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The current Organisation for Economic Co-operation and Development (OECD) guidelines for evaluating organophosphorus-induced delayed neuropathy (OPIDN) require the observation of dosed animals over several days and the sacrifice of 48 hens. Adhering to these protocols in tests with enantiomers is difficult because large quantities of the compound are needed and many animals must be utilized. Thus, developing an in vitro screening protocol to evaluate chiral organophosphorus pesticides (OPs) that can induce delayed neuropathy is important. This work aimed to evaluate, in blood and brain samples from hens, human blood, and human cell culture samples, the potential of the enantiomeric forms of methamidophos to induce acetylcholinesterase (AChE) inhibition and/or delayed neurotoxicity. Calpain activation was also evaluated in the hen brain and SH-SY5Y human neuroblastoma cells. The ratio between the inhibition of neuropathy target esterase (NTE) and AChE activities by the methamidophos enantiomers was evaluated as a possible indicator of the enantiomers' abilities to induce OPIDN. The (-)-methamidophos exhibited an IC(50) value approximately 6 times greater than that of the (+)-methamidophos for the lymphocyte NTE (LNTE) of hens, and (+)-methamidophos exhibited an IC(50) value approximately 7 times larger than that of the (-)-methamidophos for the hen brain AChE. The IC(50) values were 7 times higher for the human erythrocyte AChE and 5 times higher for AChE in the SH-SY5Y human neuroblastoma cells. Considering the esterases inhibition and calpain results, (+)-methamidophos would be expected to have a greater ability to induce OPIDN than the (-)-methamidophos in humans and in hens.

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This work evaluated the potential of the isoforms of methamidophos to cause organophosphorus-induced delayed neuropathy (OPIDN) in hens. In addition to inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE), calpain activation, spinal cord lesions and clinical signs were assessed. The isoforms (+)-, (±)- and (-)-methamidophos were administered at 50mg/kg orally; tri-ortho-cresyl phosphate (TOCP) was administered (500mg/kg, po) as positive control for delayed neuropathy. The TOCP hens showed greater than 80% and approximately 20% inhibition of NTE and AChE in hen brain, respectively. Among the isoforms of methamidophos, only the (+)-methamidophos was capable of inhibiting NTE activity (approximately 60%) with statistically significant difference compared to the control group. Calpain activity in brain increased by 40% in TOCP hens compared to the control group when measured 24h after dosing and remained high (18% over control) 21 days after dosing. Hens that received (+)-methamidophos had calpain activity 12% greater than controls. The histopathological findings and clinical signs corroborated the biochemical results that indicated the potential of the (+)-methamidophos to be the isoform responsible for OPIDN induction. Protection against OPIDN was examined using a treatment of 2 doses of nimodipine (1mg/kg, i.m.) and one dose of calcium gluconate (5mg/kg, i.v.). The treatment decreased the effect of OPIDN-inducing TOCP and (+)-methamidophos on calpain activity, spinal cord lesions and clinical signs.

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ResumoO setor magistral representa um importante segmento do mercado brasileiro de medicamentos. Entretanto, a qualidade dos produtos fornecidos pelos estabelecimentos é frequentemente discutida e a Agência Nacional de Vigilância Sanitária (ANVISA) tem demonstrado uma preocupação com os produtos magistrais, pela promoção de consultas públicas abordando o assunto e pelo aumento do rigor nas legislações específicas. Assim sendo, as farmácias magistrais desempenham um importante papel no contexto da Política Nacional de Medicamentos, que objetiva garantir a promoção do uso racional e o acesso da população a medicamentos essenciais.Tendo em vista a importância da abordagem da qualidade dos produtos manipulados, este artigo apresenta relevantes informações sobre o perfil de qualidade do serviço de saúde prestado por esse setor, mediante a revisão da legislação e de trabalhos científicos que englobam o assunto.Palavras-chave: Setor magistral. Produtos farmacêuticos manipulados. Controle de Qualidade de fármacos e medicamentos. Política Nacional de Medicamentos. MAGISTRAL PHARMACIES: IMPORTANCE AND QUALITY PROFILE AbstractThe magistral sector represents a significant segment in the Brazilian pharmaceutical market. However, the quality of magistral formulations is often questioned and the National Agency of Sanitary Vigilance (ANVISA) has demonstrated a concern regarding these products, which has been verified in many public consultations approaching this subject and in new legislation aiming to improve public health. Thus, magistral pharmacies play an important role in the context of the National Medicine Politics, which aim to assure promotion of rational use and population access to essential medicines. Due to the paramount importance of the magistral formulation quality,

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