Identification of an alginate-based formulation of paraquat to reduce the exposure of the herbicide following oral ingestion
Identification of an alginate-based formulation of paraquat to reduce the exposure of the herbicide following oral ingestion
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DOI：
10.1016/j.tox.2007.07.017
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发表时间：
2007-11-20
期刊：
影响因子：
4.5
通讯作者：
Elliott, B. M.
中科院分区：
文献类型：
--
作者：
Heylings, J. R.;Farnworth, M. J.;Elliott, B. M.
除草剂百草枯已在世界范围内广泛使用近50年，在可持续农业中发挥着重要作用。如果使用得当，这种化学品对人体健康没有已知的风险。然而，它是急性毒性的，如果浓缩的产品被口服，可能是致命的。尽管经过多年的研究，百草枯中毒还没有成功的治疗方法。近年来，我们已经将注意力转向了解如何使产品更安全，如果它是意外或故意消费。我们提出了一种新的方法，旨在保护百草枯产品，格拉莫酮。根据我们之前对胃肠道吸收百草枯的部位和机制的研究，我们已经确定了一种新的百草枯配方，Gramoxone INTEOW (R)，它可以减少百草枯在血液中的吸收。这种新配方含有多糖，海藻酸盐，一种从海藻中提取的天然产品。我们设计了一种含有表面活性剂的百草枯和海藻酸盐制剂，它具有除草活性，但具有独特的性质，即它与胃中的胃酸接触后会形成凝胶。由此产生的混合物减缓了有毒化学物质在小肠吸收部位的分散和输送。海藻酸盐还可以保护粘膜免受局部胃刺激物（如百草枯）的损害。我们的研究表明，将海藻酸盐的负荷增加到7至17 g/L之间会导致离体大鼠回肠中百草枯的体外吸收出现剂量相关的减少。这在体内也可以观察到，通过在兔体内的百草枯血浆动力学测量，曲线下面积（AUC 0-24 h）从格拉莫酮的33.8 +/- 3降低到含有17 g/L海藻酸盐的配方的12.5 +/- 6 (mu g/mL) h。这样减少对百草枯的全身接触，预计将减少该制剂的急性口服毒性。这应该对呕吐的物种特别有效，如人类，因为我们在这项调查中已经表明，海藻酸盐不仅降低血浆中百草枯的峰值值，而且还延迟达到峰值水平的时间。这为更有效的呕吐反应提供了机会，因为高粘性的凝胶物质应该在胃中停留的时间比液体格拉莫酮更长。需要进一步的研究来了解和优化这些海藻酸盐触发的百草枯凝胶制剂的安全和除草特性。然而，我们预计这种海藻酸盐技术在Gramoxone INTEON (R)中可以显著降低与除草剂相关的人类死亡率。2007爱思唯尔爱尔兰有限公司版权所有。
The herbicide paraquat has been widely used throughout the world for almost 50 years and is important in sustainable agriculture. When used correctly the chemical poses no known risk to human health. However, it is acutely toxic, and can be fatal, if the concentrated product is ingested orally. Despite many years of research there is no successful treatment for paraquat intoxication. In recent years we have turned our attention to understanding how we can make the product safer, if it is accidentally or intentionally consumed. We present in this paper a novel approach aimed at safening the paraquat product, Gramoxone. Following our previous research on the site and mechanism of paraquat absorption from the gastrointestinal tract we have identified a new formulation of paraquat, Gramoxone INTEOW (R) that reduces the absorption of paraquat into the blood. This new formulation contains the polysaccharide, alginate, a natural product extracted from sea-weed. We have designed a preparation of paraquat and alginate with surfactants that is herbicidally active but has the unique property that it gels on contact with gastric acid in the stomach. The resulting mixture slows the dispersion and delivery of the toxic chemical to its site of absorption in the small intestine. Alginates also protect the mucosa against the damaging influence of topical gastric irritants, like paraquat. Our studies have shown that increasing the loading of alginate between 7 and 17 g/L causes a dose-related reduction in paraquat absorption in vitro in isolated rat ileum. This is also observed in vivo, as measured by paraquat plasma kinetics in the rabbit where the Area Under Curve (AUC 0-24 h) was reduced from 33.8 +/- 3 for Gramoxone to 12.5 +/- 6 (mu g/mL) h for a formulation containing 17 g/L alginate. Such a reduction in systemic exposure to paraquat is expected to reduce the acute oral toxicity of the formulation. This should be particularly effective in a vomiting species such as man since we have shown in this investigation that alginates not only reduce the peak plasma paraquat values but also delay the time to peak levels. This provides the opportunity for a more effective emetic response since the highly viscous gelled material should remain in the stomach for longer than the liquid Gramoxone. Further research is required to understand and optimise the safening and herbicidal characteristics of these alginate acid-triggered gel formulations of paraquat. However, we anticipate that this alginate technology in Gramoxone INTEON (R) could have significant benefit in reducing human mortalities associated with the herbicide. (C) 2007 Elsevier Ireland Ltd. All rights reserved.