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The Efficacy of 7-Methoxytacrine in the Treatment of Central Anticholinergic Syndrome Caused by Some Incapacitating Chemical Agents

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The Efficacy of 7-Methoxytacrine in the Treatment of Central Anticholinergic Syndrome Caused by Some Incapacitating Chemical Agents 14 voJENsKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM Volume LXVlI, 1998, no. 1 THE EFFICACY OF 7-METHOXYTACRINE IN THE TREATMENT OF CENTRAL ANTICHOLINERGIC SYNDROME CAUSED BY SOME INCAPACITATING CHEMICAL AGENTS Jiří PATOČKA, Josef FUSEK Purkyně Military Medical Academy, Hradec Králové Summary Central anticholinergic syndrome evoked by some incapacitating chemical agents from the family of anticholinergics is possible to treat with some reversible centrally active inhibitors of acetylcholinesterase. /n this paper the view Of anticholinergic incapacitating agents and their biological effects is summarize as well as a survey of inhibitors of acetylcholinesterase which may be used as antidotes against intoxication by incapacitating chemical agents. The position of 7-methoxytacrine as very effective and little toxic antidote is discussed. KEY WORDS: Incapacitating chemical agents; Biological effects; Acetylcholinesterase inhibitors; Antidotes. Introduction Scopo/amine structurally resembles atropine and as a drug is Chemical weapons conceive uncommonly used in the form of soluble hydrochloride. Its meaningful resource of army (1, 2). Besides classical toxicity is approximately five times higher than chemical compounds with high lethality and the toxicity of atropine (6). ln higher, but not toxic mortality some agents were developed, which in doses, causes the same psychotic disorders as relatively small doses caused psychical and physical atropine and both drugs have been ever used harm to living power (2, 3). These compounds are for ritual and therapeutic purposes since antiquity known as incapacitating chemical agents (NCA) (12, 15). (2). From the military point of view the most important NCA are compounds with psychoto- Benactyzine mimetic effect (4, 5). These compounds are also was developed as a synthetic tranquilizer with known as psychodysleptics, fantastics, psycho- anticholinergic action. Its psychotic effect resem- delics, psycholytics or halucinogenes (6). bles atropine and the central component of Well-known psychotomimetics are compounds pharmacological effect outweigh the peripheral one. pharmacologically characterized as anticholinergic Benactyzine is also less toxic than atropine (16). drugs (7, 8). JB-336 is one of many compounds prepared by John Anticholinergic NCA Biel (code JB) (17, 18). This compound is one of the most active derivatives of substituted piperidyl- There are compounds occurring in natural sources benzilates (19, 20). (belladona alkaloids atropine and scopolamine) from any Solanaceae (Atropa belladonna, Hyosciamus Ditran niger and Datura stramonium) (9, 10) and in is a mixture of two compounds: 70 percent of N- chemically synthesized compounds as for example -ethyl-2-pyrrolidyl-methyl-cyklopentylphenyl glycolate benactyzine, JB 336, Ditran or BZ (10-12). The and 30 % of N-ethyl-3-piperidyl-cyklopentylphenylV chemical structures of all these compounds are' _glycolate (21). lt is used as soluble hydrochloride. given in Table l. Ditran was used as a model compound for the study of nervous system. lt was used for Atropine experimental as well as for psychotherapeutic is a racemic mixture of D- and L-hyoscyamine purposes (12, 22, 23, 24). Ditran was also used as a drug in the form of the well-soluble extended among addicts for its hallucinogenic hydrochloride. The minimal lethal dose for humans properties (6). is 0.1 g (13), therapeutic doses are in the interval from 0.5 to 1 mg pro dose (6). Atropine is quite BZ absorbed by mucous membranes. In small doses or QB are code names for 3-quinuclidinyl only peripheral effects were observed, in high benzilate (25). This compound is relatively little doses central and incapacitating effects were also toxic but psychical incapacitance appears already observed (14). at its very low doses (26). There is a sole compound Volume LXVII, 1998, no. 1 VOJENSKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM 15 CH3 )2- CHZOH OCOCH Atronine Scopolamlne Q H0- C- CQOCHzCH2N(C2H5)2 Q Benactyzine JB-336 ) Ĺ C2H5 C2H5 I N/ H0- C— COOCH2\ :N: + Ho ...c -coocHz -—<:) Cl Cl Dltrın H0- 0- CO 3-Quinuclidinyl benzilate (QB, BZ) Table I The chemical Structures of Some Anticholinergic Drugs which are known as Incapacitating Chemical Agents (NCA) 16 VOJENSKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM Volume LXVII, 1998, no. 1 NCA used in battle-field against people (27). The this it is evident that the incapacitance of people common mechanism of pharmacological effects of caused by BZ is long-term (9). In the military context these compounds is founded in their interaction there are important effects of NCA based on the with acetylcholine receptors and subsequent entire disorientation and the loss of contact with depolarization of excitation membranes (11, 28). environment connected with harm of imagination and From the pharmacological point of view these speech as well as the senses of desperation and compounds may be characterized as anticholinergics anxiety (36). Therefore, it is very desirable to apply with psychotomimetic effect and different affinity to the effective antidote as soon as possible the best the central and peripheral nervous systems (9, 29-32). way is in the form of self-aid or fist-aid. Clinical course of acute intoxication Table III The Survey of Symptoms of Intoxication by Anticholinergic Clinical course of intoxication with all these Drugs (NCA) - Psychological and Behavioral Symptoms compounds is actually the same as with over- dosing of_ atropine or natural belladona alkaloids Changes in Symptoms (33). Acute intoxication courses cover up changes Functions in autonomous, motoric, central, neurological, - damage of space and time cognizance behavioral, and psychological functions (26, 34, 35). - retarded mental functions The survey of these symptoms is summarized in Stupor - retarded reactions Tables Il and III. - lack of interest - incoherentia - somnolence Table Il - absence of mind with agitation - illusions The Survey of Symptoms of Intoxication by Anticholinergic Delirium - apprehensions Drugs (NCA) - Autonomous and Neurological Symptoms - disturbances - anxiety - auditory Changes in Functions Symptoms - visual Hallucination - tactile - mydriasis - smell - dryness in mouth - taste Autonomous peripheral - hyperemia of skin - space and time disorientation - tachycardia - hypertension Disturbances - erroneous interpretation of questions - - inability of orientation in life environment - retarded speech Motorical and somatical - slow gait - sudden spite or emotivity stroke Emotivity - negativism - tremor - rigidity — paranoic reaction - sudden anxiety, scare, panic fear - ataxia Senzoro-thalamical - increase of sensitivity to pain Amnesia - inability to remember - loss of tactile and thermic receptivity Dream states - slight remembrances of the past - hypotonia - delirium - fine tremor Aphasia - inability to coherent speech - somnolence - irritation Agnosia - loss of ability to formulate thoughts - excitation - complete inability to speak Telencephalical - afasia - apraxia - decrease of rate and accuracy in - visual and auditory agnosia Intellect solving problems - disarthria - inability to comprehend questions - loss of speech - vertigo - nystagmus Therapeutic drugs used as antidotes All therapeutic drugs used for the treatment of The time course of acute intoxication is different central anticholinergic syndrome are compounds for individual compounds. ln the case of the most with cholinomimetic effects. Only three compounds of important NCA BZ, the first symptoms appeared this type were recommended as antidotes for the 30 min after drug application. This first phase of ' therapy of acute intoxication by NCA: Physostig- intoxication has a vegetative character. Delirium mine, tacrine, and 7-methoxytacrine. All these phase of intoxication begins after 1 to 1.5 hrs and compounds are both peripherally and centrally culmination of symptoms is observed between effective cholinesterase inhibitors which exert both 4 to 8 hrs. The lethargical phase of intoxication peripheral and central cholinomimetic actions. The develops usually after 12 to 24 hrs (12, 26). From chemical structures of all these compounds are Volume LXVII, 1998, no. 1 VOJENSKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM 17 OCONHCH3 N N | I CH3 CH3 Physostigmine NH2 NH2 CH30 \ / I z CÔÛN ~ N Tacrine 7-Methoxytacrine Table /V The Chemical Structures Of Some Antidotes Used for Treatment of Anticho/inergic Syndrome Evoked by Anticholinergic Drugs (NCA) given in Table IV. 7-Methoxytacrine (7-MEOTA) 7-methoxy-9-amino-1,2,3,4-tetrahydroacridine is Physostigmine (eserine) a simple derivative of tacrine. The compound is alkaloid from the plant Physostigma venenosum was developed in our Institute (49), where many Balf. growing in West Africa and known here as compounds of this type have been synthesized and Calabar bean (37). These beans were used in this tested as antidotes against NCA intoxication (52, geographical area of Africa for the poison ordeal (15). 53). 7-methoxytacrine has been drawn for its low Physostigmine is widely used in modern medicine toxicity and good therapeutic effect. The LD50 value (38, 39) but its toxicity is too high. Therefore its in mice (i.v.) is 125 mg/kg (54). Also in other animal numerous analogues used as cholinergic drugs species the acute toxicity of 7-methoxytacrine was were synthesized and evaluated (40-42). The acute lower than the toxicity of tacrine (54). The time of toxicity of physostigmine in mice after i.m. application course of the pharmaceutical action of 7- is expresSed by LD50 value of 0.6 mg/kg (41).
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