín de la señora Murakami, I will explore the difference between “pseudo-translation” and “textual cloning”. According to Emily Apter, both terms address problematic originality in the field of translation studies. They are conceptually related, but emphasize distinctly different problems and questions as textual cloing shifts the terms of translation studies from textual veracity to the condtions of the original’s reproducibility. Consequently, the whole concept of originality as an essentialist category becoms subject to dispute.
For Bellatin, translating functions as an intensified modality of writing. For his character Shiki Nagaoka, as long as a text has not passed the translation test, it does not really qualify as “literature” and, more specifically, as “universal literature”. Consequently, translation destabilizes traditional notions of authorship, originality and intellectual property: translating does not result in loss, but enhances the literary value of a text. Furthermore, the use of translators is a way to dwell upon the international circulation of artistic production
Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700
Full text linkBACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores.METHODS: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined.RESULTS: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects.CONCLUSIONS: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.EDITOR’S PERSPECTIVE: </p
A phase 1, single-center, double-blind, placebo-controlled study in healthy subjects to assess the safety, tolerability, clinical effects, and pharmacokinetics-pharmacodynamics of intravenous cyclopropyl-methoxycarbonylmetomidate (ABP-700) after a single ascending bolus dose
No full textBackground: Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships.
Methods: Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated.
Results: Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index.
Conclusions: This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile
