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Reversal of general anesthesia by administration of methylphenidate, amphetamine, modafinil, amantadine, and/or caffeine

a general anesthesia and reversal technology, applied in the direction of diagnostic recording/measuring, drug composition, biocide, etc., can solve the problems of anesthesia-induced loss of consciousness, unpredictable timing of emergence, pharmacokinetics and pharmacodynamics, etc., to facilitate emergence of the subject, reduce or eliminate the effect of delirium, and restore mobility or consciousness in the subj

Inactive Publication Date: 2013-11-21
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides anesthesia-reversing agents and methods of use to speed up the process of emerging from general anesthesia. These agents help to reduce the effects of anesthesia and prevent delirium, a common side effect of emerging from anesthesia. The anesthesia-reversing agents can be methylphenidate, amphetamine, modafinil, amantadine, or caffeine, and can be administered to patients either before or after the anesthesia agent is stopped. This invention is useful for perioperative anesthetized patients and can help to reduce the amount of anesthesia administered during surgery.

Problems solved by technology

The timing of emergence can be unpredictable because many factors including the nature and duration of the surgery, and the age, physical condition and body habitus of the patient, can greatly affect the pharmacokinetics and pharmacodynamics of general anesthetics.
Although the actions of many drugs used in anesthesiology are pharmacologically reversed when no longer desired (e.g. muscle relaxants, opioids, benzodiazepines, and anticoagulants), this is not the case for general anesthetic induced loss of consciousness.
This current clinical paradigm of passive emergence is dangerous because patients are highly susceptible to potentially severe complications such as laryngospasm, respiratory depression, hemodynamic instability, and delirium.
In addition, operating room (OR) time, estimated to cost between $12.37 to $17.11 per minute at MGH, is an expensive resource that is squandered during the time spent waiting for patients to emerge from general anesthesia.
At present, there is no agent available to actively induce emergence from general anesthesia.
This is largely due to our limited knowledge of the molecular mechanisms of general anesthetic actions, hampering the development of drugs that antagonize the actions of general anesthetics.

Method used

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  • Reversal of general anesthesia by administration of methylphenidate, amphetamine, modafinil, amantadine, and/or caffeine
  • Reversal of general anesthesia by administration of methylphenidate, amphetamine, modafinil, amantadine, and/or caffeine
  • Reversal of general anesthesia by administration of methylphenidate, amphetamine, modafinil, amantadine, and/or caffeine

Examples

Experimental program
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Effect test

example 1

[0225]The inventors herein assessed if methylphenidate (MPH) induces emergence from isoflurane anesthesia. The inventors first tested whether methylphenidate affects time to emergence from a standardized general anesthetic with isoflurane. The inventors then assessed two possible mechanisms by which methylphenidate may act: (1) increased arousal, or (2) increased minute ventilation. To test for increased arousal, the inventors performed experiments to assess whether methylphenidate induces restoration of righting under continuous isoflurane anesthesia. The inventors also performed spectral analysis of electroencephalogram recordings to assess changes induced by methylphenidate during continuous isoflurane anesthesia. To test for increased minute ventilation, the inventors obtained plethysmography and arterial blood gas data to analyze changes in respiratory status induced by methylphenidate.

[0226]Thus, one aspect of the present invention is based on the inventors discovery that in a...

example 2

[0229]Methylphenidate Hastens Time to Emergence from a Standardized Isoflurane Anesthetic.

[0230]FIG. 1A provides a schematic of the protocol for this experiment. As shown in FIG. 1B, the median time to emergence for animals that received normal saline was 280 seconds (n=12), versus 91 seconds (n=12) for animals that received methylphenidate (5 mg / kg IV). The median difference in time to emergence between these two groups was 200 seconds with a 95% confidence interval computed using the Mann-Whitney test of [155, 331] seconds. This median difference was statistically significant (p<0.0001, two-sided Mann-Whitney test). The % recovery of consciousness in rats of was faster for D-MGH than L-MPH, as shown in FIG. 7.

[0231]Methylphenidate Induces Emergence During Continuous Inhalation of Isoflurane

[0232]To assess if methylphenidate increases arousal, the inventors performed the following experiments during continuous inhalation of isoflurane. Because isoflurane was not discontinued, any e...

example 3

[0233]Droperidol Inhibits Methylphenidate-Induced Emergence Behavior

[0234]In a group of animals (n=6) continuously inhaling isoflurane at a dose sufficient to maintain loss of righting as above, the protocol illustrated in FIG. 2A was repeated with the exception that droperidol (0.5 mg / kg IV) was administered in place of normal saline. None of the animals exhibited purposeful movement in response to the administration of droperidol or subsequent removal of the temperature probe. Five minutes after droperidol, the highest dose of methylphenidate used in this study (5 mg / kg) was administered. These animals generally exhibited no purposeful movement after methylphenidate administration, although some sluggish limb movements were occasionally observed. None of these animals had return of righting, compared to the 11 of 12 animals that had return of righting after receiving normal saline prior to the same dose of methylphenidate (FIG. 2D). The 95% Bayesian confidence interval for the dif...

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Abstract

The present invention generally relates to compositions comprising anesthesia-reversing agents which facilitate or increase the time of awakening or reverse the effects of general anesthesia-induced unconsciousness. In some embodiments, the anesthesia reversing agent can be selected from any or a combination of methylphenidate (MPH), amphetamine, modafinil, amantadine, caffeine, or analogues or derivatives thereof. In some embodiments, compositions comprising at least one or more anesthesia-reversing agents can be used to facilitate awakening from anesthesia without or decreasing occurrence of delirium, and can be used in methods to treat or prevent the symptoms associated with emergence delirium, as well as treat a subject oversedated with general an esthesia. The invention also relates to methods for administering these compositions comprising anesthesia-reversing agents to subjects and for use.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority under 35 U.S.C. 119(e) of U.S. Provisional Patent Application Ser. No. 61 / 378,977 filed on Sep. 1, 2010, and U.S. Provisional Patent Application Ser. No. 61 / 483,475 filed on May 6, 2011, the contents of each are incorporated herein by reference in their entirety.GOVERNMENT SUPPORT[0002]The present application was made with Government Support under Grant No: DP1-OD003646, K08-GM094394 and K08-GM083216 awarded by the National Institutes of Health (NIH). The Government of the United States has certain rights thereto.FIELD OF THE INVENTION[0003]The present invention relates to a method and compositions for rapidly reversing general anesthesia, and facilitates awakening of a subject from general anesthesia. In particular, the present invention relates to a method and compositions for facilitating emergence or awakening from perioperative anesthesia, and a method for controlling and facilitating anesthesia accor...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4458
CPCA61K9/0019A61K31/13A61K31/137A61K45/06A61K31/4458A61K31/522A61K31/165A61P23/00A61B5/37A61B5/374A61B5/4821
Inventor BROWN, EMERY NEALSOLT, KENCOTTEN, JOSEPH F.CHEMALI, JESSICA J.DEBROS, FREDERICK M.
Owner THE GENERAL HOSPITAL CORP
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