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Methods of inducing anesthesia

Inactive Publication Date: 2014-01-16
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a type of anesthetic or sedative drug that can be injected under the skin using a needle and syringe. These drugs can make people insensitive to pain or reduce their perceived pain. The term "pharmaceutically acceptable" refers to a substance that doesn't interact with the compound used in the drug in a negative way. The term "composition" refers to the mixture of the compound and a substance that makes it easier to give the drug to patients. This patent is important for those who work in the field of anesthesia or sedation.

Problems solved by technology

A highly specific “induced fit” model between protein and ligand, as proposed for enzyme-substrate binding, (Koshland, Proc Natl Acad Sci USA 1958; 44: 98-104) is problematic since it implies the conservation of specific binding sites across non-homologous proteins to compounds (i.e., anesthetics) not found in nature.

Method used

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  • Methods of inducing anesthesia
  • Methods of inducing anesthesia
  • Methods of inducing anesthesia

Examples

Experimental program
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Effect test

example 1

[0385]Hydrocarbon Molar Water Solubility Predicts NMDA Vs. GABAA Receptor Modulation

[0386]Background:

[0387]Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABAA) receptors. Clinical and experimental anesthetics exhibiting receptor family specificity often have low water solubility. We determined that the molar water solubility of a hydrocarbon could be used to predict receptor modulation in vitro.

[0388]Methods:

[0389]GABAA (α1β2γ2s) or NMDA (NR1 / NR2A) receptors were expressed in oocytes and studied using standard two-electrode voltage clamp techniques. Hydrocarbons from 14 different organic functional groups were studied at saturated concentrations, and compounds within each group differed only by the carbon number at the w-position or within a saturated ring. An effect on GABAA or NMDA receptors was defined as a 10% or greater reversible current change from baseline that was statistically different from zero.

[0390]Results:

[0391]Hydrocarbon moiet...

example 2

1,1,2,2,3,3,4-heptafluorocyclopentane (CAS#15290-77-4) Induces Anesthesia

[0422]All known inhalation anesthetics modulate multiple unrelated anesthetic receptors, such as transmembrane-3 (TM3) receptors, transmembrane-4 (TM4) receptors, or both TM3 and TM4 receptors. We tested a series of homologous n-alcohols, n-alkanes, n-alkenes, n-alkynes, n-aldehydes, primary amines, 1-alkylfluorides, dialkyl ethers, alkyl benzenes, esters, haloalkanes, ketones, sulfides, and thiols that differed only by 1 or 2 carbon chain lengths. We studied the effects of these drugs on NMDA receptors (a member of the TM3 superfamily) and GABAA receptors (a member of the TM4 superfamily) at saturating drug concentrations in an oocyte two-electrode voltage clamp model. For GABAA versus NMDA receptors, we found that there is no correlation between specificity and vapor pressure, carbon chain length, or molecular volume. However, there exists a water solubility-specificity cut-off value equal to about 1.1 mM wit...

example 3

1,1,2,2,3,3,4,5-octafluorocyclopentane (CAS#828-35-3) Induces Anesthesia

[0426]1,1,2,2,3,3,4,5-octafluorocyclopentane (CAS#828-35-3) caused a loss of righting reflex in 4 healthy Sprague-Dawley rats at a concentration of 3.3±0.4 (mean±SD) percent of 1 atmosphere. This agent has a faint but pleasant odor and induced anesthesia very rapidly without excitement or coughing. After discontinuing the agent, rats were awake and ambulatory in less than 1 minute. As predicted by its water solubility, 1,1,2,2,3,3,4,5-octafluorocyclopentane potentiates GABAA, glycine, and some inhibitory potassium channels in vitro, but has no effect on NMDA receptors up to a saturating aqueous concentration. Despite a lack of NMDA receptor effects, 1,1,2,2,3,3,4,5-octafluorocyclopentane is able to produce the desired pharmacologic endpoints of unconsciousness and immobility that appears similar to desirable effects produced by conventional agents.

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Abstract

The present invention provides methods for determining the selectivity of an anesthetic for an anesthetic-sensitive receptor by determining the molar water solubility of the anesthetic. The invention further provides methods for modulating the selectivity of an anesthetic for an anesthetic-sensitive receptor by altering or modifying the anesthetic to have higher or lower water solubility. The invention further provides methods of inducing anesthesia in a subject by administering via the respiratory pathways (e.g., via inhalational or pulmonary delivery) an effective amount of an anesthetic compound identified according to the present methods.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 61 / 681,747, filed Aug. 10, 2012, and of U.S. Provisional Patent Application No. 61 / 670,098, filed Jul. 10, 2012, the contents of which are hereby incorporated herein by reference in the entiretySTATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with government support under Grant No. GM092821 awarded by National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention provides methods for determining the selectivity of an anesthetic for an anesthetic-sensitive receptor by determining the molar water solubility of the anesthetic. The invention further provides methods for modulating the selectivity of an anesthetic for an anesthetic-sensitive receptor by altering or modifying the anesthetic to have higher or lower water...

Claims

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Application Information

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IPC IPC(8): A61K31/357A61K31/045A61K31/341A61K31/025A61K31/351
CPCA61K31/357A61K31/025A61K31/351A61K31/341A61K31/045A61P11/00A61P23/00A61P25/20A61P43/00A61K31/34A61K31/015A61K31/02A61D7/04A61M16/01A61K9/007A61K31/08
Inventor BROSNAN, ROBERT J.
Owner RGT UNIV OF CALIFORNIA