ABSTRACT
The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE-reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)-5-chloro-3-(hydroxyimino) indolin-2-one oxime (Câ-HIN) and 2-(5-chloro-2-oxoindolin-3-ylidene)-hydrazinecarbothioamide (Câ-OXHS) was higher than 1000 µM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 µM. Our screening showed that Câ-HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Câ-HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Câ-HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase-1 (PON-1) activity among groups treated. In conclusion, Câ-HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Câ-HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.
Subject(s)
Cholinesterase Inhibitors/toxicity , Isatin/pharmacology , Malathion/toxicity , Oximes/pharmacology , Animals , Artemia , Cholinesterase Reactivators/administration & dosage , Cholinesterase Reactivators/chemistry , Cholinesterase Reactivators/pharmacology , Disease Models, Animal , Drug Discovery/methods , Female , Insecticides/toxicity , Isatin/administration & dosage , Isatin/chemistry , Lethal Dose 50 , Male , Oximes/administration & dosage , Oximes/chemistry , Rats , Rats, WistarSubject(s)
Antidotes/therapeutic use , Cholinesterase Reactivators/therapeutic use , Insecticides/poisoning , Organophosphorus Compounds , Pralidoxime Compounds/therapeutic use , Adolescent , Antidotes/administration & dosage , Child , Cholinesterase Reactivators/administration & dosage , Cholinesterases/blood , Erythrocytes/enzymology , Female , Humans , Infant , Infusions, Intravenous , Male , Pralidoxime Compounds/administration & dosageABSTRACT
Após revisäo bibliográfica, faz-se uma síntese dos aspectos clínicos e terapêuticos relacionados com as intoxicaçöes por pesticidas inibidores da colinesterase, objetivando fornecer atualizaçäo ao médico generalista e, desta forma, melhorar o atendimento e diminuir a mortalidade ora existente