Correlation of general anesthetic potency with solubility in membranes

Janoff, Andrew S.; Pringle, Michael J.; Miller, Keith W.

doi:10.1016/0005-2736(81)90017-1

Cited by 148 publications

(76 citation statements)

References 20 publications

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“…Several theories have been postulated as to why this cutoff 10 McIntyre C 12 McIntyre McIntyre or Stepan C 14 Stepan C 16 McIntyre Stepan C 18 Stepan C 18 (12,20) have associated this cutoff with a limit in solubility. They proposed that as the alkyl chain increases, lipid solubility increases at a rate faster than the change in partition coefficient (lipid/aqueous).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Evaluation of N -Alkyl Betaines and N -Alkyl- N , N -Dimethylamine Oxides with Variations in Chain Length

Birnie

Malamud

Schnaare

2000

Antimicrob Agents Chemother

144

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Alkyl betaines and alkyl dimethylamine oxides have been shown to have pronounced antimicrobial activity when used individually or in combination. Although several studies have been conducted with these compounds in combinations, only equimolar concentrations of the C 12 /C 12 and C 16 /C 14 chain lengths for the betaine and the amine oxide, respectively, have been investigated. This study investigates the antimicrobial activity of a wide range of chain lengths (C 8 to C 18 ) for both the betaine and amine oxide and attempts to correlate their micelle-forming capabilities with their biological activity. A broth microdilution method was used to determine the MICs of these compounds singly and in various molar ratio combinations. Activity against both Staphylococcus aureus and Escherichia coli was investigated. Antimicrobial activity was found to increase with increasing chain length for both homologous series up to a point, exhibiting a cutoff effect at chain lengths of approximately 16 for betaine and 14 for amine oxide. Additionally, the C 18 oleyl derivative of both compounds exhibited activity in the same range as the peak alkyl compounds. Critical micelle concentrations were correlated with MICs, inferring that micellar activity may contribute to the cutoff effect in biological activity.As more resistant organisms continue to emerge in society, the identification of additional antimicrobial agents becomes increasingly more important. Compounds such as surfactants are an area to be investigated. Betaines and amine oxides, two types of amphoteric surfactants, have been shown to exhibit antimicrobial activity against a variety of microorganisms (7,16,18,25). Although each of these compounds has shown pronounced activity alone, they have also been used in combination to exhibit a synergistic effect (6).An equimolar mixture of N-alkyl betaine and N-alkyl-N,Ndimethylamine oxide was patented in 1978 in a compound called C31G (17). With chain lengths ranging from C 8 to C 18 and buffered in a citrate buffer, C31G was first shown to have pronounced wound healing and deodorizing effects, as well as antimicrobial sensitivity. Further studies showed C31G has exhibited pronounced activity not only against bacteria, but also against yeasts, fungi, sperm, and enveloped viruses (4,6,14,23). Although several studies have been published about this compound in reference to the extent of antimicrobial activity, little work has been conducted with any other chain lengths besides the following two chain-length combinations: (i) C 12 betaine-C 12 amine oxide and (ii) C 16 betaine-C 14 amine oxide. Additionally, only an equimolar ratio of the two components has been investigated.The structures of these two components are shown in Fig. 1. The variation in length of the long hydrocarbon tail is thought to influence the extent of antimicrobial activity. Like most other surfactants, they are believed to be membrane perturbants, disrupting the cell membrane of the microorganism (26). It is believed that interaction with the surface of th...

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Section: Discussionmentioning

confidence: 99%

Antimicrobial Evaluation of N -Alkyl Betaines and N -Alkyl- N , N -Dimethylamine Oxides with Variations in Chain Length

Birnie

Malamud

Schnaare

2000

Antimicrob Agents Chemother

144

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“…In this classical work, he demonstrates the correlation between anesthetic effect and lipid solubility, measured as distribution coefficient in water-alcohol. Over the years, however, the Overton lipid theory lost ground to theories assuming proteins as the critical target (but for modern lipid theories see Janoff et al, 1981;Ries and Puil, 1999a, b). Today, protein theories focus on ion channels (Franks and Lieb, 1994).…”

Section: Microscopic Effectsfmodulating Activity Of Critical Ion Chanmentioning

confidence: 99%

Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling

Århem

Klement

Nilsson

2003

Neuropsychopharmacol

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The mechanisms of anesthesia are surprisingly little understood. The present article summarizes current knowledge about the function of general anesthetics at different organization levels of the nervous system. It argues that a consensus view can be constructed, assuming that general anesthetics modulate the activity of ion channels, the main targets being GABA and NMDA channels and possibly voltagegated and background channels, thereby hyperpolarizing neurons in thalamocortical loops, which lead to disruption of coherent oscillatory activity in the cortex. Two computational cases are used to illustrate the possible importance of molecular level effects on cellular level activity. Subtle differences in the mechanism of ion channel block can be shown to cause considerable differences in the modification of the oscillatory activity in a single neuron, and consequently in an associated network. Finally, the relation between the anesthesia problem and the classical consciousness problem is discussed, and some consequences of introducing the phenomenon of degeneracy into the picture are pointed out.

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“…The experimental observation that the potency of an anesthetic correlates with its partition coefficient between olive oil and water has led to the working hypothesis that all general anesthetics cause a common structural alteration in excitable membranes (1). One school of thought suggests that all anesthetics interact with neuronal membrane lipids, resulting in a common biophysical alteration of the lipid bilayer (2). Such alterations in the physical state of the bilayer are theorized either to directly alter membrane function, or to secondarily alter membrane protein structure and function (3,4).…”

Section: Introductionmentioning

confidence: 99%

Manipulation of rat brain fatty acid composition alters volatile anesthetic potency.

Evers¹,

Elliott²,

Lefkowith³

et al. 1986

J. Clin. Invest.

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The molecular mechanism of volatile anesthetic action remains unknown. Attempts to elucidate this mechanism have been complicated by the absence of models in which changes in neuronal cellular properties can be correlated with changes in whole animal anesthetic effect. In this study we describe a model where dietinduced alterations in rat brain fatty acid composition are correlated with alterations in volatile anesthetic potency. Rats maintained on a fat-free diet showed significant depletion of arachidonic acid (20:4&6; 5,8,11,14-eicosatetraenoic acid) and docosahexaenoic acid (22:6w3; 4,7,10,13,16,19,-docosahexaenoic acid) in brain, and a corresponding increase in Mead acid (20: 3w9; 5,8,11-eicosatrienoic acid). These fat-deprived rats were significantly more sensitive to all volatile anesthetics tested than were age-controlled rats on a normal diet. Parenteral supplementation of the fat-deprived animals with linolenic acid (18: 303, 9,12,15-octadecatrienoic acid) completely reconstituted the docosahexaenoic acid content of brain without affecting anesthetic sensitivity. In contrast, supplementation of the fat-deprived rats with linoleic acid (18:2w6; 9,12-octadecadienoic acid) caused a dramatic decrease in anesthetic sensitivity, but only a small change in whole brain arachidonate content. Further analysis revealed that linoleate supplementation of fat-deprived animals resulted in a preferential noraiztion of the arachidonate content of brain phosphatidylinositol as compared with other brain phosphoglycerides. These results demonstrate for the first time a correlation between changes in membrane composition and anesthetic effect, and indicate that the precise fatty acid composition (perhaps in specific phospholipids) of brain is important in the mechanism of volatile anesthetic action.

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Correlation of general anesthetic potency with solubility in membranes

Cited by 148 publications

References 20 publications

Antimicrobial Evaluation of N -Alkyl Betaines and N -Alkyl- N , N -Dimethylamine Oxides with Variations in Chain Length

Antimicrobial Evaluation of N -Alkyl Betaines and N -Alkyl- N , N -Dimethylamine Oxides with Variations in Chain Length

Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling

Manipulation of rat brain fatty acid composition alters volatile anesthetic potency.

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