Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig

Abstract

-Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD 50 /oxime ED 50 ) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl 2 . The 24-hr median lethal dose (LD 50 ) for the four by intramuscular (IM) injection and the median effective dose (ED 50 ) were determined. In the ED 50 study, male guinea pigs clipped of hair received 2x LD 50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED 90 ) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 μmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl 2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl 2 . Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED 90 < 149 μmol/kg against all three topical OPs tested.

Evaluating the broad-spectrum efficacy of the acetylcholinesterase oximes reactivators MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against phorate oxon, sarin, and VX in the Hartley guinea pig

“…Based on these observations, it might be postulated that doses of 150 mg/kg and up were approaching the LD 50 of the oxime itself. However, this may not be the case as the LD 50 of HLö-7 DMS was previously reported to be 314 mg/ kg (Snider et al, 2016a), which is approximately twice the level administered here.…”

“…In contrast to the GB and VX study results, where protection never exceeded 60% after 80+ mg/kg HLö-7 DMS, the PHO-challenged groups produced increased survival up to 100% at 135 mg/kg before group lethality began to occur. This discrepancy may be attributable to differences in toxicokinetics of PHO versus CWNAs, where, when the level of exposure is controlled, the latter have been found to be substantially more lethal with faster onset of toxicity than the former (Wilhelm et al, 2014; Snider et al, 2016a,b). This delay in onset of toxicity for PHO may explain why a higher level of HLö-7 DMS is necessary to obtain the same 50% protection of the study population (ED 50 value of 96 mg/kg), i.e., to ensure enough of the oxime is still in circulation when PHO begins to exert its toxic effects.…”

“…Although the ED 50 of MMB4 DMS for PHO was 29 mg/kg (or approximately five times higher than for the CWNAs), it was still substantially lower than the 2-PAM Cl equimolar dose of 65.3 mg/kg. With a LD 50 of 679 mg/kg (Snider et al, 2016a), the TI for MMB4 DMS ranged from 23 to 128. The substantially higher TI displayed by MMB4 DMS indicates that higher doses of this oxime could still be administered before concerns regarding oxime-induced toxicity arise.…”

Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance

“…Moreover, diplatin offered significant beneficial outcomes in suppressing A549, H292, and LTEP-A-2 xenograft tumors with an average ED 50 at 52 mg/kg, which was comparable to that of CBP, and nearly 10-fold larger than that of DDP. Therapeutic index (TI) is the ratio of LD 50 to ED 50 for a drug; a large TI indicates a wider window of safety for an effective treatment (Snider et al, 2016). We found the TI of diplatin, DDP, and CBP to be 9.53, 2.17, and 2.52, respectively, giving diplatin the largest window of safety.…”

Methylene blue can act as an antidote to pesticide poisoning of bumble bee mitochondria

“…Atropine alleviates pesticide poisoning 57 – 60 , while oximes act as antidotes against specific pesticides 59 , 61 – 63 . Magnesium sulfate can be used for managing the poisoning with organophosphorus pesticides 64 and aluminum phosphide 65 .…”