3-Quinuclidinyl benzilate

3-Quinuclidinyl benzilate (QNB) — IUPAC name 1-azabicyclo[2.2.2]octan-3-yl hydroxy(diphenyl)acetate; US Army code EA-2277; NATO code BZ; Soviet code Substance 78[1] — is an odorless and bitter tasting military incapacitating agent.[2] BZ is an antagonist of muscarinic acetylcholine receptors whose structure is the ester of benzilic acid with an alcohol derived from quinuclidine.

3-Quinuclidinyl benzilate
Bonding model
Ball and stick model
Names
IUPAC name
1-azabicyclo[2.2.2]octan-3-yl hydroxy(diphenyl)acetate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.164.060
MeSH Quinuclidinyl+benzilate
UNII
Properties
C21H23NO3
Molar mass 337.419 g·mol−1
Appearance White crystalline powder
Melting point 164 to 165 °C (327 to 329 °F; 437 to 438 K)
Boiling point 322 °C (612 °F; 595 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Physiochemical characteristics

BZ is odorless. BZ is a white crystalline powder with a bitter taste. It is stable in most solvents, with a half-life of three to four weeks in moist air; even heat-producing munitions can disperse it. It is extremely persistent in soil and water and on most surfaces. BZ is soluble in water, soluble in dilute acids, trichloroethylene, dimethylformamide, and most organic solvents, and insoluble with aqueous alkali.[3][4]

Effects

BZ affects both the peripheral nervous system (PNS) and CNS. BZ inhibits glandular secretions, leading to a dry mouth and foul breath. Cutaneous vasodilation and skin flushing may be noted due to decreased capillary tone. Hyperthermia is due to elevated body temperature secondary to inhibition of sweating and inability to dissipate heat. Vision loss is from a loss of accommodation reflexes and decreased depth of field secondary to ciliary muscle paralysis and mydriasis. Paralytic ileus is commonly seen as a result of anticholinergic toxicity. This can lead to fatal colic in equids. Urinary retention is also a common anticholinergic effect following exposure to BZ.

CNS signs of disorientation, agitation, tremor, ataxia, stupor, coma, and seizures may occur from inhibition of central muscarinic receptors. It is unknown whether animals hallucinate like people, but they do appear distressed. Rhabdomyolysis can be seen secondary to seizures and agitation. If severe, myoglobinuric kidney failure could develop.

At low doses BZ will have the effects of dry mouth, decreased gastric motility, inhibition of sweating, increase in heart rate, papillary dilation and loss of accommodation, mild sedation and mental slowing. At high doses these effects are severe. There are marked disturbances of function levels of the central nervous system (CNS), motor coordination, attentiveness, and control of thought and the learning process will all decline in function. Confusion, restlessness, impairment of perception and interpretation, and memory span are observed. The first symptoms occur depending on the route of administration, judgement and deficient insight are all features of the syndrome of effects BZ causes. Hallucinations will become present and if the dose is of a high enough dosage subjects may become stuporous or even comatose for several hours.[5]

Mechanism of action

BZ is absorbed by all the usual routes of administration (oral, parenteral and inhalational). The inhalational route is the more pronounced route of administration than the oral.[6] Experimental studies have been performed with parenteral administration and intravenious (i.v.) administration occur with no loss due to direct involvement of BZ in the transport system. In the bloodstream, BZ is bound to the plasma proteins (particularly the protein albumin), and the compound is transported to the sites of effect— namely the CNS and PNS (central nervous system and peripheral nervous system) respectively.[6] BZ is an antagonist of muscarinic acetylcholine receptors and binds to all subtypes of muscarinic acetylcholine receptors.[7]

Toxicity

Based on data from more than 500 reported cases of accidental atropine overdose and deliberate poisoning, it has been estimate that the median lethal oral dose to be approximately 450 mg (with a shallow probit slope of 1.8). Some estimates of lethality with BZ have been grossly erroneous, and ultimately the safety margin for BZ is inconclusive due to lack of human data at higher dosage ranges. Though some researchers have estimated it to be 0.5 to 3.0 mg/kg and an LD01 is 0.2 to 1.4 mg/kg (Rosenblatt, Dacre, Shiotsuka, & Rowlett, 1977).[8]

History

Invention and research

BZ was invented by the Swiss pharmaceutical company Hoffman-LaRoche in 1951.[9] The company was investigating anti-spasmodic agents, similar to tropine, for treating gastrointestinal ailments when the chemical was discovered.[9] It was then investigated for possible use in ulcer treatment, but was found unsuitable. At this time the United States military investigated it along with a wide range of possible nonlethal, psychoactive and psychotomimetic incapacitating agents including psychedelic drugs such as LSD and THC, dissociative drugs such as ketamine and phencyclidine, potent opioids such as fentanyl, as well as several glycolate anticholinergics.[10][11] By 1959, the United States Army showed significant interest in deploying it as a chemical warfare agent.[9] It was originally designated "TK", but when it was standardized by the Army in 1961, it received the NATO code name "BZ".[9] The agent commonly became known as "Buzz" because of this abbreviation and the effects it had on the mental state of the human volunteers intoxicated with it in research studies at Edgewood Arsenal in Maryland.[9] As described in retired Army psychiatrist James Ketchum's autobiographical book Chemical Warfare: Secrets Almost Forgotten (2006), work proceeded in 1964 when a general envisioned a scheme to incapacitate an entire trawler with aerosolized BZ; this effort was dubbed Project DORK.[12] BZ was ultimately weaponized for delivery in the M44 generator cluster and the M43 cluster bomb, until all such stocks were destroyed in 1989 as part of a general downsizing of the US chemical warfare program.

Use and Alleged use

The U.S. Army tested BZ as well as other "psycho-chemical" agents on human subjects at Edgewood Arsenal in Maryland from 1955 to 1975, according to declassified documents.[13][14]

In February 1998, the British Ministry of Defence accused Iraq of having stockpiled large amounts of a glycolate anticholinergic incapacitating agent known as Agent 15.[15] Agent 15 is an alleged Iraqi incapacitating agent that is likely to be chemically identical to BZ or closely related to it. Agent 15 was reportedly stockpiled in large quantities prior to and during the Persian Gulf War. However, after the war the CIA concluded that Iraq had not stockpiled or weaponized Agent 15.[16][17]

According to Professor Konstantin Anokhin at the Institute of Normal Physiology in Moscow, BZ was the chemical agent used during the 2002 Nord-Ost siege to incapacitate terrorists but due to overdose 204 of the hostages perished;[18] but many other agents have also been proposed, and none definitively confirmed.

In January 2013, an unidentified U.S. administration official, referring to an undisclosed U.S. State Department cable, claimed that "Syrian contacts made a compelling case that Agent 15, a hallucinogenic chemical similar to BZ,[19] was used in Homs".[20] However, in response to these reports a U.S. National Security Council spokesman stated "The reporting we have seen from media sources regarding alleged chemical weapons incidents in Syria has not been consistent with what we believe to be true about the Syrian chemical weapons program".[17][21]

Detection and protection

BZ is odorless and has a bitter taste and is nonirritating with delayed symptoms several hours after contact.[2][4]

Treatment

Antidotes for BZ include 7-MEOTA and can be administered in tablet or injection form. Atropine and Tetrahydroaminoacridine (THA) have also been used as treatments, THA has been shown to reduce the effects of BZ within minutes.[22][23]

References
  1. Conant, Eve (22 November 2002). "More Questions Than Answers". Newsweek. Retrieved 15 April 2018.
  2. QNB: Incapacitating Agent. Emergency Response Safety and Health Database. National Institute for Occupational Safety and Health. Accessed April 20, 2009.
  3. US Army FM 3-9
  4. Handbook of toxicology of chemical warfare agents. Gupta, Ramesh C. (Ramesh Chandra), 1949- (Second ed.). London: Academic Press. 21 January 2015. p. 152. ISBN 978-0-12-800494-4. OCLC 903965588.CS1 maint: others (link)
  5. Handbook of toxicology of chemical warfare agents. Gupta, Ramesh C. (Ramesh Chandra), 1949- (Second ed.). London: Academic Press. 21 January 2015. p. 154. ISBN 978-0-12-800494-4. OCLC 903965588.CS1 maint: others (link)
  6. Handbook of toxicology of chemical warfare agents. Gupta, Ramesh C. (Ramesh Chandra), 1949- (Second ed.). London: Academic Press. 21 January 2015. pp. 152–153. ISBN 978-0-12-800494-4. OCLC 903965588.CS1 maint: others (link)
  7. Handbook of toxicology of chemical warfare agents. Gupta, Ramesh C. (Ramesh Chandra), 1949- (Second ed.). London: Academic Press. 21 January 2015. p. 153. ISBN 978-0-12-800494-4. OCLC 903965588.CS1 maint: others (link)
  8. Goodman, Ephraim. (2010). Historical contributions to the human toxicology of atropine : behavioral effects of high doses of atropine and military uses of atropine to produce intoxication. Wentzville, Missouri: Eximdyne. p. 74. ISBN 978-0-9677264-3-4. OCLC 858939565.
  9. Kirby, Reid. "Paradise Lost: The Psycho Agents", The CBW Conventions Bulletin, May 2006, Issue no. 71, pp. 2-3, accessed December 11, 2008.
  10. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. (1984)
  11. Ketchum - Chemical Warfare: Secrets Almost Forgotten (2006)
  12. Army’s Hallucinogenic Weapons Unveiled
  13. "Vets feel abandoned after secret drug experiments". CNN. March 1, 2012.
  14. "U.S. Army Chemical Research and Development Laboratories Technical Report" (PDF). U.S. Army. May 1964.
  15. Iraqi `zombie gas' arsenal revealed
  16. Intelligence Update: Chemical Warfare Agent Issues (Report). CIA. April 2002. Retrieved 28 January 2013. We assess that Iraq never went beyond research with Agent 15—a hallucinogenic chemical similar to BZ—or any other psychochemical. Agent 15 became an issue after a 9 February 1998 British press release claimed that the UK had information, thought to be reliable, that Iraq had large quantities of this chemical agent in the 1980s. UNSCOM and intelligence information indicated that Iraq researched a number of psychochemicals, including Agent 15, BZ, and PCP; however, UNSCOM indicated it saw no evidence of Iraqi importation of large quantities, weaponization, procurement of militarily significant quantities of precursors, or industrial production of these agents
  17. Jeffrey Lewis (25 January 2013). "Why everyone's wrong about Assad's zombie gas". Foreign Policy. Retrieved 28 January 2013.
  18. https://www.theguardian.com/world/2002/oct/28/russia.richardnortontaylor
  19. Intelligence Update: Chemical Warfare Agent Issues
  20. Rogin, Josh (15 January 2013). "Secret State Department cable: Chemical weapons used in Syria". Foreign Policy The Cable. Retrieved 16 January 2013.
  21. "U.S. plays down media report that Syria used chemical weapons". Reuters. 16 January 2013. Retrieved 28 January 2013.
  22. Handbook of toxicology of chemical warfare agents. Gupta, Ramesh C. (Ramesh Chandra), 1949- (Second ed.). London: Academic Press. 21 January 2015. p. 156. ISBN 978-0-12-800494-4. OCLC 903965588.CS1 maint: others (link)
  23. Goodman, Ephraim. (2010). Historical contributions to the human toxicology of atropine : behavioral effects of high doses of atropine and military uses of atropine to produce intoxication. Wentzville, Missouri: Eximdyne. p. 72. ISBN 978-0-9677264-3-4. OCLC 858939565.
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