Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides

A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1–20; compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10–16) and cyclic (17–20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30–32, sulfoxide 33, sulfone 34 and sulfonamides 35–36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.     

Fatty Acid‐Derived Pro‐Toxicants of the Rat Selective Toxicant Norbormide

Norbormide [5‐(α‐hydroxy‐α‐2‐pyridylbenzyl)‐7‐(α‐2‐pyridylbenzylidene)‐5‐norbornene‐2,3‐dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB‐derived pro‐toxicants ( 3a  –  i , 4a  –  i , and 5a  –  i ) were prepared in an effort to ‘mask’ this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague–Dawley, wild Norway, and wild ship rats is described. Most notably, pro‐toxicant 3d was revealed to be free of all pre‐cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two‐choice bait‐palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB‐derived toxicants with enhanced palatability and efficacy profiles.     

“氯敌鼠”防治对农田小哺乳动物群落结构的影响及群落演替分析

对不同防治对策下施用氯敌鼠作为杀鼠剂对农田小哺乳动物群落结构的影响进行了研究．结果表明,杀鼠剂对群落组成有很大影响,灭鼠时机、灭鼠次数不同,群落的反应也不同．秋季灭鼠,小哺乳动物数量逐年下降,３ 年后可达到较低密度．群落多样性也逐年下跌,且回升极弱．春季灭鼠,数量可持续在低水平,群落多样性较其它处理高,对化学灭鼠破坏的生物多样性有较强的恢复力．灭鼠频次的增加对小哺乳动物总体数量降低有强化作用．可以认为,化学灭鼠明显地降低了群落中小哺乳动物的密度,也降低了群落的多样性．促使小哺乳动物群落向着优势种突出、种类单调、群落稳定性差的方向演替．     

溴敌隆防治高原鼠兔和高原鼢鼠的研究

溴敌隆(Bromadiolone)是近年来新出现的第二代抗凝血杀鼠剂中的一个新品种,最近已在欧洲各国、加拿大、美国市场上出售。青海省化工科研设计所在国内首先合成。     

士的宁杀灭高原鼢鼠的试验研究

士的宁(strychnine)是从番木鳖(Shrychox nuxvomica)种子提得的一种生物碱。作为兴奋剂用于医疗方面和作为生化试剂使用,但作为杀鼠剂用来防治害鼠,国内尚未见有报道。在国外,士的宁被用于防治危害森林草地、作物地内的地下鼠和其它有害哺乳动物(Marsh,1978;Barnes,1980;Crouch,1980;Anthony,1984)。作者于1983-1984年期间针对草原主要害鼠之一--高原鼢鼠(Myospalax baileyi)进行了灭杀试验研究。     

鼠药中毒引起消化道出血25例临床诊治分析

目的：城市中杀鼠药中毒容易被临床医师忽视,其引起消化道出血也极易误诊和漏诊,本文分析抗凝血杀鼠药中毒至消化道出血患者的临床表现和诊治方法。方法：回顾性分析2010年1月至2013年8月间我院收治的25例杀鼠药中毒并出现消化道出血病例,对其临床表现和诊治方法进行分析总结,病例均以维生素K1抗凝血方法进行治疗,并比较分析治疗前后患者的凝血酶原时间（PT）、国际正常化比率（INR）、活化部分凝血活酶时间（APTT）、纤维蛋白原（FIB）和出血时间（TT）等出凝血指标进行检测,并进行比较分析。结果：25例因抗凝血杀鼠药物中毒并导致消化道出血患者经维生素K1等抗凝血方法治疗患者全部治愈,消化道出血停止,凝血指标恢复正常,治疗前后患者的凝血指标存在明显差异（P〈0.05）。结论：抗凝血法对杀鼠药中毒导致消化道出血进行治疗的临床效果显著,值得推广。     

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia—with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb% = 61.0 ± 3.6) and 1,3,4-oxadiazole 10 (metHb% = 52.4 ± 0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120 mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.     

鼠药中毒引起消化道出血25例临床诊治分析

目的:城市中杀鼠药中毒容易被临床医师忽视,其引起消化道出血也极易误诊和漏诊,本文分析抗凝血杀鼠药中毒至消化道出血患者的临床表现和诊治方法。方法:回顾性分析2010年1月至2013年8月间我院收治的25例杀鼠药中毒并出现消化道出血病例,对其临床表现和诊治方法进行分析总结,病例均以维生素K1抗凝血方法进行治疗,并比较分析治疗前后患者的凝血酶原时间(PT)、国际正常化比率(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和出血时间(TT)等出凝血指标进行检测,并进行比较分析。结果:25例因抗凝血杀鼠药物中毒并导致消化道出血患者经维生素K1等抗凝血方法治疗患者全部治愈,消化道出血停止,凝血指标恢复正常,治疗前后患者的凝血指标存在明显差异(P0.05)。结论:抗凝血法对杀鼠药中毒导致消化道出血进行治疗的临床效果显著,值得推广。     

Ecological Risk Assessment Approaches Within the Regulatory Framework

Ecological risk assessment has a short history but a framework similar to human health risk assessment. The Toxic Substances Control Act (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) played a significant role in the development of the ecological risk process. Data developed and risk procedures used within TSCA and FIFRA have become generally standardized. Fundamental components of the risk process require data on the effects of chemicals in the form of concentration (or dose) — response profiles for species and an exposure profile to quantify the magnitude, spatial and temporal patterns of exposure relevant to significant biological endpoints being studied. Risk characterization generally involves comparing exposure and effects using point estimates (e.g., quotient method) but risk estimation is moving toward a probabilistic approach by comparing distributions of values with more consideration of the sources of uncertainty. Ecological testing guidelines in TSCA and FIFRA are discussed along with the risk characterization process used in each statute.     

Prodrugs of N-dicarboximide derivatives of the rat selective toxicant norbormide

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant ‘taste’ or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to ‘mask’ this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality.