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1 Investigations of kinetic interactions between lipid emulsions, hydroxyethyl starch or dextran and organophosphorus compounds J. VON DER WELLEN, F. WOREK, H. THIERMANN & T. WILLE Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany Context Numerous studies demonstrated a limited efficacy of clinically used oximes in case of poisoning by various organophosphorus compounds. A broad spectrum oxime antidote covering all organophosphorus nerve agents and pesticides is still missing and effective (bio-) scavengers have not yet been marketed. Objective. The interactions of the available and clinically approved hydroxyethyl starch, dextran and lipid emulsions with organophosphorus nerve agents and pesticides were investigated in order to provide an in vitro base for the evaluation of these compounds in human organophosphorus poisoning. Materials and methods. The degradation kinetics of organophosphorus compounds by the glucose derivatives and lipid emulsions were investigated with an acetylcholinesterase inhibition assay. Results. The incubation of organophosphorus compounds with TRIS-Ca 2 buffer resulted in a time-dependent degradation of the nerve agents with half-lives of 42 min for cyclosarin, 49 min for sarin, 99 min for tabun, 107 min for soman 19 h for malaoxon and 54 h for VX. In contrast, incubation with all tested compounds resulted in a stabilisation of the organophosphorus compounds. Discussion. Our results suggest that binding of lipophilic organophosphorus compounds could result in a reduced spontaneous and enzyme-induced degradation of the toxic compounds. Conclusion. High dose lipid emulsions and glucose derivatives stabilised organophosphorus compounds in vitro. Keywords Lipid emulsion; In vitro kinetic; Organophosphorus compound Introduction The high human toxicity of organophosphorus compounds (OP) developed for use as OP pesticides with the appalling number of approximately 300 000 fatal human poisonings mainly from self-harm per year pose a major problem in the public healthcare sector particularly in developing coun- tries. 1 Furthermore, the remaining stockpiles 2 as well as the easy synthesis of highly toxic chemical warfare nerve agents 3,4 remain a threat for the civilian population and mili- tary personnel thus calling for the development of effective medical countermeasures. OP pesticides and nerve agents exert their acute toxic effect primarily via covalent binding and thus inhibition of the vitally important enzyme ace- tylcholinesterase (AChE) resulting in a culmination of the neurotransmitter acetylcholine at cholinergic synapses. 4–6 If untreated – the paralysis of the respiratory muscles in connection with the strong secretion in the respiratory tract leads finally to respiratory arrest and death. 7–9 Therefore, a prompt administration of capable antidotes is a question of vital importance. 10 In general, the therapy is based on the administration of muscarinic receptor antagonists (atro- pine) to antagonize effects of superelevated acetylcholine at affected organs and the application of reactivators (oximes) to restore AChE function. At present, oxime-based AChE reactivators are the only causal therapy removing the OP moiety from the enzyme and thereby restoring the enzyme’s physiological function. However, numerous in vitro and in vivo studies demonstrated a limited efficacy of the clini- cally used oximes, obidoxime and pralidoxime, in case of poisoning by various OP nerve agents and pesticides. A broad spectrum oxime antidote covering all OP nerve agents and pesticides is still missing. 11,12 Stoichiometric and catalytic (bio-)scavengers are under development but have not yet been marketed. 13,14 Studies showed an inactivation of nerve agents by glucose derived cyclodextrins most probably via inclusion followed by a bimolecular nucleophilic substitution reaction at the OP phosphorus atom. 15,16 For the clinical physician glucose derivatives are available as hydroxyethylstarch (HES, α-1,4 glycosidic linkages for chain and α-1,6 for arborisation) and dextran ( α-1,6 glycosidic linkages for chain and α-1,3 for arbori- sation) known as volume expanders in emergency medicine. Another approach in clinical toxicology is the use of lipid emulsions which are believed to absorb and incorporate lipo- philic compounds (e.g. antidepressants and local anaesthetics) removing them from their primary site of toxicity. 17–19 Most Clinical Toxicology (2013), Early Online: 1–5 Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2013.857025 ORIGINAL ARTICLE Received 13 August 2013; accepted 14 October 2013. Address correspondence to Timo Wille, Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. Tel: 49-89-3168-2305. Fax: 49-89-3168-2333. E-mail: [email protected] Clinical Toxicology Downloaded from informahealthcare.com by Memorial University of Newfoundland on 11/12/13 For personal use only.

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Page 1: Investigations of kinetic interactions between lipid emulsions, hydroxyethyl starch or dextran and organophosphorus compounds

1

Investigations of kinetic interactions between lipid emulsions,

hydroxyethyl starch or dextran and organophosphorus

compounds

J. VON DER WELLEN , F. WOREK , H. THIERMANN & T. WILLE

Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany

Context Numerous studies demonstrated a limited effi cacy of clinically used oximes in case of poisoning by various organophosphorus compounds. A broad spectrum oxime antidote covering all organophosphorus nerve agents and pesticides is still missing and effective (bio-)scavengers have not yet been marketed. Objective . The interactions of the available and clinically approved hydroxyethyl starch, dextran and lipid emulsions with organophosphorus nerve agents and pesticides were investigated in order to provide an in vitro base for the evaluation of these compounds in human organophosphorus poisoning. Materials and methods. The degradation kinetics of organophosphorus compounds by the glucose derivatives and lipid emulsions were investigated with an acetylcholinesterase inhibition assay. Results . The incubation of organophosphorus compounds with TRIS-Ca 2 � buffer resulted in a time-dependent degradation of the nerve agents with half-lives of 42 min for cyclosarin, 49 min for sarin, 99 min for tabun, 107 min for soman 19 h for malaoxon and 54 h for VX. In contrast, incubation with all tested compounds resulted in a stabilisation of the organophosphorus compounds. Discussion. Our results suggest that binding of lipophilic organophosphorus compounds could result in a reduced spontaneous and enzyme-induced degradation of the toxic compounds. Conclusion . High dose lipid emulsions and glucose derivatives stabilised organophosphorus compounds in vitro .

Keywords Lipid emulsion; In vitro kinetic; Organophosphorus compound

Introduction

The high human toxicity of organophosphorus compounds (OP) developed for use as OP pesticides with the appalling number of approximately 300 000 fatal human poisonings mainly from self-harm per year pose a major problem in the public healthcare sector particularly in developing coun-tries. 1 Furthermore, the remaining stockpiles 2 as well as the easy synthesis of highly toxic chemical warfare nerve agents 3,4 remain a threat for the civilian population and mili-tary personnel thus calling for the development of effective medical countermeasures. OP pesticides and nerve agents exert their acute toxic effect primarily via covalent binding and thus inhibition of the vitally important enzyme ace-tylcholinesterase (AChE) resulting in a culmination of the neurotransmitter acetylcholine at cholinergic synapses. 4 – 6 If untreated – the paralysis of the respiratory muscles in connection with the strong secretion in the respiratory tract leads fi nally to respiratory arrest and death. 7 – 9 Therefore, a prompt administration of capable antidotes is a question of vital importance. 10 In general, the therapy is based on the

administration of muscarinic receptor antagonists (atro-pine) to antagonize effects of superelevated acetylcholine at affected organs and the application of reactivators (oximes) to restore AChE function. At present, oxime-based AChE reactivators are the only causal therapy removing the OP moiety from the enzyme and thereby restoring the enzyme ’ s physiological function. However, numerous in vitro and in vivo studies demonstrated a limited effi cacy of the clini-cally used oximes, obidoxime and pralidoxime, in case of poisoning by various OP nerve agents and pesticides. A broad spectrum oxime antidote covering all OP nerve agents and pesticides is still missing. 11,12 Stoichiometric and catalytic (bio-)scavengers are under development but have not yet been marketed. 13,14

Studies showed an inactivation of nerve agents by glucose derived cyclodextrins most probably via inclusion followed by a bimolecular nucleophilic substitution reaction at the OP phosphorus atom. 15,16 For the clinical physician glucose derivatives are available as hydroxyethylstarch (HES, α -1,4 glycosidic linkages for chain and α -1,6 for arborisation) and dextran ( α -1,6 glycosidic linkages for chain and α -1,3 for arbori-sation) known as volume expanders in emergency medicine.

Another approach in clinical toxicology is the use of lipid emulsions which are believed to absorb and incorporate lipo-philic compounds (e.g. antidepressants and local anaesthetics) removing them from their primary site of toxicity. 17 – 19 Most

Clinical Toxicology (2013), Early Online: 1–5

Copyright © 2013 Informa Healthcare USA, Inc.

ISSN: 1556-3650 print / 1556-9519 online

DOI: 10.3109/15563650.2013.857025

ORIGINAL ARTICLE

Received 13 August 2013 ; accepted 14 October 2013 .

Address correspondence to Timo Wille, Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. Tel: � 49-89-3168-2305. Fax: � 49-89-3168-2333. E-mail: [email protected]

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Page 2: Investigations of kinetic interactions between lipid emulsions, hydroxyethyl starch or dextran and organophosphorus compounds

Clinical Toxicology Early Online 2013

2 J. v. d. Wellen et al.

OP are lipophilic compounds too and consequently lipid emulsions have been tested in two rodent pesticide poisoning studies with contradictory results. 20,21

We investigated interactions of the available and clinically approved therapeutics HES, dextran and lipid emulsions with OP nerve agents and pesticides in order to provide an in vitro base for the evaluation of the effect of these clinically established therapeutic agents in human OP poisoning.

Materials and methods

Materials

5,5 ′ -Dithiobis(2-nitrobenzoic acid) (DTNB) and acetylth-iocholine iodide (ATCh) were supplied by Sigma-Aldrich (Taufkirchen, Gemany). Tabun (GA), sarin (GB), soman (GD), cyclosarin (GF) and VX were made available by the German Ministry of Defence. Paraoxon-ethyl (PXE) and malaoxon were purchased from Dr. Ehrenstorfer (Augs-burg, Germany). As lipid emulsions Lipofundin MCT 20%, Lipofundin 20% N and Lipofundin 10% N (Braun, Melsun-gen, Germany) were tested. The glucose derivatives hydroxy-ethyl starch (HAES and HyperHAES, Fresenius Kabi, Bad Homburg, Germany) and dextran with a molecular weight of 40 000, 70 000 (AppliChem, Darmstadt, Germany) and 200 000 (Sigma-Aldrich, Taufkirchen, Germany) all 10% in distilled water were examined. All other chemicals were from Merck (Darmstadt, Germany).

Nerve agent and pesticide dilutions

Nerve agent (0.1% in acetonitrile) and pesticide (1% in acetonitrile) stock solutions were stored at ambient tempera-ture and working solutions were prepared in distilled water just before the experiment. All solutions were kept on ice until use.

Human erythrocyte ghosts

Freshly drawn heparinized human whole blood was centri-fuged at 3000 rpm for 10 min. Plasma was removed and the red blood cells were washed three times with an approxi-mately three-fold volume of phosphate buffer (0.1 M, pH 7.4). Then, haemoglobin-free human erythrocyte ghosts were prepared as AChE source and stored at � 80 ° C. 15

AChE assay

AChE activities were measured spectrophotometrically at 412 nm for 5 min (Shimadzu UV 2600, Duisburg, Germany) with a modifi ed Ellman assay using pre-warmed (37 ° C) polystyrol cuvettes containing 100 μ l (0.3 mM) DTNB as chromogen in 3000 μ l of phosphate buffer (0.1 M, pH 7.4). 22 Finally 50 μ l ATCh (0.45 mM) were added as substrate. All experiments were performed at 37 ° C. All concentrations refer to fi nal concentrations.

Degradation kinetics of nerve agents

The degradation kinetics of nerve agents by the glucose derivatives and lipid emulsions were investigated with an

AChE inhibition assay. 600 μ l of glucose derivative or lipid emulsion were mixed with nerve agent resulting in fi nal con-centrations of 150 μ M (GA), 100 μ M (GB), 20 μ M (GD), 5 μ M (GF) and 20 μ M (VX) and were incubated at 37 ° C. In case of the G-type nerve agents seven samples were taken over a period of 6 h, VX samples every 24 h over 5 days. 5 μ l samples were added to a pre-warmed (37 ° C) poly-styrol cuvette that previously had been fi lled with 3000 μ l phosphate buffer (0.1 M; pH 7.4), 100 μ l DTNB (0.3 mM fi nal concentration) and 10 μ l AChE. Finally, 50 μ l ATCh (0.45 mM fi nal concentration) was added as substrate for the AChE and the enzyme activity was measured spectrophoto-metrically. Spontaneous hydrolysis of the nerve agents was assessed in 600 μ l TRIS-buffer (0.1 M) supplemented with CaCl 2 (1 mM) as a reference for the degradation potency of the investigated compounds.

Calculations of the degradation kinetics of G-type nerve agents and VX

The recorded AChE inhibition curves were analysed by non-linear regression analysis to determine the fi rst-order inhibi-tion rate constant k 1 (see Fig. 1A using GD as example, for original registration). 23 Then, k 1 was plotted against time. With previously determined inhibition standard curves it was possible to calculate the respective nerve agent con-centrations in the incubate (see Fig. 1B with calculated GD concentrations as example).

Degradation kinetics of pesticides

Due to the lower toxicity of the pesticides paraoxon-ethyl and malaoxon compared to the nerve agents a different method was used. 500 μ l of distilled water was mixed with pesticides resulting in defi ned fi nal concentrations of 125 – 1000 nM for paraoxon-ethyl and of 250 – 4250 nM malaoxon. Then 2 μ l of this mixture was transferred into a tube containing 50 μ l human erythrocyte ghosts. After 20 min of incubation at 37 ° C a 10 μ l sample was taken into a pre-warmed polystyrol cuvette and the AChE activity was measured spectrophoto-metrically and referred to control AChE resulting in a linear relationship for paraoxon-ethyl (Fig. 2A). For malaoxon, however, a non-linear curve was recorded.

500 μ l of the lipid emulsions or glucose derivatives (or TRIS-Ca 2 � -buffer as control) were mixed with pesticide resulting in fi nal concentrations of 750 nM PXE and 1875 nM malaoxon. At defi ned time points (0, 24, 48 and 72 h) 2 μ l samples were incubated with 50 μ l human erythrocyte ghosts. After exactly 20 min of incubation (37 ° C) 10 μ l samples were taken to a pre-warmed cuvette and the AChE activity was measured for 5 min. AChE activity was referred to control AChE.

Data analysis

The analysis of the data and the calculation of the kinetic constants were performed with GraphPad Prism 5.0 (GraphPad, San Diego, USA). All experiments were carried out in duplicate.

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Page 3: Investigations of kinetic interactions between lipid emulsions, hydroxyethyl starch or dextran and organophosphorus compounds

Copyright © Informa Healthcare USA, Inc. 2013

Lipid emulsions, HES, dextran and OP 3

Fig. 1. (A). Time dependent degradation of GD by spontaneous degradation. Original registration of degradation kinetics of 20 μ M GD by spontaneous hydrolysis in TRIS-Ca 2 � -buffer after 2 – 360 min. Data show a rapid decrease in inhibition of samples from the incubate resulting in a higher enzyme activity and thus higher absorption. (B). Degradation of GD. Spontaneous hydrolysis in TRIS-Ca 2 � -buffer ( � ) and degradation of GD in Lipofundin 10% ( · ), HyperHAES ( � ) and dextran 200 000 ( � ). Data are means of two replicates � SD.

Fig. 2 . (A). Calibration curve for paraoxon-ethyl. Human erythrocyte ghosts were incubated with paraoxon-ethyl (125 – 1000 nM). After 20 min residual activity was determined. The experiment was performed in duplicate. Error bars were smaller than used symbols. Concentrations in the samples with the test compounds were derived from this curve via linear regression. (B). Degradation of PXE. Spontaneous hydrolysis in TRIS-Ca 2 � -buffer ( � ) and degradation of GA in Lipofundin 10% ( · ), HyperHAES (� ) and dextran 200 000 ( � ). Data did not reveal a net degradation by all tested compounds. Spontaneous hydrolysis was not detectable. Data are means of two replicates � SD. Results

Nerve agents

The incubation of nerve agents with TRIS-Ca 2 � buffer resulted in a time-dependent degradation of all nerve agents. The reaction could be best described by a one-phase mono-exponential equation and resulted in half-lives of 42 � 2 min for GF, 49 � 1 min for GB, 99 � 1 min for GA, 107 � 2 min for GD and 53 � 2 h for VX. In contrast, incubation of nerve agents with most of the test compounds resulted in a stabi-lisation of the OP (cf. Fig. 1B for GD). The only exception was GA leading to a mono-exponential degradation in the presence of test compounds (Fig. 3). There were no marked differences in between the groups of the tested lipid emul-sions, HESs and dextrans detectable (data not shown).

Pesticides

Malaoxon was stabilised by the test compounds and no degradation was detectable compared to spontaneous hydrolysis in TRIS-Ca 2 � buffer with a half-live of 19 � 1 h. Paraoxon-ethyl showed neither spontaneous hydrolysis in TRIS-buffer nor in combination with test compounds during 72 h (Fig. 2B).

Discussion

The in vitro investigation of the degradation of OP by clini-cally used glucose derivatives and lipid emulsions demon-strated a negligible effect on degradation of nerve agents and pesticides, which is in the line with data of animal studies showing only small effects of a lipid emulsion. 20,21 Quite the contrary the investigated compounds caused a potent stabili-sation of OP compared to spontaneous hydrolysis in TRIS-buffer (Fig. 1B) and the hypothesis that lipid emulsions and glucose derivatives might have a benefi cial effect on OP degradation could not be verifi ed in this in vitro model.

Glucose derivatives have been described to bind nerve agents 24,25 and similar to the clinically used sugammadex for antagonizing rocuronium in general anaesthesia, 26 it was tested whether dextrans or HES bind OP. However, interac-tions between glucose derivatives and OP are weak. 25 The binding of OP to glucose derivatives might protect from spontaneous hydrolysis during incubation and result in lib-eration of intact OP during massive dilution in the cuvette explaining the stabilisation.

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Clinical Toxicology Early Online 2013

4 J. v. d. Wellen et al.

Fig. 3. Degradation of GA. Spontaneous hydrolysis in TRIS-Ca 2 � -buffer ( � ) and degradation of GA in Lipofundin 10% ( · ), HyperHAES ( � ) and dextran 200 000 ( � ). Data are means of two replicates � SD.

Although the specifi c mechanism of lipid emulsions in the treatment of poisonings is unknown, it is likely that lipid emulsions act as a ‘ ‘ lipid sink ’ ’ absorbing and incorporat-ing lipophilic drugs and separating them from the primary site of toxicity. 18,19,27 Promising results showed benefi ts in treatment of acute poisoning with local anaesthetics, calcium antagonists, tricyclic antidepressants and beta-blockers. As many OP pesticides and nerve agents are lipo-philic, lipid emulsions might represent a new approach for OP poisoning. 28 In two rodent studies with parathion and paraoxon poisoning administration of lipid emulsion did not protect the animals. 20,21 In the parathion study a prolonged time to apnoea was recorded and the authors hypothesized a delayed metabolisation of parathion into its active form paraoxon by absorption of parathion to lipid emulsion. If this mechanism is considered as relevant for a protective effect of lipid emulsions, the benefi cial effect would only be transient since OP absorbed to lipids would be released over time and would induce delayed toxicity. In addition, binding of lipophilic OP to lipid emulsion could result in a reduced spontaneous and enzyme-induced degradation of the toxic compounds. In the end, these mechanisms could result in a delayed but continuous release of lipophilic agents into the systemic circulation and fi nally into target tissues which could explain an increased mortality as was shown in animal studies with the lipid soluble drug amitriptyline. 29,30 Yet, this delayed onset toxicity might also allow an administration of effective medical countermeasures . A s alternate protective mechanisms of lipid emulsions, an improved contractility of the myocardium in vivo has been described by an increase of intracellular fatty acids with subsequent improved ATP synthesis, 31 a direct inotropic effect 32 or the activation of ventricular calcium channels. 33

The experimental setup of the present in vitro study required the incubation of rather high OP and test compound concentrations which were most likely substantially higher than in an in vivo situation. However, the current studies give no evidence for a benefi cial effect of hydroxyethyl starch, dextran and lipid emulsions. 20,21 The therapeutic effect of

lipid emulsions, the safety and a possible interaction with OP antidotes, atropine and oximes, need to be investigated in further in vitro and in vivo studies.

In conclusion, high dose lipid emulsions and glucose derivatives stabilised OP nerve agents and pesticides in vitro .

Declaration of interest

The authors report no declarations of interest. The study was funded by the German Ministry of Defence.

The design, performance, data interpretation and manuscript writing was under the control of the authors and has not been infl uenced by the German Ministry of Defence.

References

Gunnell D , Eddleston M , Phillips MR , Konradsen F . The global 1. distribution of fatal pesticide self-poisoning: systematic review . BMC Public Health 2007 ; 7 : 357 . Marrs TC . Toxicology of organophosphate nerve agents . In: 2. Marrs TC , Maynard RL , Sidell FR , eds. Chemical Warfare Agents: Toxicology and Treatment . Chichester, West Sussex: John Wiley & Sons Ltd. ; 2007 : 191 – 221 . Bryant PJR , Ford-Moore AH , Perry BJ , Wardrop AWH , Watkins TF . 3. The preparation and physical properties of isopropyl methylphospho-nofl uoridate (Sarin). J Chem Soc 1960 : 1553 – 1555 . Holmstedt B . Pharmacology of organophosphorus cholinesterase in-4. hibitors . Pharmacol Rev 1959 ; 11 : 567 – 688 . Aldridge WN , Reiner E . Enzyme Inhibitors as Substrates – Interac-5. tions of Esterases with Esters of Organophosphorus and Carbamic Acids . Amsterdam: North-Holland Publishing Company; 1972 . Taylor P , Radic Z , Hosea NA , Camp S , Marchot P , Berman HA . Struc-6. tural bases for the specifi city of cholinesterase catalysis and inhibi-tion . Toxicol Lett 1995 ; 82 – 83 : 453 – 458 . Grob D . The manifestations and treatment of poisoning due to nerve 7. gas and other organic phosphate anticholinesterase compounds . AMA Arch Intern Med 1956 ; 98 : 221 – 239 . Kwong TC . Organophosphate pesticides: biochemistry and clinical 8. toxicology . Ther Drug Monit 2002 ; 24 : 144 – 149 . Lee EC . Clinical manifestations of sarin nerve gas exposure . JAMA 9. 2003 ; 290 : 659 – 662 . Eyer F , Worek F , Eyer P , Felgenhauer N , Haberkorn M , Zilker T , 10. Thiermann H . Obidoxime in acute organophosphate poisoning. 1: clinical effectiveness . Clin Toxicol 2009 ; 47 : 798 – 806 . Jokanovic M , Prostran M . Pyridinium oximes as cholinesterase reacti-11. vators . Structure-activity relationship and effi cacy in the treatment of poisoning with organophosphorus compounds. Curr Med Chem 2009 ; 16 : 2177 – 2188 . Worek F , Thiermann H . The value of novel oximes for treatment of 12. poisoning by organophosphorus compounds . Pharmacol Ther 2013 ; 139 : 249 – 259 . Masson P , Rochu D . Catalytic bioscavengers: the next generation of 13. bioscavenger-based medical countermeasures . In: Gupta R , ed. Hand-book of Toxicology of Chemical Warfare Agents . London: Academic Press; 2009 : 1053 – 1065 . Nachon F , Brazzolotto X , Trovaslet M , Masson P . Progress in the de-14. velopment of enzyme-based nerve agent bioscavengers . Chem Biol Interact 2013 ; doi: 10.1016/j.cbi.2013.06.012. Wille T , Tenberken O , Reiter G , M ü ller S , Le Provost R , 15. Lafont O , et al . Detoxifi cation of nerve agents by a substituted beta-cyclodextrin: application of a modifi ed biological assay . Toxicology 2009 ; 265 : 96 – 100 . van Hooidonk C , Breebaart-Hansen JC . Stereospecifi c reaction of iso-16. propyl methyl-phosphonofl uoridate (sarin) with alpha-cyclodextrin . Recueil 1970 ; 89 : 289 – 299 .

Clin

ical

Tox

icol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and

on 1

1/12

/13

For

pers

onal

use

onl

y.

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Lipid emulsions, HES, dextran and OP 5

Jamaty C , Bailey B , Larocque A , Notebaert E , Sanogo K , Chauny 17. JM . Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies . Clin Toxicol 2010 ; 48 : 1 – 27 . Ozcan MS , Weinberg G . Intravenous lipid emulsion for the 18. treatment of drug toxicity. J Intensive Care Med 2012; doi: 10.1177/0885066612445978 . Turner-Lawrence DE , Kerns W . Intravenous fat emulsion: a potential 19. novel antidote . J Med Toxicol 2008 ; 4 : 109 – 114 . Bania TC , Chu J , Stolbach A . The effect of intralipid on organophos-20. phate toxicity in mice . Acad Emerg Med 2005 ; 12 : 12 . Dunn C , Bird SB , Gaspari R . Intralipid fat emulsion decreases respi-21. ratory failure in a rat model of parathion exposure . Acad Emerg Med 2012 ; 19 : 504 – 509 . Worek F , Mast U , Kiderlen D , Diepold C , Eyer P . Improved deter-22. mination of acetylcholinesterase activity in human whole blood . Clin Chim Acta 1999 ; 288 : 73 – 90 . Aurbek N , Thiermann H , Szinicz L , Eyer P , Worek F . Analysis of inhi-23. bition, reactivation and aging kinetics of highly toxic organophospho-rus compounds with human and pig acetylcholinesterase . Toxicology 2006 ; 224 : 91 – 99 . M ü ller S , Koller M , Le Provost R , Lafont O , Estour F , Wille T , et al . 24. In vitro detoxifi cation of cyclosarin (GF) by modifi ed cyclodextrins . Toxicol Lett 2011 ; 200 : 53 – 58 . Estour F , Letort S , M ü ller S , Kalakuntla RK , Le Provost R , Wille T , 25. et al . Functionalized cyclodextrins bearing an alpha nucleophile - a promising way to degrade nerve agents . Chem Biol Interact 2013 ; 203 : 202 – 207 . Adam JM , Bennett DJ , Bom A , Clark JK , Feilden H , Hutchinson EJ , 26. et al . Cyclodextrin-derived host molecules as reversal agents for the

neuromuscular blocker rocuronium bromide: synthesis and structure-

activity relationships . J Med Chem 2002 ; 45 : 1806 – 1816 .

Cave G , Harvey M . Intravenous lipid emulsion as antidote beyond 27.

local anesthetic toxicity: a systematic review . Acad Emerg Med 2009 ;

16 : 815 – 824 .

Zhou Y , Zhan C , Li Y , Zhong Q , Pan H , Yang G . Intravenous lipid 28.

emulsions combine extracorporeal blood purifi cation: a novel thera-

peutic strategy for severe organophosphate poisoning . Med Hypoth-

eses 2010 ; 74 : 309 – 311 .

Perichon D , Turfus S , Gerostamoulos D , Graudins A . An assessment 29.

of the in vivo effects of intravenous lipid emulsion on blood drug con-

centration and haemodynamics following oro-gastric amitriptyline

overdose . Clin Toxicol (Phila) 2013 ; 51 : 208 – 215 .

Litonius E , Niiya T , Neuvonen PJ , Rosenberg PH . No antidotal effect 30.

of intravenous lipid emulsion in experimental amitriptyline intoxica-

tion despite signifi cant entrapment of amitriptyline . Basic Clin Phar-

macol Toxicol 2012 ; 110 : 378 – 383 .

Van de Velde M , Wouters PF , Rolf N , Van Aken H , Flameng W , 31.

Vandermeersch E . Long-chain triglycerides improve recovery from

myocardial stunning in conscious dogs . Cardiovasc Res 1996 ;

32 : 1008 – 1015 .

Stehr SN , Ziegeler JC , Pexa A , Oertel R , Deussen A , Koch T , 32.

H ü bler M . The effects of lipid infusion on myocardial function and

bioenergetics in l-bupivacaine toxicity in the isolated rat heart . Anesth

Analg 2007 ; 104 : 186 – 192 .

Huang JM , Xian H , Bacaner M . Long-chain fatty acids activate calci-33.

um channels in ventricular myocytes . Proc Natl Acad Sci USA 1992 ;

89 : 6452 – 6456 .

Clin

ical

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oria

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onal

use

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