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The History of Military Toxicology

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The History of Military Toxicology HISTORICAL ARTICLE THE HISTORY OF MILITARY TOXICOLOGY Jiří Bajgar, Josef Fusek Military Medical Academy, Hradec Králové; (Rector: doc. MUDr. S. Bùma, CSc.) However, the name of the Department as well as the term ãmilitary“ were excluded from the title. The Institute was designated as the Medical Research Institute for foreign journals only. On the other hand, in the Czech journals which were freely circulated abroad, the word ãmilitary“ was present as well as other specifications such as military rank. At this time, the Department was equipped with tech- niques on very sophisticated basis, e.g. fluorimeter Farrand, Auto Analyzer Technicon, ultracentrifuge MSE etc. The staff of the Department was also on high level able to cover the research of toxic substances from synthesis and analy- sis (Ing. F. Ornst, CSc.) later on through toxicity testing COL Assoc. Prof. J. Bajgar, (1944) COL Prof. J. Fusek (1945) (MUDr. M. Krejcar, CSc.; MUDr. V. Hrdina, CSc.), inclu- ding percutaneous route of administration (MUDr. V. Research on protection against CWA was very intense Vondráček, CSc.), biochemical characterization in vitro in the former Czechoslovakia. As early as pre-WW II, this and in vivo (MUDr. Tulach, CSc. and MUDr. A. Jakl, research was conducted at the Military Technical Institute CSc.), histochemical evoluation (MUDr. R. Urban, CSc.) in Prague. In the fifties, the medical and technical topics and development of antidotal treatment (Dr. J. Vachek). In were separated and the medical aspects were delegated to the year 1968, Prof. Fink was named the Head of the who- the Department of Toxicology (DTOX), Military Medical le institute (Purkyně Military Medical Research and Academy (MMA), Hradec Králové. Military toxicology is Postgraduate Institute). New chief of the DTOX was Doc. a prime responsibility of the DTOX. The MMA was foun- MUDr. V. Vondráček, CSc. Prof. Fink was in this post till ded in 1951 and the DTOX, without experience or equip- 1971. Then he had to leave the Army as a result of a politi- ment, began its work on 1 September 1951 in one room of cal persecution during the so called ãperiod of normalizati- the civilian Medical Faculty of Charles University. Its total on“ which started after the year 1969. equipment on hand was one typewriter and two masks. Although the political situation changed substantially All the activities were focused to education, however, re- after the Prague Spring, all activities of the DTOX more or search work begun. Technical equipment was enlarged, e.g. less continued. During the seventies to eighties, COL. Prof. Lange’s photometer, oscilometer, Warburg instrument. The Ing. Jiří Matoušek, DrSc. was a new member of the DTOX first head of the Department was Prof. MUDr. Zdeněk staff. His work focused on development of new decontami- Fink, DrSc.. nation agents that resulted in a decontamination kit based In the sixties initial scientific work focused on research on sorption mechanical principle (DESPRACH) for the into the mode of action of mustard gas, cyanide and nerve Czechoslavak Army and Civil Defence. In the year of 1973, agents. The results of this research were classified secret COL Prof. MUDr. V. Hrdina, CSc. was named the Head of and had little or no publicity and practically no outlet into the Department. scientific journals. One result of this research was the de- Education at the MMA, which was focused on military velopment and production of pralidoxime (PAM Spofa) toxicology, began to consider more modern techniques of which was introduced into the Armed Forces. In 1965, the video, movies, computers, etc. More than 10 movies were lay syringe (LIS) for self-administration of atropine was int- produced at the DTOX. These dealt with, amongst other roduced into the Czechoslovak Army. This particular rese- subjects, clinical laboratory diagnosis of organophosphate arch effort during the sixties and later into the seventies, and other chemicals poisoning. resulted in the assessment of the maximal available doses of Some research works on intoxication with psychotomi- nerve agents for man. metic compound, e.g., LSD-25, IDPN and BZ and their tre- By the end of the sixties and the Prague Spring, the first atment were done and prospective antidotes were studied in publications of the DTOX were seen in scientific literature. a more detailed fashion. New concrete antidotes against ACTA MEDICA (Hradec Králové) 1997;40:79-82 79 nerve agents (FOSAN, CHONOL I and II, RENOL) prop- After an accident in which Prof. Bajgar fractured two hylactic antidote against organophosphates (PANPAL) and vertebra, COL Prof. MUDr. J. Fusek, DrSc. became the antidote (7-MEOTA) against psychotomimetic compound new head of DTOX and also the rector of the whole BZ were real results of this research which were finalized Academy. Other officers of the staff of the DTOX include: by the end of the eighties. LTC MUDr. O. Krs, CSc. (histology); LTC doc. MUDr. J. Modernization also was also seen in the means of ad- Kassa, CSc. (biochemistry) and LTC Ing. J. Cabal, CSc. ministration; the autoinjector GAI containing atropine and (decontamination). There are also very qualified and expe- obidoxime was developed for the Army in cooperation with rienced civilian research professionals participating in rese- the former GDR. After the so-called ãvelvet revolution“, arch in the following areas: Dr. J. Vachek (antidotal a new head of the DTOX was elected (COL doc. MUDr. J. treatment and development of antidotes); doc. RNDr. J. Bajgar, DrSc.), and research dealing with further study of Patočka, DrSc. (enzymology); MUDr. J. Herink, DrSc. action of CWA and their antidotes was continuing in two (electroencephalography); RNDr. M. Koupilová, CSc. (be- research projects designated as OTRAL and SOMAN. havioral techniques) and Ing. J. Bielavskù (synthesis of che- OTRAL described the toxic effect of the new nerve micals). Their contributions are of great importance for the agent GV, with properties similar to G, as well as V. com- final results in the many and varied areas. pounds, and GV’s medical treatment by the usual antidotes, There was also another research direction: in the sixties which is difficult. Cholinesterase activity in the blood fol- there were some rumors in the press concerning testing and lowing GV and other nerve agents (soman, sarin, VX) into- weaponization of psychotomimetic agents in some NATO xication, corresponded to activity in the target organs and countries. As a reaction to this information, the Czecho- enabled us to assess the degree of inhibition corresponding slovak Army proposed a testing of potential psychotomi- to different symptoms. metic agents which might be identified for military use and Some aziridine neurotoxins were characterized using experimental work was begun. electrophysiological and behavioral methods including the LSD-25 was tested as the first compound. Some chan- method for testing of non-lethal effect (spontaneous motor ges in the content of catecholamines, acetylcholine and activity). The suitability and sensitivity of the method was cholinesterase activity in the brain were observed, inclu- demonstrated using various derivatives of aziridines, nerve ding the influence of LSD-25 on behaviour in laboratory agents, mustard and BZ. rats and in some cases dogs. The effect of LSD-25 was tes- Further details on the action of antidote (7-MEOTA) ted on two groups of officer volunteers simulating the work against BZ intoxication, expecially different inhibitions of of a commander and his staff during military operations. molecular forms of rat brain acetylcholinesterase (AChE) Members of the staff with LSD-25 administration were una- by 7-MEOTA and good tolerance following administration ble to work after 30-45 minutes following administration to healthy volunteers were reported. (60 µg/person, p.o.), and this lasted for a 3-6 hour period. SOMAN: Inhibition of AChE in the rabbit red blood However, according to data in the literature, as well as (RBC) cells to zero activity by soman was described. A re- an increasing amount of baseline data we were establishing, infusion of these erythrocytes to normal rabbits, with a cor- it was becoming clear that LSD-25 could represent a model responding decrease of up to 60 % of controls (caused by for study of psychotomimetic effect rather than chemical mixing with normal RBC) was demonstrated in these ani- warfare agent; a weaponized compound would not be LSD. mals. All animals survived 24 h following transfusion. Therefore attention was focused on the group of anti- An increase of DNA content in the liver was also de- cholinergic as well as psychotomimetic effects. From this monstrated following from 1h to 3 days of soman adminis- group of compounds, JB-336, Ditran, BZ and others were tration. Synthesis and physico chemical properties of the studied. Later on, BZ was found to be the most important ester and amide of 4-substituted 2-pyridinealdoxime and tet- and it was studied in detail. According to a character of this roxime were characterized. Their biological effects were compound, physostigmine as a military antidote was first compared with those of HI-6. proposed. However, its side effects and relatively high toxi- All compounds suppressed cholinergic and noncholi- city were stimulating the drive to search for a new drug, pre- nergic changes following soman poisoning, however, supe- ferably with reversible cholinesterase inhibitors. riority of HI-6 and its ability to reactivate inhibited AChE Because of the known effects of Tacrin as a representa- in the brain was observed. The best prophylactic, 5 hours tive of this group, some other acridine derivatives were synt- lasting effect was PANPAL (combination of pyridostigmi- hesized and characterized with the intent to find ne, benactyzine and trihexyphenidyle). The prophylactic ef- a substance less toxic than Tacrin. fect was demonstrated when administered 2 hours before Hundreds of compounds were synthesized and anticho- soman intoxication. Moreover, the subsequent antidotal tre- linesterase activity was tested and tens of them were cha- atment with HI-6 and benactyzine potentiated the prophy- racterized toxicologically.
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