Centre for Pesticide Suicide Prevention, and Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Clin Toxicol (Phila). 2022 Oct;60(10):1163-1175. doi: 10.1080/15563650.2022.2105709. Epub 2022 Aug 11.
The bipyridyl herbicide paraquat was first introduced into agriculture in the 1960s by Imperial Chemical Industries. Due to issues with unintentional poisoning, the centrally acting emetic PP796 was added in 1976 to the company's 20% paraquat ion soluble liquid (SL20) formulations (Gramoxone) at a concentration of 0.5 g/L or 0.05% (equivalent to 0.071 mg/kg in a 70 kg adult ingesting a minimum lethal dose of 10 mL) to induce early vomiting (within 30 min), reduce paraquat absorption from the gut, and prevent deaths. Its presence in paraquat products was subsequently mandated by the Food and Agriculture Organization Committee of Experts on Pesticides in Agriculture (predecessor to the current FAO/WHO Joint Meeting on Pesticide Specifications). However, no primary pre-clinical or clinical data have been published regarding the effectiveness of PP796. We reviewed the published literature and unpublished company reports for data on the effectiveness of PP796.
PubMed and Google were searched for published studies on the emetic using the search terms "paraquat" and ["emetic" or "PP796"]. Company documents reporting pre-clinical and clinical studies were accessed at the website of (https://usrtk.org/pesticides/paraquat-papers/). Primary study reports were sought as well as overviews written by company toxicologists.
Pre-clinical dog and monkey studies indicated that the PP796 EC50 dose for vomiting was around 0.5-2 mg/kg. Further increasing the PP796 concentration speeded up the time to first vomit and reduced the amount of paraquat absorbed (as assessed by the 0-24 h plasma area-under-the-curve) 100-fold compared to a control group receiving no PP796. However, the dose selected for paraquat SL20 formulations by the company (0.5 g/L or 0.05%) was based exclusively on a phase II study in the early 1970s involving five volunteers receiving 3 different doses, with only two individuals actually vomiting, supplemented by data from 37 patients taking 2 mg in clinical trials. A UK-mandated toxicovigilance study in the 1980s identified only 21 patients ingesting paraquat SL20 with PP796 for whom data on time to vomit was available; of these patients, 11 vomited within 30 min (52.4%, 95%CI 31-73.7%). No effect on mortality could be identified from any study of paraquat SL containing 0.05% PP796. A clinical study in Sri Lanka 30 years after the emetic was first introduced, of a revised formulation (Gramoxone Inteon) containing a three-fold higher amount of PP796, as well as MgSO4 and an alginate, showed increased rates of early vomiting and modestly reduced mortality for patients ingesting up to 100 mL.
Pre-clinical studies showed a clear dose response for PP796 to cause early vomiting, with effective doses in the 0.5-20 mg/kg range. A too low concentration of PP796 was selected for paraquat formulations based on an inadequate phase II study. Currently, evidence that PP796 at 0.05% in paraquat SL20 causes more rapid vomiting after ingestion is weak or unpublished; no evidence of clinical benefit or fewer deaths has been identified. There is no evidence to support the FAO/WHO Joint Meeting on Pesticide Specifications mandate to include PP796 or any other emetic in paraquat products. Products with higher emetic concentrations have been developed but are not widely used; it is possible they may prevent deaths.
联吡啶类除草剂百草枯于 20 世纪 60 年代由英国帝国化学工业公司首次引入农业领域。由于存在非故意中毒的问题，1976 年，在公司的 20%百草枯离子可溶液（SL20）制剂（Gramoxone）中加入了中枢作用催吐剂 PP796，浓度为 0.5g/L 或 0.05%（相当于 70kg 成人摄入最小致死剂量 10mL 时的 0.071mg/kg），以诱导早期呕吐（在 30min 内），减少百草枯从肠道吸收，并防止死亡。此后，粮农组织农药专家委员会（现为粮农组织/世卫组织农药规格联席会议的前身）要求百草枯产品中必须含有 PP796。然而，目前尚未发表关于 PP796 有效性的任何主要临床前或临床数据。我们查阅了已发表的文献和公司未发表的报告，以获取有关 PP796 有效性的数据。
在 PubMed 和 Google 上使用搜索词“paraquat”和["emetic"或"PP796"]搜索关于催吐剂的已发表研究。在 （https://usrtk.org/pesticides/paraquat-papers/）网站上访问了报告临床前和临床研究的公司文件。我们还寻找了主要的研究报告以及公司毒理学家撰写的综述。
狗和猴子的临床前研究表明，催吐剂 PP796 的 EC50 剂量约为 0.5-2mg/kg。进一步增加 PP796 浓度可以加快首次呕吐的时间，并减少百草枯的吸收量（通过 0-24h 血浆曲线下面积评估），与未接受 PP796 治疗的对照组相比，降低了 100 倍。然而，公司选择的百草枯 SL20 制剂的剂量（0.5g/L 或 0.05%）完全基于 20 世纪 70 年代早期的一项 II 期研究，该研究涉及 5 名志愿者接受了 3 种不同剂量的药物，只有 2 人实际呕吐，此外还补充了 37 名在临床试验中服用 2mg 药物的患者的数据。20 世纪 80 年代英国授权的毒理学监测研究仅确定了 21 名摄入含有 PP796 的百草枯 SL20 的患者，这些患者中有数据表明呕吐时间的有 11 人在 30min 内呕吐（52.4%，95%CI 31-73.7%）。从任何含有 0.05%PP796 的百草枯 SL 研究中都无法确定死亡率的影响。30 年前首次引入催吐剂后，斯里兰卡进行了一项临床研究，评估了一种修订后的制剂（Gramoxone Inteon），其中含有三倍剂量的 PP796 以及硫酸镁和藻酸盐，结果显示早期呕吐率增加，摄入 100ml 以内的患者死亡率略有降低。
临床前研究表明，PP796 具有明确的剂量反应，能有效引起早期呕吐，有效剂量在 0.5-20mg/kg 范围内。基于一项不充分的 II 期研究，选择了太低浓度的 PP796 用于百草枯制剂。目前，关于百草枯 SL20 中 0.05%的 PP796 摄入后是否能更快引起呕吐的证据薄弱或未发表；没有发现临床受益或死亡率降低的证据。没有证据支持粮农组织/世卫组织农药规格联席会议授权在百草枯产品中添加 PP796 或任何其他催吐剂。虽然已经开发了具有更高催吐剂浓度的产品，但它们并未广泛使用；这些产品有可能预防死亡。
