Every day, individuals worldwide are acutely and chronically poisoned with organophosphate (OP) pesticides (e.g., malathion, diazinon, chlorpyrifos, etc.). As well, the possibility of nerve agent (sarin, VX, novichok, etc.) attack from terrorist organizations is a real threat as evidenced by recent events in Syria, Iraq, UK, etc. Both OP pesticides and military nerve agents are OP toxins. Current antidotes to poisoning from these toxins do not provide adequate survival outcomes and do not protect from the neurological damage that can occur from exposure. As well, accurate diagnosis of organophosphate (OP) toxin poisoning is critical to guiding appropriate therapy. Currently available diagnostic tests incorporate a common methodology with innate deficiencies that reduces the accuracy of detecting and quantitating an exposure.
Every day, individuals worldwide are acutely and chronically poisoned with organophosphate (OP) pesticides. As a group, organophosphates (OP) represent the largest volume of pesticides used worldwide (e.g., chlorpyrifos, malathion, diazinon, etc.). According to the EPA, 20 million pounds of organophosphate pesticides were used in the US in 2012. Several hundred OP pesticides exist and as of 2015, the EPA listed 36 OPs registered for use in the US. The World Health Organization estimates approximately 3,000,000 acute OP pesticide poisonings per year worldwide with 300,000 deaths. But the WHO also states that there is no good tracking system in place and that many go unreported. With ~1.8 billion agricultural workers worldwide, most of whom use pesticides, the actual number may be considerably higher. On the average, seven pesticide applications on crops are performed per year. With the OP pesticide class representing about one third of all insecticides in use, a good percentage of the 1.8 billion agricultural workers worldwide are chronically being exposed to these pesticides.
OPs are also incorporated into flame retardants and plasticizers (PFRs) which are a group of chemicals widely added to consumer products and growing in use. Recently in the news, Aerotoxic Syndrome in airline pilots and crews is caused by OPs used in aviation lubricants. For proper treatment, accurate diagnosis is imperative. Unfortunately a number of clinical situations can mimic symptoms of OP poisoning (e.g., nicotine, mushroom poisoning, botulism, etc.).
Exposure to organophosphate pesticides has been associated with increased incidence of dementia and Alzheimer’s disease. (Paul 2018, Jokanovic 2018, Lin 2015, Hayden 2010, etc.). In the US there are currently 5.7 million cases of Alzheimer’s disease. This number is projected to grow to 7.1 million cases by 2025 and to 13.8 million by 2050. The current annual cost burden on the US healthcare system to care for Alzheimer’s patients is $277 billion. Projections state this cost burden to grow to $1.1 trillion annually by 2050. A rapid, easy to use diagnostic point of care test that can reliably detect acute and chronic OP pesticide exposure would allow affected individuals to be quickly identified and removed from the toxic environment and properly treated.
The use of nerve agents as a lethal weapon by radical political groups and unstable governments is a clear and present danger. Starting in the 1980’s, the Iraqi military used tabun against Iran. In the 1990’s Terrorist group Aum Shinrikyo released sarin in the Matsumoto and Tokyo subways (1990s). (Nozaki H 1995) (Macilwain 1993) (Brown MA 1998) On August 21, 2013 the Syrian Arab Republic utilized sarin in the Ghouta area of Damascus in Syria in 2013 resulting in ~3,600 exposures, 1429 deaths. (Sellstrom A 2013) (The White House 2013) Since that date, 85 confirmed chemical attacks using chlorine, mustard gas, or nerve agents have occurred; sarin having been confirmed at least 7 times (4 attacks with sarin by Syrian gov’t in 2013*, and attacks on Syria’s Talmenes April 2014*, Sarmin March 2015*, and Ltamenah March 2017* [*UN confirmed] (Kimball D 2018). At least 50 of the 85 attacks have been confirmed to be carried out by the Syrian government (Watch 2018). Further, evidence strongly suggests that on April 4, 2017, a Syrian government warplane attacked with a nerve agent a town in the northwestern governorate of Idlib, Khan Sheikhoun, killing at least 90 people, 30 of them children (Kimball D 2018). On April 7, 2018, a major chemical weapons attack using sarin occurred in Douma, a suburb outside of Damascus, Syria, killing at least several dozen civilians (Kimball D 2018). On February 13, 2017 North Korea’s Kim Jong-nam was assassinated with highly toxic VX when two women attacked him with the lethal chemical weapon at Kuala Lumpur International Airport in Malaysia (Paddock RC 2017). Further, According to OPCW, Sergei Skripal, a former Russian military officer and double agent for the UK’s intelligence services, and his daughter Yulia Skripal were poisoned in Salisbury, England, with a Novichok nerve agent. (Salisbury attack: Chemical weapons watchdog confirms UK findings on nerve agent 2018) A police officer was also taken into intensive care after being contaminated when he went to Sergei Skripal’s house. June 30, 2018 Two British nationals in Amesbury, seven miles from Salisbury, were exposed to Novichok, killing one. (Amesbury Novichok poisoning: Couple exposed to nerve agent 2018).
There are more than 8.5 million U.S. and EU military personnel. Military and civilian support personnel are supplied with Mark I Kits (auto-injectors) containing atropine and 2PAM to be used in case of a nerve-gas attack. For civilian response, nerve agent antidotes are carried by EMS first responders and are strategically pre-deployed across the country in large ChemPack containers. Although these existing antidotes are helpful, substantial improvement is needed to increase survival outcomes and reduce neurological damage from nerve agent exposure.
Homeland Security Scenario #7 anticipates that a nerve agent attack event would produce 6,000 casualties with tens of thousands of individuals requiring monitoring and decontamination.
It is well documented in the scientific literature that the primary challenges of treating exposure to organophosphate (OP) compounds (i.e., OP pesticides and nerve agents) are in improving survival and preventing neurological damage.
Countervail is pursuing the development of a novel drug technology and an innovative diagnostic technology to provide improved protection against organophosphorus compound poisoning.
AverTox® (galantamine hydrobromide) is a tertiary alkaloid and phenanthrene derivative that has been demonstrated to have two mechanisms of action that contribute to it protective effect against organophosphate toxicity. First, as a reversible acetylcholinesterase inhibitor, AverTox acts to competitively shield acetylcholinesterase, a vital neurological enzyme, from the irreversible inhibition of the OP toxin. Secondly, as an allosteric potentiating ligand, AverTox acts to modulate nicotinic cholinergic receptors by removing acetylcholine from overly stimulated neuronal receptors. The combination of these two mechanisms of action is believed to contribute to AverTox’s high protective properties against OP toxins.
Countervail has substantially advanced the development of AverTox® as a medical countermeasure against organophosphate compound toxicity (e.g., OP pesticides and nerve agents). The data from multiple studies in three different animal models support the following characteristics.
- Significantly improves survival and neuroprotection outcomes over currently available drugs
- Broad efficacy across all OP compounds
- Effective when given orally or by injection
- Effective when given before or after an exposure
- Crosses Blood-Brain-Barrier to protect CNS*
- Long shelf life at room temperature storage
- Safe “Repurposed” drug
- Known ability to economically manufacture
- IP protected
Countervail is developing a new point of care rapid diagnostic test technology for use in detecting and quantitating exposure to these OP toxins. The test technology incorporates a patented novel use of special nanoparticles to directly capture a reliable biomarker present in blood following an OP exposure. This direct detection of the biomarker eliminates the problematic issues seen with current tests that can produce variable results. Countervail’s innovative diagnostic technology can be used as a visually read screening test to qualitatively detect the presence of an exposure and can be further used to determine the degree of exposure incurred by the individual to aid in therapy decisions. Furthermore, Countervail’s innovative diagnostic technology broadly detects poisoning from all organophosphate toxins.
Since military nerve agents (sarin, VX, etc.) are also OP toxins, Countervail’s diagnostic technology also has a national security application in detecting nerve agent exposure as well as exposure to OP pesticides.
Countervail’s novel OP exposure diagnostic test technology offers the following attributes:
- IP protected innovative nanoparticle design
- Easy to use, Rapid, Lateral flow point-of-care test
- Qualitative screen visually read
- Quantitative analysis read by compact portable reader
- Broad spectrum ability to detect exposure to any OP toxin
- Can also be used for differential diagnosis to rule out other clinical conditions that produce similar symptoms
- Eliminates the need for a comparison baseline or population average cutoff required by current tests.