Effective skin decontamination with RSDL® (reactive skin decontamination lotion kit) following dermal exposure to a Novichok class nerve agent.

In recent years, various poisoning incidents have been reported, involving the alleged use of the so-called Novichok agents, resulting in their addition to the Schedule I list of the Organisation for the Prohibition of Chemical Warfare (OPCW). As the physicochemical properties of these agents are different from the 'classical' nerve agents, such as VX, research is needed to evaluate whether and to what extent existing countermeasures are effective. Here, we evaluated the therapeutic potential of RSDL® (Reactive Skin Decontamination Lotion Kit) for the neutralization of percutaneous toxicity caused by Novichok agents, both in vitro and in vivo. Experiments showed the three selected Novichok agents (A230, A232, A234) could be degraded by RSDL lotion, but at a different rate. The half-life of A234, in the presence of an excess of RSDL lotion, was 36 min, as compared to A230 (<5 min) and A232 (18 min). Following dermal exposure of guinea pigs to A234, application of the RSDL kit was highly effective in preventing intoxication, even when applied up until 30 min following exposure. Delayed use of the RSDL kit until the appearance of clinical signs of intoxication (3-4 h) was not able to prevent intoxication progression and deaths. This study determines RSDL decontamination as an effective treatment strategy for dermal exposure to the Novichok agent A234 and underscores the importance of early, forward use of skin decontamination, as rapidly as possible.

Pharmacokinetics and efficacy of atropine sulfate/obidoxime chloride co-formulation against VX in a guinea pig model.

Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation.

In vitro decontamination efficacy of the RSDL® (Reactive Skin Decontamination Lotion Kit) lotion component against riot control agents: Capsaicin, Mace™ (CN) and CS.

The study examined the degradation of riot control agents (RCAs): 2-chloroacetophenone (CN), 2-chlorobenzalmalononitrile (CS), and capsaicin, using the Reactive Skin Decontamination Lotion Kit (RSDL®) lotion and evaluated the the direct liquid phase reactivity of the RSDL lotion component with each RCA. RSDL lotion was mixed with the selected RCAs at different molar ratios. Reactivity of the active ingredient potassium 2,3-butanedione monoximate (KBDO) with the RCA was observed for one hour. Samples of 10 µL were taken and quenched, analyzed for residual RCA using LC-MS. CN, was degraded at molar ratios of two and above in less than 2 min. At a molar ratio of 1:1 KBDO:CN, ∼90 % of CN was degraded within 2 min, the remaining 10 % residual CN was observed for one hour without any change. CS, degradation of more than 68 % of CS was achieved at 20:1 M ratio of KBDO:CS within 1 h of reaction time. For capsaicin, no degradation was observed regardless of the higher molar ratios of up to 20:1 and longer reaction times of up to one hour. This study provides evaluation of neutralizing action of the RSDL lotion without assessment of the physical removal component by the RSDL Kit.

In vivo efficacy of the Reactive Skin Decontamination Lotion (RSDL®) kit against organophosphate and carbamate pesticides.

In this study, we assessed the efficacy of the Reactive Skin Decontamination Lotion (RSDL®) Kit against parathion and aldicarb pesticide dermal exposure in a guinea pig model. The pesticides inhibit acetylcholinesterase (AChE) leading to signs and symptoms of hyperactivity of organs due to accumulation of acetylcholine. The RSDL Kit has been shown to physically remove and chemically degrade chemical warfare agents. Degradation occurs from a nucleophilic substitution reaction between an active ingredient in the RSDL lotion, potassium 2,3-butanedione monoximate (KBDO), with susceptible sites in these compounds. In the present study, guinea pigs dermally exposed to parathion and aldicarb were decontaminated with RSDL to mitigate the toxic effects of the pesticides. It is observed that animals exposed to 749 mg/kg of parathion (n = 3) died within 24 h without RSDL decontamination; however, RSDL-treated animals (n = 3) showed only mild signs of neurotoxicity. The RSDL-treated animals had an AChE inhibition of 0-58% while the untreated animals had up to 86% inhibition. Similarly, RSDL has been demostrated to prevent aldicarb neurotoxicity effects. The percent inhibition of AChE activity during the 24 h post challenge of 9 mg aldicarb/kg of animal weight ranged from 25% to 61% with severe signs of intoxication while only up to 5% with mild or no signs of intoxication in the case of RSDL-decontaminated animals. Generally, it has been shown that the toxic effects of the organophosphate and carbamate pesticides can be prevented via decontamination using the RSDL Kit.

Contact transfer risk from fentanyl-contaminated RSDL® Kit.

The RSDL® (Reactive Skin Decontamination Lotion) Kit contains a lotion-impregnated sponge extensively studied for the removal or neutralization of chemical warfare agents from skin. Pilot investigation of efficacy with industrial threat compounds noted that synthetic opioid fentanyl citrate was removed by the RSDL Kit but not chemically inactivated by the lotion. This implies that after use the RSDL Kit will contain intact fentanyl, which may pose a dermal health hazard if the fentanyl is then transferred to skin after use without proper handling. This in vitro investigation studied the contaminated RSDL Kit using three different concentrations of fentanyl with a skin contact time of 15 min under direct interaction from passive contact, light touch, and leaning with one hand. It was demonstrated that the expected transfer of fentanyl from contaminated RSDL depends on 1) the concentration of fentanyl and 2) the area of the exposed surface. From a toxicological perspective, the contact risk of fentanyl under the conditions tested can be considered low but not absent. The present study determined that a contaminated RSDL Kit, used for removal of fentanyl, should be handled with proper care. Use of protective gloves in operational use and washing skin afterwards is advised to prevent undesired contamination.

Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigs.

The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels. Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect. At both sarin challenge doses, 54 µg/kg and 84 µg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals. Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans.

Degradation of pesticides with RSDL® (reactive skin decontamination lotion kit) lotion: LC-MS investigation.

This study examined the degradation of organophosphate (OP) and carbamate pesticides using RSDL® (Reactive Skin Decontamination Lotion Kit) lotion. Degradation occurs from a nucleophilic substitution (SN) reaction between an ingredient in the RSDL lotion, potassium 2,3-butanedione monoximate (KBDO), with susceptible sites in the pesticides. Evaluation at several molar ratios of KBDO:test articles using liquid chromatography-mass spectrometry (LC-MS) techniques was performed. The OP test articles, parathion, paraoxon, parathion-methyl, paraoxon-methyl and chlorpyrifos were effectively degraded at molar ratios of four and above in less than 6min contact time. Malathion and malaoxon were similarly converted to inactive by-products at molar ratios as low as two in less than 4min. A minimum molar ratio of nine was found to be effective against the carbamate pesticide carbofuran. In the case of aldicarb, complete destruction was achieved at a molar ratio of fifteen and a reaction time of one hour. It is important to note that these studies are based on a direct liquid phase RSDL lotion reaction with the toxic chemicals without the added physical removal decontamination efficacy component provided by the sponge component of the RSDL kit. The RSDL kit is intended to be used to remove or neutralize chemical warfare agents (CWA) and T-2 toxin from the skin. In actual use, the majority of the CWA decontamination occurs through the combined action of the sponge in both removing the chemical from the skin, and in rapidly mixing the chemicals at a high molar ratio of KBDO:CWA within the pores of the sponge to enhance rapid neutralization of the chemical.