Protective Drugs in Acute Large-Dose Exposure to Organophosphates: A Comparison of Metoclopramide and Tiapride with Pralidoxime in Rats

Petroianu, Georg; Al‐Hasan, Muath; Nurulain, Syed M.; Arafat, Kholoud; Sheen, R.; Saleh, Ayman; Schmitt, Andrea

doi:10.1213/01.ane.0000143349.17443.91

Cited by 15 publications

(18 citation statements)

References 21 publications

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“…in the low micromolar range, these compounds increased the paraoxon IC 50 in human AChE less than two-fold (Petroianu et al, 2005a;2003a). Pretreatment of paraoxon poisoned rats (~75% of lethal dose) with MCP and RAN resulted in a slight decrease in mortality, RAN being somewhat more effective than MCP (Petroianu et al, 2005b;2005c). The aim of the present study was to investigate the potential protective effect of MCP and RAN against inhibition of human AChE by the highly potent nerve agent VX.…”

Section: Discussionmentioning

confidence: 94%

“…MCP and RAN were reported to exhibit a limited protective effect against the OP-pesticide paraoxon in vitro with human AChE and in rats in vivo (Petroianu et al, 2005a;2005b;2005c;2003b;2003a;Petroianu 2003c). At human clinically relevant MCP and RAN concentrations, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Petroianu and coworkers presented data on a protective effect of the reversible cholinesterase inhibitors metoclopramide (MCP) and ranitidine (RAN) against the organophosphorus compound (OP) paraoxon in vitro with human AChE and BChE and in vivo in rats (Petroianu et al, 2005a;2005b;2005c;2003b;2003a;2003c). The D 2 antagonist and 5-HT 4 agonist metoclopramide and the H 2 antagonist ranitidine are widely used in clinical medicine.…”

Section: Introductionmentioning

confidence: 99%

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Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

et al. 2005

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The repeated misuse of highly toxic organophosphorus-type (OP) chemical warfare agents ('nerve agents') emphasizes the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators ('oximes') is considered to be ineffective with certain nerve agents due to low oxime efficacy. Therefore, pretreatment with carbamate-type compounds, e.g. pyridostigmine, was recommended to improve antidotal efficacy. Recently, the clinically used reversible AChE inhibitors metoclopramide (MCP) and ranitidine (RAN) were shown to exhibit some protective effect against the OP pesticide paraoxon in vitro and in vivo. The present study was undertaken to investigate a potential protective effect of MCP and RAN against inhibition of human AChE by the nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl)methylphosphonothioate). Hemoglobin-free human erythrocyte membranes were incubated with various, human relevant MCP (0.5-2 microm) and RAN (0.5-5 microm) concentrations starting 1 min before addition of VX (1-40 nm). Both compounds failed to increase VX IC(50) values. In addition, human AChE was incubated with higher than human relevant therapeutic concentrations of MCP (1 microm-1 mm) and RAN (1 microm-2.0 mm) and inhibited by 40 nm VX. At concentrations higher than 100 microm MCP and RAN caused a concentration dependent increase of residual AChE activity 15 min after addition of VX. These data indicate that MCP and RAN may be ineffective in protecting human AChE against inhibition by the nerve agent VX at human relevant doses.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

et al. 2005

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“…It is therefore conceivable that reactivation of acetylcholinesterase in the periphery, by normalizing oxygen supply to the brain, can reverse these central symptoms of organophosphate poisoning without necessarily reactivating acetylcholinesterase in the central nervous system. Studies of our group have shown that, in rats, organophosphate (paraoxon (6), methyl-paraoxon (7)) -induced mortality can be reduced by administration of oximes (pralidoxime (11), trimedoxime (13), obidoxime (12)), but that the protection conferred is insufficient considering that, depending on the organophosphate dose administered, 30-90% of the animals die despite oxime treatment [111][112][113][114].…”

Section: Brain Entry Of Oximesmentioning

confidence: 99%

Entry of Oximes into the Brain: A Review

Lorke

Kalász

Petroianu

et al. 2008

CMC

175

120

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The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

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“…However, the clinical results of administering antidotal therapy for organophosphate poisoning are far from perfect [4,6,16,26,28], and there are many ongoing experimental trials using other therapeutic and protective agents for controlling the signs and symptoms of poisoning, and especially those related to the nicotinic effects that are not controlled by atropine. Examples of such trials include antihistamine diphenhydramine [5,12], alpha-2-adrenoceptor agonists [7,29] and metoclopramide, which is a dopamine D2 receptor antagonist [14,22-24]. …”

Section: Introductionmentioning

confidence: 99%

Metoclopramide protection of diazinon-induced toxicosis in chickens

Al-Zubaidy

Mohammad

2007

J Vet Sci

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The efficacy of metoclopramide for preventing organophosphate insecticide-induced (diazinon) toxicosis was evaluated in 7~14 days old chicks. Injection of metoclopramide at 25 mg/kg, s.c. 15 min before diazinon increased the oral 24 h median lethal dose of the insecticide in the chicks by 80%. Metoclopramide alone inhibited the in vitro and in vivo plasma and whole brain cholinesterase activities of the chicks. Metoclopramide pretreatment at 100 mg/kg, s.c. reduced the extent of cholinesterase inhibition that was caused by diazinon (10 mg/kg, p.o.) in the plasma and whole brain by 24% and 7%, respectively. Diazinon at 10 mg/kg, p.o. produced signs of cholinergic toxicosis in the chicks, and these signs included salivation, lacrimation, gasping and convulsions within 2 h, and the 2-h and 24-h lethalities were 88 and 100%, respectively. Metoclopramide at the dose rates of 12.5, 25, 50, 100 and 200 mg/kg, s.c. given 15 min before diazinon (10 mg/kg, p.o.) variably decreased the occurrence of toxic manifestations in the chicks. The highest dose of metoclopramide (200 mg/kg, s.c.) reduced the 2-h and 24-h lethality of diazinon to 75% each and it reduced the overall toxicity score of diazinon by 32%. The data suggest that metoclopramide pretreatment only partially protected chicks against the acute toxicity of diazinon.

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Protective Drugs in Acute Large-Dose Exposure to Organophosphates: A Comparison of Metoclopramide and Tiapride with Pralidoxime in Rats

Cited by 15 publications

References 21 publications

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

Entry of Oximes into the Brain: A Review

Metoclopramide protection of diazinon-induced toxicosis in chickens

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