Protective Effect of Early and Late Administration of Pralidoxime against Organophosphate Muscle Necrosis

Santos, Regina Paes dos; Cavaliere, Maria José; Puga, F.R.; Narciso, Emerson; Pelegrino, J.R.; Calore, Edenilson Eduardo

doi:10.1006/eesa.2001.2138

Cited by 10 publications

(5 citation statements)

References 17 publications

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“…demonstrated a hepatoprotective effect of pralidoxime against methamidophos‐induced (30 mg/kg) toxicity in rats. Necrosis of the diaphragm induced by methamidophos was also found to be protected against by pralidoxime under in vivo conditions . In our work, we also observed a protection/reactivation effect of oximes on methamidophos‐inhibited AChE, using obidoxime and pralidoxime as positive controls for comparison with the new oximes.…”

Section: Discussionsupporting

confidence: 72%

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Lugokenski

Gubert

Bueno

et al. 2012

Basic Clin Pharma Tox

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Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 lM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 lM, whereas 2(3-(phenylhydrazono) butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 lM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning. Acetylcholinesterase (EC 3.1.1.7, AChE) is an enzyme that catalyses the hydrolysis of acetylcholine to choline and acetate. The biological function of this enzyme is to terminate acetylcholine activity in the terminal nervous junction with its effector organs or post-synaptic sites [1]. The mechanism of action of organophosphorus (OP) compounds with anticholin-esterase activity involves the phosphorylation of the serine hydroxyl group in the active site of AChE, leading to an inactive enzyme (AChE-OP) [2]. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death [3]. Methamidophos is a potent AChE inhibitor used to control plague of insects on a variety of crops [4] and may present anticholinesterase activity against human cholinesterases [5,6]. In Brazil in particular, methamidophos is commonly used on many crops, including cotton, soybeans and wheat, resulting in food [7] and occupational exposure [8]. A recent study demonstrated that over 90% of small farmers use methamido-phos and nearly 60% of them exhibit typical OP intoxication symptoms [9]. Mechanistically, methamidophos may inhibit AChE by covalently binding a serine residue (Ser203) in the active site, and this moiety could form two dif...

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Section: Discussionsupporting

confidence: 72%

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Lugokenski

Gubert

Bueno

et al. 2012

Basic Clin Pharma Tox

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“…Some studies have revealed necrosis in the diaphragmatic and intercostal muscles in the autopsies of some cases, together with greatly elevated CK levels due to rhabdomyolysis. Some intoxication cases with acute renal failure due to rhabdomyolysis requiring hemodialysis have also been forwarded (20)(21)(22)(23). Fourteen (41%) patients were observed to have elevated CK levels in our study.…”

Section: Discussionmentioning

confidence: 55%

Factors Affecting the Prognosis in Acute Insecticide Intoxications Containing Organic Phosphorus

Kozacı¹,

Gökel²,

Açıkalın³

et al. 2012

JAEM

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Objective: The goal of the study was to investigate the complications encountered during the follow up and treatment of the patients intoxicated with insecticides that contain organic phosphorus and assess the effects of these complications on the treatment periods of these patients. Material and Methods: Patients who presented to the tertiary care emergency department with the diagnosis of intoxication with insecticides containing organic phosphorus (OPi) between March 2004-September 2005 were included into the study. Results: Thirty four patients were included into the study. Seven of them underwent mechanical ventilation due to respiratory failure. The Glasgow Coma Scale (GCS) score was found to be <9 in patients with respiratory insufficiency. Eight of them had an initial serum amylase level of >300 U/L. The total dose of atropine used in these patients and the duration of hospital stay were found to be higher than in the other patients. Conclusion:The clinical presentation and course of the patients especially with respiratory failure and hyperamylasemia are observed to be more serious, their atropine needs are greater r and they have longer hospital stays. GCS is a useful parameter in determining the need for intubation. (JAEM 2012; 11: 93-7)

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“…Once the aged phosphorus acylation cholinesterase was formed, PAM can hardly break down the bond between the OP-AChE conjugates to release the enzyme for performing its physiological roles. Since the reactivation of AChE is time-dependent, adequate therapy requires to be operated for OP poisoning as soon as possible. − Herein, it is important to state that unlike other analytical tools used in the present study, by exploiting the dual-responsive ratiometric fluorescence response of GQD@Tb/GMP ICP nanoprobes and taking advantage of the smartphone with superiority in image scanning and data computing, the point-of-use analytical platform established in this study not only favors for direct detection of AChE in real samples but also enables direct monitoring the OPs poisoning and treatment with AChE as a biomarker, which is readily available in the clinical scenario for early diagnosis and therapy.…”

Section: Resultsmentioning

confidence: 99%

Stimulus Response of GQD-Sensitized Tb/GMP ICP Nanoparticles with Dual-Responsive Ratiometric Fluorescence: Toward Point-of-Use Analysis of Acetylcholinesterase and Organophosphorus Pesticide Poisoning with Acetylcholinesterase as a Biomarker

Liu

et al. 2020

ACS Appl. Mater. Interfaces

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In this study, by rationally designing the stimulus response of graphene quantum dot (GQD)-sensitized terbium/guanine monophosphate (Tb/GMP) infinite coordination polymer (ICP) nanoparticles, we have constructed a smartphone-based colorimetric assay with ratiometric fluorescence, which could be applied for the detection of acetylcholinesterase (AChE) and organophosphorus pesticides (OPs) directly. First, GQDs with abundant functional groups were chosen as the guest, which not only could be used as one of the signal readouts but also served as the antenna ligand to further sensitize the fluorescence of the host Tb/GMP. Upon being excited at 330 nm, the green fluorescence of the Tb/GMP host is highly enhanced, while the blue fluorescence of GQDs is suppressed due to the confinement of the ICP host. With the presence of thiocholine (TCh), an enzymatic product hydrolyzed from acetylthiocholine (ATCh) by AChE, the competitive coordination of Tb3+ between GMP and TCh results in the collapse of the ICP network and thereby the release of GQDs into the solution; thus, the fluorescence of Tb/GMP turns off and the fluorescence of GQDs turns on. The dual-responsive ratiometric fluorescent intensity change leads to the corresponding green-to-blue fluorescent color change obviously, which constitutes a novel mechanism for the colorimetric analysis of AChE. Moreover, when OPs are subsequently introduced, the activity of AChE is blocked, thus preventing the stimulus response of GQD@Tb/GMP ICP nanoparticles, leading to the fluorescent color change from greenish-blue to green, which could also be employed for OP detection. Benefitting from the high sensitivity, good reliability, and the obvious color changes, the method demonstrated here is a promising candidate to realize smartphone-based point-of-use applications, which is of great importance for timely clinical diagnosis and treatment of OPs related to health issues with AChE as an exposure biomarker in less industrialized countries, in remote settings, or even in home care services.

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Protective Effect of Early and Late Administration of Pralidoxime against Organophosphate Muscle Necrosis

Cited by 10 publications

References 17 publications

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Effect of Different Oximes on Rat and Human Cholinesterases Inhibited by Methamidophos: A Comparative In Vitro and In Silico Study

Factors Affecting the Prognosis in Acute Insecticide Intoxications Containing Organic Phosphorus

Stimulus Response of GQD-Sensitized Tb/GMP ICP Nanoparticles with Dual-Responsive Ratiometric Fluorescence: Toward Point-of-Use Analysis of Acetylcholinesterase and Organophosphorus Pesticide Poisoning with Acetylcholinesterase as a Biomarker

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