Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED₅₀), and therapeutic index (TI = oxime 24-h LD₅₀/oxime ED₅₀) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO). All OPs are representative of the broader classes of G and V chemical warfare nerve agents and persistent pesticides. MMB4 DMS and HLö-7 DMS were previously identified as comparative efficacy leads warranting further evaluations. 2-PAM Cl is the U.S. FDA-approved standard-of-care oxime therapy for OP intoxication. Briefly, PRs were determined in male guinea pigs by varying the subcutaneously (SC) delivered OP dose followed then by therapy with fixed levels of the oxime and atropine (0.4 mg/kg; administered intramuscularly [IM]). ED₅₀s were determined using a similar approach except the OP dose was held constant at twice the median lethal dose (2 × LD₅₀) while the oxime treatment levels were varied. The ED₅₀ information was then used to calculate the TI for each OP/oxime combination. Both MMB4 DMS and HLö-7 DMS provided significant protection, i.e., higher PR against GB, VX, and PHO when compared to atropine controls, but significance was not readily demonstrated across the board when compared against 2-PAM Cl. The ED₅₀ values of MMB4 DMS was consistently lower than that of the other oximes against all three OPs. Furthermore, based on those ED₅₀s, the TI trend of the various oximes against both GB and VX was MMB4 DMS > HLö-7 DMS > 2-PAM Cl, while against PHO, MMB4 DMS > 2-PAM Cl > HLö-7 DMS.

有机磷（OP）化合物，包括杀虫剂和化学战神经毒剂（CWNA），作为可能的恐怖主义武器或通过意外暴露（无论是从制造设施中意外释放还是在运输过程中）而对普通人群构成威胁。为了减轻这些威胁带来的毒性，非常需要一种对多种OP有效且速效的治疗方案。本文所述的工作旨在评估保护率（PR），中位有效剂量（ED ₅₀）和治疗指数（TI =肟24-h LD ₅₀ /肟ED ₅₀MMB4 DMS，HLö-7DMS和2-PAM Cl）对OPs沙林蛋白（GB），VX和磷酸氧根（PHO）的抗性。所有OP均代表G和V化学战神经毒剂和持久性农药的更广泛类别。MMB4 DMS和HLö-7DMS先前被确定为比较功效的线索，需要进一步评估。2-PAM Cl是美国FDA批准的用于OP中毒的护理标准肟疗法。简而言之，通过改变皮下（SC）递送的OP剂量，然后用固定水平的肟和阿托品（0.4 mg / kg；肌内注射[IM]）进行治疗，确定雄性豚鼠的PR。ED ₅₀的测定采用类似方法，不同的是OP剂量恒定保持在致死剂量中值的两倍（2×LD ₅₀），而肟的处理水平却有所不同。然后将ED ₅₀信息用于计算每种OP /肟组合的TI。MMB4 DMS和HLö-7DMS均提供了显着的保护，即与阿托品对照相比，对GB，VX和PHO的PR更高，但与2-PAM C1相比，其有效性却不容易得到全面证明。对于所有三个OP，MMB4 DMS的ED ₅₀值始终低于其他肟。此外，基于这些ED ₅₀ s，各种肟对GB和VX的TI趋势为MMB4 DMS>HLö-7DMS> 2-PAM Cl，而对PHO，MMB4 DMS> 2-PAM Cl>HLö-7 DMS。