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Fiotdrrn Clirt Phormcicol ( 1992) 6 , 309-3 I8 0 Elsevier. Paris

Effects of paraldehyde on the convulsions induced by administration of soman in rats P Carpentier, G Lallement, N Bodjarian, A Tarricone, G Blanchet Centre de Recherches du Service de Santk des Armies, Unite de Neurotoxicologie, BP 87,38702 La Tronche Cedex, France (Received 6 April 1992; accepted 30 July 1992)

Summary - The ability of paraldehyde, a potent central nervous system depressant, to prevent the convulsions induced by the organophosphate soman, an irreversible inhibitor of acetylcholinesterase, was studied in rats. Paraldehyde (0.1-500 mg k g , im) administered 10 min before soman (100 p g k g , sc) did not protect against seizures. Co-administered with atropine sulfate (I0 m g k g , im), paraldehydc produced a clear dose-dependent anticonvulsant response. Although this pre-treatment could delay the occurrence of death, it did not produce any change in the soman-induced 24 h mortality rate. Thus, co-administration of paraldehyde and atropine sulfate might constitute a valuable tool to be used against the convulsant consequences of soman poisoning. However, supplementary premcdication, in addition to paraldehyde and atropine sulfate, remains necessary to improve the antilethal capacity of the pre-treatment. soman I paraldehyde I atropine /seizure I rat

Introduction The organophosphorus compound soman, an irreversible acetylcholinesterase inhibitor, is wellknown to produce overt convulsions and subsequent irreversible brain damage (Lemercier et al, 1983; McLeod et al, 1984). Soman-induced seizures are particularly resistant to classical medications of organophosphate poisoning. Thus, whereas moderate doses of atropine sulfate could sometimes reduce the duration of seizures (Samson et al, 1985; Pazdernik et al, 1986), only high doses of the muscarinic antagonist were reported to exert clear anticonvulsant activity (Shih, 1990; 1991 ; Shih et af, 1991; Capacio et af, 1991). On the other hand, benzodiazepines, such as diazepam, could prevent or block soman seizures when they were administered either prophylactically (Martin et af, 1985) or curatively in the very first minutes of the

intoxication (Lipp, 1972, 1973; Shih, 1991). However, benzodiazepines d o not alleviate ongoing status epilepticus once it has been established (Sparenborg et al, 1990). Owing to this special refractoriness of the soman-induced seizures, the design of better anticonvulsant antidotes still remains a goal of crucial interest for medical management of exposed subjects. In this field of research, we were interested in the anticonvulsant effects of paraldehyde. This compound, the exact mode of action of which is still unknown (Lockman, 1989), produces a rather universal depressing action on neuronal activity at different levels of the peripheral and central nervous systems (De Elio et af, 1949). Moreover, although toxic side-effects (pulmonary edema, cardiac failure etc) have led to infrequent clinical use, paraldehyde has been shown to provide excellent anticonvulsant protection on various models of

3 10

P Carpentier et al

experimental seizures and intractable human epilepsy on which conventional anticonvulsant drugs (diazepam, phenytoin, phenobarbital) were ineffective (De Elio et al, 1949; Browne, 1983; Curless et al, 1983; Lockman, 1989; Ramsay, 1989). Above all, paraldehyde was recently reported (Momsett et al, 1987) to prevent or even to interrupt the seizures produced by the muscarinic agonist pilocarpine in rats pre-treated by lithium. Moreover, all rats administered with lithium, pilocarpine and paraldehyde survived whereas, in the conditions used, the mortality of lithium pilocarpine was 100%(Momsett et al, 1987). This particularly wide spectrum of action of paraldehyde, as a potent neuronal depressant and antiepileptic agent, and its special effectiveness on the cholinergically induced seizures produced by lithium and pilocarpine, a model of seizures which is thought to be very similar to that of soman (eg Turski et al, 1989), led us to believe that this compound might exert promising beneficial activity against the convulsive consequences of the cholinergic stimulation created by soman. Although the protective activity of atropine sulfate is far from complete and its anticonvulsant potential restrained to high dosages, it is the most common antidote for soman poisoning and is currently recommended as a valuable and even indispensable standard medication. The usefulness of atropine sulfate relies on its ability to minimize soman-induced mortality and, probably through its capacity to antagonize at least a part of the cholinergic hyperstimulation produced by soman, to enhance or even reveal the anticonvulsant potential of drugs (eg, diazepam, MK-801) that do not act on the cholinergic system (Shih, 1990; 1991). It thus seems reasonable to predict that paraldehyde and atropine sulfate used as combined pre-treatments might give fruitful results. Therefore, in the present study, the ability of various doses of paraldehyde to prevent the seizures produced in rats by sublethal dose of soman was investigated, in the presence or the absence of the muscarinic blocker atropine sulfate. Although a search for anticonvulsant activity constitutes the major issue of this work, effects of the pre-treat-

ments used on behavioral and lethal consequences of soman administration were also recorded.

Materials and methods Animals

Male Wistar rats (ICO:WI (IOPS AF/HAN); Iffa Credo, Les Oncins, France), weighing 300-320 g served as subjects. They were maintained on a 12 MI2 h light /dark cycle with full-spectrum light provided between 07 00 and 19 00 hours. They were given food and water ad libitum. Surgical preparation f o r electroencephalographic recordings

Under pentobarbital (Sanofi, France) deep anesthesia (ip; 70 mgkg; injection volume 360 pl), three monopolar screw electrodes were inserted through the parietal bone 4 mm lateral to the longitudinal fissure and 4.5 (left side), 2.3 and 4.8 mm (right side) respectively posterior to the bregma. As controlled on post-mortem vertico-frontal sections, the tips of electrodes were positioned 2.2 - 2.4 mm down in the somatosensory (the most caudally implanted electrodes) and the motor (the most rostrally implanted electrode) areas of the frontoparietal cortex. Animals recovered six days prior to experiments. Drugs

Soman (pinacolyl methylphosphonofluoridate; > 97% pure by gas chromatography; supplied by the Centre d'Etudes du Bouchet, France) was freshly prepared daily in ice-cold 0.9% (w/v) saline and administered subcutaneously under neck skin (injection vol: 500 pl) at a dose of 100 p g k g . Atropine sulfate (Sigma Chemical Co, St Louis, MO, USA) was dissolved in saline and injected (10 mg/kg; im; injection vol: 200 pl) in the thigh muscles of the right hind leg. Paraldehyde (Fluka Chemie AG, Buchs, Switzerland) was diluted in saline and injected at different doses (0.1, 0.5, 5, 50, 500 m g k g ; im; injection vol: 150 pl) in the thigh muscles of the left hind leg. As regularly assessed by IR spectrography, the paraldehyde stock solution (>97% pure, according to the manufacturer) contained far less than 1% acetic acid. Therefore, none of the detrimental effects observed after paraldehyde injection could be attributed to this highly

31 1

Paraldehyde and soman seizures

toxic by -product of paraldehyde hydrolysis (Browne, 1983). All drug injections were given between 10 00 and 1 1 00 hours.

Experimental procedures The day of the experiment, implanted rats were connected to an EEG recorder (Alvar Reega Minidix, Montreuil, France). Using ipsilateral and contralateral motor/somatosensory derivations, baseline EEG was recorded from freely moving animals for at least 30 min prior to drug administration. Then, atropine sulfate at a fixed dose (10 mg/kg), paraldehyde at different doses (0.1 to 500 mgkg), or both atropine and paraldehyde were administered 10 min prior t o injection of s o m a n ( n = 9 - 14 per pre-treatment group) or saline ( n = 3 per pre-treatment group). The reproducibility of the toxic effects of soman was verified throughout the experiment. A total of 30 animals receiving no pre-medications (replaced by saline) were intoxicated to this purpose and served as controls. Following injections, the different patterns o f EEG changes elicited by each treatment were observed continuously for a period o f 3 h. The behavioral signs of intoxication, the progression of mortality and the 24 h lethality were also noted.

animals treated by the highest doses of paraldehyde (50-500 mgkg). All rats displayed apparently normal behavior at 24 h. Intoxicated rats without pre-treatment

In untreated animals, soman (100 p g k g ) rapidly produced obvious respiratory disorders (hypersalivation, upper airways obstruction, dyspnea, apnea)

BASELINE

1

RETREATMENT SOMAP

PREl C I A I PERIOD

iElZURE ONSET

SEIZURE PERIOD

PERIO 0

I:

+ -111

+ 5min

.20min

NONE-

: PARA-

fwww

w

Data anal.vsis The number of deaths at 24 h and the number of rats exhibiting seizures were observed in the different pretreatment groups and compared to those recorded in the group exposed to soman alone. Significant differences were evaluated using the Yates' x2 test. Differences in latency-to-death and latency-to-spike activity on EEG observed in the different experimental groups were analyzed using the non-parametric Mann and Whitney's U-test.

Results When injected in naive rats, none of the pre-treatments produced convulsant or lethal effects. While atropine sulfate produced hyperreactive behavior, paraldehyde generally induced slight prostration and immobility. Occasional coughs and discrete periods of laboured breathing were noted in the

1-

AS

Fig. 1. Representive serial EEG recordings (contralateral derivations are shown: From left somatosensory area to right motor area) from treated rats that survived more than 1.5 h after soman (100 p k g , sc) administration. Four main types of EEG patterns could be seen: ( I ) Permanent and well-stabilized seizures as observed in intoxicated rats receiving no pre-treatment (I) or pre-treated by PARA alone (11); (2) Permanent but attenuated and badly stabilized seizures as observed in approximately SO% of the convulsive rats pre-treated by AS (Illa) or by AS + PARA (IVa): (3) Rapidly interrupted seizures as observed in approximately 50% of the convulsive rats pretreated by AS (IIIb) or by AS + PARA (IVb); (4) Absence of seizures as observed in more than 60% of the total rats pre-treated by AS + PARA (1Vc).

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P Carpentier et u/

and generalized tonic-clonic convulsions. It was consistently noted that the occurrence of rapid death (in the first 60 min of the intoxication) was well-correlated with particularly severe respiratory distress. In rats which survived longer, the behavioral convulsive episodes could persist 1 h or more. Afterwards, the motor movements tended to diminish and the animals fell into a profound comatose state. In good agreement with the clinical convulsions, initial discrete spike activity appeared on EEG in less than 10 min (table I) and progressed

rapidly (within minutes) into a continuous and homogeneous pattern of generalized status epilepticus of very high amplitude and frequency (fig 1). In this group, more than half of the treated animals died in less than 30 min and a few survived the first 3 hours of the intoxication (table 11). Intoxicated rats pre-treated by atropine sulfate

The prophylactic administration of atropine sulfate to soman-intoxicated animals suppressed excessive

Table I. Seizure activity in treated rats Pre-treatmenrl

Number spikingb

Permanent Seizurese

Interrupted Seizures1

Spike Latency8

~

None

34/35 (97.1%)

34/34 (1 00%)

0134 (0%)

8.52 f 0.9 ( n = 34)

AS (10)

12/14 (85.7%)

6/12 (50%)

6/12 (50%)

10.9f 1.5 ( n = 12)

9/10 719 8/10 41I 3c

919 717 8/8 314

019

018 114

24/29 (82.7%)

24/24 ( I 00%)

0124 (0%)

319

013

3/3

8 f 2.0 ( n = 3)

8/10

6/8

218

8.1 k 1.2 ( n = 8)

4/10

214

214

51.2 f 31.5 ( n = 4)1k

019

0

0

8115 (53.3%)

711 5 (46.6%)

PARA (0.1) PARA (0.5) PARA (5) PARA (50/500) Total PARAm AS (10) + PARA (0.1) AS (10) + PARA (0.5) AS ( 10) + PARA (5) AS(lO)+ PARA (500) Total AS

+ PARA

15/38d (39.4%)

017

7.3 f 0.8 11.8f 1.8 7.5 f 1 .O 7.5 f 0.6

( n = 9) (n=7)h ( n = 8) ( n = 4)

> 3 hJ'

Rats were administered with soman (100 pgkg, sc) 10 minutes after im injection of AS andlor PARA (doses in m g k g are given in parentheses); Ratio of number and percentage of rats exhibiting at least one sequence of spike activity versus total number of rats tested. Significant differences between pre-treatment groups and the group exposed to soman alone were evaluated with Yates' x* test; c P < 0.01; d P < 0.001; e Ratio of number (and percentage) of rats showing permanent seizures versus total number of convulsive rats; Ratio of number (and percentage) of rats showing interrupted seizures (see text and fig 1) versus total number of convulsive rats; g Average time (min f SEM) between soman administration and first spike activity. Significant increase in spike latency between each pre-treatment group and control group (h P < 0.05; I P < 0.01; J obvious difference. statistics not required). and between each PARA or PARA + AS groups and AS group were evaluated with Mann and Whitney's U-test (k P < 0.01; I obvious difference, statistics not required). Since the effect of the highest doses of PARA on soman-induced seizures seemed profoundly biased by the rapid occurence of death (see text), the 13 rats administered with 50 or 500 m g k g of PARA were not included in these data a

313

Paraldehyde and soman seizures

upper airways secretion, reduced the severity of the respiratory disorders but did not avoid the appearance of brief but violent episodes of clinical convulsions which were usually repeated several times for a period of 1-10 min. After this, the animals fell into a long-lasting phase of complete immobility and comatose prostration. Compared to soman-intoxicated rats receiving no pre-treatment, the total number of atropine-pretreated animals showing epileptiform discharges on EEG as well as the latency-to-spike activity was not significantly modified (table I). However, only 50% of these convulsive rats (table I) expe-

rienced permanent generalized status epilepticus, the pattern of which profoundly differed from those displayed by the intoxicated unpretreated animals (fig 1). By comparison, epileptiform discharges were generally of lower frequency and voltage and were characterized by their heterogeneous aspect consisting of a hazardous succession of isolated spikes, rhythmed spiking activity or bursts of polyspiking of various duration. Moreover, in the other 50% of convulsive animals, atropine sulfate pre-treatment was shown to provide partial anticonvulsant activity. Thus, in these subjects, although the pre-treatment did not impede

Table 11. Mortality in treated rats. Pre - t reutmenr

Percentage mortality

N

0.5 h

1.0 h

2.0 h

Death Lcrtency?

b

3.0 h

24 h

None

35

5 1.4

74.2

88.5

94.2

97.1

39.1 f 6.5 (n = 33)

AS (10)

14

14.2

14.2

35.7

50

92.8

82.7 f 21.7 ( n =7)

PARA (0. I )

10 9 10

60 0 30

90 11.1 40

13

100

90 22.2 40 100

90 44.1 60 100

90 44.4d 6oC 100

PARA (0.5) PARA ( 5 ) PARA (50/500)

100

f

23.5 f 2.4 ( n = 9) 94f24.6(n=4)f 66.5 f 29.3 ( n = 6) 12.9 f 2.0 ( n = 13)

+

AS ( 10) PARA (0.I )

9

22.2

44.4

44.4

44.4

88.8

28.5 f 7.7 (n = 4)

10

10

40

80

90

90

65.4f 13.4(n=9)9

10

0

10

30

so

80

92.0 f 20.1 ( n = 5 ) g

9

0

0

0

0

100

AS (10) + PARA (0.5) AS ( 10) + PARA ( 5 ) AS (10) + PARA (500)

> 180h

Same conditions as indicated in table I; Cumulated percentages of dead rats noted at different times after soman administration. Significant differences between the number of deaths observed at 24 h in pre-treatment groups and that noted in the group exposed to soman alone were evaluated with Yates'X2 test (C P < 0.01; P < 0.001); Average time (min f SEM) following soman administration to death occurence. These data were established from the number n of rats (indicated in brackets) which died within the first 3 hours of intoxication. Significant increases in the latency-to-death observed in the different pre-treatment groups compared to that noted in the control group (soman alone) were evaluated with Mann and Whitney's U-test; (f P < 0.05; g P < 0.01; obvious difference, statistics not needed). With the obvious exception of the group co-administered with AS and 500 m g k g of PARA, none of the PARA or PARA + AS pre-treatments showed any significant increase in the latency-to-death compared to that observed in the AS pre-treatment group a

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P Carpentier ot t i /

the initiation of paroxysmal activity, the duration of seizures was strikingly shortened and limited to the initial 1-10 min period. All epileptiform activity was then abolished on EEG and never re-occurred (table I, fig 1). Finally, atropine sulfate delayed the occurrence of death but did not significantly reduce the 24 h mortality rate noted i n unprotected animals (table 11). Intoxicated rats pre-treated by paraldehyde The respiratory disorders, motor convulsions and electrographic seizures normally elicited by soman were not modified by the lowest dose of paraldehyde (0.1 mgkg). As shown in tables I and 11, this pre-treatment did not produce any significant change in either the electrographic (percentage spiking, spike latency) or the lethality (percentage mortality, death latency) parameters as previously measured in the unprotected intoxicated subjects. On the other hand, whereas the intermediate doses (0.5-5 mgkg) did not impede the production of the soman-induced clinical and electrographic seizures (table I, fig l ) , they produced an obvious increase in the rhythm and amplitude of the respiratory movements. Correlatively, the latency-todeath was clearly prolonged. This was especially true in the group receiving the 0.5 mgkg dose of paraldehyde in which survival duration was statistically increased (compared to unpretreated somanintoxicated controls) and was of the same order of magnitude as that found in intoxicated animals pre-treated by atropine sulfate alone (table 11). Moreover, a significant reduction in the 24 h mortality rate was observed. However, the surviving rats often showed signs of a profound comatose state with accompanying apparent cyanosis and were unable to move and feed at 24 h. Finally, within the minutes which followed soman injection, the most massive doses of paraldehyde (50-500 mgkg) induced asynchronous thoracic movements, chaotic laboured breathing and phases of dramatic dyspnea. All the animals died in less than 15 min (table 11). Thus, the apparent anticonvulsant activity of paraldehyde noted in this

group (table I ) was certainly atypical and biased by the almost immediate death which, in numerous cases, occurred before seizure activity was establi shed. Intoxicated rats pre-treated by atropine sulfate and paraldehyde At least in the first hours of the intoxication, the combined injection of atropine sulfate and paraldehyde reproduced the ‘atropinic’ suppression of the upper airways secretions and the ‘paraldehydic’ increase in rhythm and amplitude of the thoracic movements. This was observed for every dose of paraldehyde used. Thus, the acute brutal respiratory desynchronization produced by the highest dose of paraldehyde was still not observed when this pre-treatment was co-administered with atropine sulfate. The partial anticonvulsant effect produced by atropine sulfate was strikingly improved by paraldehyde since only 39.4% of all the rats treated (all paraldehyde doses together) and none of the animals administered with 500 m g k g of paraldehyde displayed the brief but violent paroxystic sequences observed in the atropine sulfate group during the 3 hours of EEG observation (table 1). As in atropine sulfate-pretreated rats, the electrographic seizures could be categorized in either permanent (but attenuated and badly stabilized, see fig 1 ) or rapidly interrupted epileptiform patterns (table I , fig I ) . Following the convulsive phase, the animals gradually fell into a profound comatose state, with accompanying laboured breathing, respiratory depression and apparent cyanosis. As a general rule, the duration of survival in intoxicated rats co-administered with atropine sulfate and paraldehyde was strikingly prolonged when the dose of paraldehyde was raised (table 11). Thus, when medium doses (0.5-5 mg/kg) of paraldehyde were combined to atropine sulfate, the latency-to-death was similar to that observed in intoxicated rats subjected to either of the separate pre-treatments. However, the time of death was considerably more delayed (> 3 h) when the most massive dose (500 mgkg) of paraldehyde was co-

Paraldehyde and soman seizures

administered with atropine sulfate (table 11). Unfortunately, none of the doses of paraldehyde used in combination with atropine sulfate showed any improvement in the 24 h mortality rate normally observed in intoxicated animals (table 11).

Discussion The behavioral and electrographic consequences of soman poisoning described in the present study are in good agreement with numerous other observations on the subject. For instance, it was noted that soman-induced death, when occurring within the very early moments of the intoxication, was systematically correlated with the most severe signs of respiratory distress. This and the observations that atropine sulfate and/or paraldehyde pre-treatments could induce, in certain circumstances, apparent respiratory facilitation and concomitant increase in latency-to-death, without necessarily accompanying anticonvulsant activity, supported the common opinions that: a) prominent respiratory impairment was the major cause of acute death following soman intoxication (Rickett et al, 1986) and b) dissociated causal mechanisms might lead either to rapid mortality or to seizures (Martin et al, 1985). We also found that the preventive administration of atropine sulfate to soman-intoxicated rats, a) prolonged the latency-to-death probably partly through suppression of the excessive bronchial secretions thus facilitating respiration, b) was only marginally protective against the 24 h mortality, c) failed to impede the appearance of convulsions but, d) was sometimes able to reduce the duration of seizures. These observations are very similar to results published elsewhere ( e g : Samson et al, 1985; Pazdernik et a l , 1986; Shih, 1990; Shih, 199 I ) . Probably, more complete anticonvulsant activity could be expected using higher doses of atropine sulfate (McDonough et a l , 1989; Shih, 1990; Capacio and Shih, 1991). In these latter cases, atropine is believed to exert some supplementary action through nicotinic or other receptors such as the NMDA subtypes of glutamatergic receptors (Shih, 1991; Shih et ul, 1991).

315

On the mortality parameters, the prophylactic administration of paraldehyde produced different effects which depended on the doses used and on the presence or absence of atropine sulfate in the pre-treatments. For instance, paraldehyde alone may prolong (0.5-5 mg/kg) or reduce (50-500 mg/kg) the latency-to-death in intoxicated animals. This beneficial or, adversely, detrimental activity on the soman-induced mortality seems well-correlated to the apparent ability of paraldehyde to exert prominent facilitatory (through amplification of respiratory movements) or debilitating (through respiratory desynchronization) interactions on the respiratory function, and then, to either counteract or potentiate the initial respiratory depression produced by the organophosphorus compound itself. The aggravation of the overall toxicity of soman by the most massive doses of paraldehyde might possibly be related, in addition to the observed respiratory dysfunction, to the other toxic side-effects (cardiovascular, metabolic etc) known to be produced by the overdosed medication (Browne, 1983; Ramsay, 1989; Von Burg and Stout, 1991). Additionally, atropine sulfate and the medium doses of paraldehyde (0.5-5 mg/kg), when coadministered, did not produce any synergistic beneficial effects on the latency-to-death criterion. Moreover, atropine sulfate even seemed to exert some detrimental activity since the high survival scores provided by paraldehyde alone were not reproduced when both the pre-treatments were administered together. On the other hand, atropine sulfate surprisingly suppressed the very rapid death normally produced by the most massive dose of paraldehyde. At the moment, all attempts to precisely explain these complicated interactive effects of atropine sulfate and paraldehyde o n soman-induced mortality remain profoundly delusive as long as further details on the mode of action of paraldehyde are not available (Lockman, 1989). Concerning the main issue of the present study, which was an attempt to prevent the seizures produced by soman, it was shown that paraldehyde alone, whatever the dose used, did not provide any anticonvulsant protection. The efficacy of paralde-

316

P Carpentier et a1

hyde as a nervous depressant thus seems less universal than previously thought (see Introduction). On the contrary, combination of paraldehyde and atropine sulfate produced a significant degree of protection against soman poisoning in terms of convulsion. Therefore, previous reduction of muscarinic hyperstimulation by atropine sulfate appears as a pre-requisite allowing paraldehyde to express its anticonvulsant potential. Such a synergistic benefit between atropine sulfate and paraldehyde is quite analogous to other pharmacological results (Braitman and Sparenborg, 1989; McDonough et al, 1989; Shih, 1990; Shih et al, 1991) showing that, in soman poisoning, the excitatory amino-acid receptor antagonist MK-80 1 and the inhibitory amino-acid receptor agonist diazepam became effective anticonvulsants especially in the presence of the anticholinergic atropine sulfate. From these latter findings and from other observations, several authors have postulated (McDonough et al, 1987; Shih, 1990; Shih et a1 1991) that a) soman-induced seizures primarily depend on abnormal muscarinic stimulation, and b) that various other non-muscarinic systems (possibly the nicotinic, glutamatergic or GABAergic systems) might be concomitantly or subsequently recruited and involved in the genesis or maintenance of the cerebral hyperactivity produced by the organophosphorus compound. It is then possible that paraldehyde may more easily counteract the electrographic consequences of the secondary non-muscarinic abnormal activities than those resulting from the muscarinic hyperstimulation itself. As one additional remark, the full protection provided by paraldehyde (used as sole pre-treatment) against lithium-pilocarpine lethality and seizures (Morrisett et al, 1987) is far from being reproduced in soman poisoning. Indeed, this discrepancy could be globally attributed to the greater overall toxic potency of soman in relation to its ability to irreversibly inhibit acetylcholinesterase, to produce subsequent muscarinic and nicotinic overstimulation and to simultaneously interact with more targets than lithium-pilocarpine ( e g : Silver, 1974; Clement, 1985; Marquis, 1985; Bakry et al, 1988; Lau et al, 1988). The fact that even a high dose of

paraldehyde (5 mg/kg) was unable to prevent soman-induced convulsions, whereas a considerably weaker dose (0.3 mgkg) was shown by Morrisett's team (Morrisett et al, 1987) to prevent or block lithium-pilocarpine status epilepticus, indicates that soman and lithium-pilocarpine seizures do not differ only in their degree of severity but also in their causal mechanisms which might be far more dissimilar than previously believed (Turski et al, 1989). It is then probable that, in addition to the known shared mechanisms such as the elevation in cerebral acetylcholine content (Shih, 1982; Jope et al, 1987) or the involvement of excitatory amino acids (Ormandy et al, 1989; Shih, 1990) other neurochemical systems or supplementary exacerbating factors might be specifically implicated in soman poisoning, thus contributing to lower the threshold for seizures or to facilitate their spreading and maintenance. From a practical point of view, this suggests that the use of muscarinic agonist cannot readily serve without precautions as a suitable tool to evaluate the anticonvulsant potentiality of drugs against intoxication by anticholinesterase agents. In conclusion, paraldehyde when co-administered with atropine, provided interesting anticonvulsant activity. Simultaneous protection against the lethal consequence of soman poisoning is expected from the addition to the combined atropine and paraldehyde pre-treatments, of an acetylcholinesterase reactivator ( e g the oxime HI-6) andor an acetylcholinesterase reversible inhibitor ( e g the carbamate pyridostigmine). These medications were demonstrated to significantly increase the 24-h survival rate in animals exposed to multiple LD50 doses of soman (Capacio and Shih, 1991; Shih et al, 1991). It must be recalled here that the currently recommended standard medication against human soman poisoning is usually composed of the combined administration of a) an antimuscarinic compound (eg atropine sulfate), b) an oxime and/or a carbamate drug and, c) an anticonvulsant antidote which is normally a benzodiazepine such as diazepam. According to our results, paraldehyde might constitute an interesting alternative to the third component of this medication. This compound might also be considered as a pos-

Paraldehyde and soman seizures

sible adjunct treatment t o be used either occasionally w h e n standard antidotes fail t o control soman-induced status epilepticus or systematically if a synergistic effect between benzodiazepine and paraldehyde is further demonstrated. All these possible applications o f paraldehyde t o the treatment o f soman intoxication in man require supplementary studies to be evaluated.

Acknowledgments The authors wish to thank FJ Hemming for correction of the English manuscript, D Riou and C Grosnom for excellent secretarial service. This work was supported by grants from the Direction des Recherches et Techniques (DRET contract nos 87/1075; 90/1009 J).

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Effects of paraldehyde on the convulsions induced by administration of soman in rats.

The ability of paraldehyde, a potent central nervous system depressant, to prevent the convulsions induced by the organophosphate soman, an irreversib...
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