Efficacy of Biperiden and Hi-6 As a Prophylactic Combination Against Convulsions Produced by a Highly Toxic Organophosphorus Compound

30 VOJENSKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM Volume LXX, 2001, no. 1

EFFICACY OF BIPERIDEN AND HI-6 AS A PROPHYLACTIC COMBINATION AGAINST CONVULSIONS PRODUCED BY A HIGHLY TOXIC ORGANOPHOSPHORUS COMPOUND

Ivan SAMNALIEV Military Medical Academy, Soﬁa, Bulgaria

Introduction and atropine 2.1 mg/kg + HI-6 72 mg/kg were injected i.m. 15, 30, and 60 min prior to intoxication Inhibition of enzyme acetylcholinesterase (AChE, with 2.0 LD50 TMPhF (1,1,2 - trimethylpropyl me- EC 3.1.1.7.) at central nervous system by highly thylphosphonofluoridate, 92 % purity) and 120 min toxic organophosphorus compounds (OPC) causes before exposure to 1.5 LD50 TMPhF. Biperiden and a cholinergic crisis which is the most probable atropine were applied in equimolar doses - 3.1x10'6 “trigger” mechanism for the convulsive activity mol. The volume of injection was 0.1 ml/100 g observed after intoxication. It is known that the body weight. . convulsions produced by OPC may cause brain damages and long-term effects with neurobehavioral, Animals. 210 male albino rats “Wistar” were cognitive and neuromuscular disturbances (McLeod, separated into following groups: 1985; USAMRICD report, 1998). Therefore the I. Biperiden + HI—6 - 12 rats per each time interval. abolishment of convulsions plays a very important II. Atropine + HI-6 - 12 rats per each time interval role in the prophylactic of organophosphorus poi- and soning. Significant attention has been paid to this III. Control group - none anticonvulsant pretreat- problem during last years but it is yet not resolved. ment and poisoned with TMPhF (12 rats per each There are different pharmacological approaches time interval). 60 rats were used to determine LD50 to prevent or abolish the convulsive activity. The of TMPhF by Litchfield-Wilcoxon’s method. pretreatment with a potent central acting cholinoly- tic combined with a cholinesterase reactivator may Evaluation of toxic signs. Signs of intoxication ameliorate to a great extent the symptoms of OP were graded from 0 to 6 as follow: 0 - none of the intoxication and to prevent the delayed neuropathy selected signs present; 1 - hyper-activity; 2 -2

as well. In previous investigations a relatively high chewing or salivation; 3 - fasciculations or body anticonvulsive activity of biperiden have been de- tremor; 4 - subconvulsive movements; 5 - convuls- monstrated (Anderson et al., Capacio, Shih, 1991). ions and 6 - death. The most severe sign observed was noted at 5, 10, 15, 30 min and 1, 1.5, 2, 2.5, 3, The purpose of current study was to assess the 3.5, 4 and 24 hr after intoxication. The grades for a prophylactic efficacy of a drug combination which given animal were summed across the observation consist of biperiden and cholinesterase reactivator time to obtain a severity score. For each experi- HI-6 applied 15, 30, 60 and 120 minutes prior to ment (15, 30, 60 and 120 min) the anticonvulsive challenge by a highly toxic OP compound. efficacy of biperiden + HI-6 was compared to those for atropine and HI-6 using the Student’s t-test. Statistic significance was judged at a probability Material and Methods level of 0.05.

Drugs and dosage: Cholinolytics: Biperiden lac- tate 5.0 mg/ml (Knoll Pharm. CO., Germany) and Results atropine Sulfate Substance (Sopharma, Bulgaria). HI-6 - (2-hydroxyiminomethyl-pyridinium-l-methyl) The results obtained are summarized in Figs. 1, (4-aminocarbonyl-pyridinium-1-methyl) ether di- 2, 3 and 4. chloride was synthesized at MMA, Soﬁa. The drug Pretreatment regimen containing biperiden and combinations: Biperiden 1.25 mg/kg + HI-6 72 mg/kg HI—6 applied 15, 30 and 60 min before exposure Volume LXX, 2001, no. 1 VOJENSKÉ ZDRAVOTNICKÉ LISTY - SUPLEMENTUM 31 provided very good protection against the toxic signs “S‘Â'S' BP'O'HI induced by 2.0 LD50 TMPhF. At the same time the '/ﬂ MH ...1 second drug combination tested - atropine + HI-6 ,LJ

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0. v .0. / / central antimuscarinic effects of biperiden and pe- 10m 30min eomın 90min 120mm 180nln 240mm 24h ripheral effects of HI-6. Fig. 2. Anticonvulsive activity of the examened drug combinations applied 30 min before exposure to 2 L050 TMPhF › Biperiden is a synthetic, tertiary antimuscarinic - p<0.001 Bp+Hl-8 :A+Hl-6 - * - p<0.05; '2 - p<0.01; '” compound. It has strong atropine-like blocking effects in the CNS, and on parasympathetic struc- tures. Biperiden is used for the treatment of par- 32 voJENSKÉ ZDRAVOTNICKÉ LISTY- SUPLEMENTUM Volume LXX, 2001, no. l kinsonian syndrome (Anderson et al., 1994). Anti- References parkinsonian anticholinergic drugs, like biperiden, l. ANDERSON, D., et al.: Efﬁcacy of injectable anticholiner- have been reported to have anti-N-methyl-D-aspar— gic drugs against soman-induced convulsive/anticonvulsive tate (ant—NMDA) activity (Olney et al., 1987). Thus, activity. Drug and Chem. Toxicol., 1994, 17 (2), p. 139-148. › the anticonvulsant properties of biperiden may be 2. CAPACIO, B. — SHIH, TM.: Anticonvulsant actions of related to the multiple action characteristics. anticholinergic' drugs in Soman poisoning. Epilepsia, 1991, 32, p. 604—615. In summary, the drug combination biperiden and 3. McLEOD, C.: Pathology of nerve agents: Perspectives on management. Fund. Appl. Toxicol., 1985, 5, p. 53-58. HI-6 is more effective than atropine and HI-6 ap- 4. OLNEY, J. — PRICE, M. — SALLES, K., et al.: Eur. J. plied 15, 30 and 60 min before exposure to 2.0 LD50 Pharmacol., 1987, 142, p. 319. TMPhF. Further work is needed to determine the 5. USAMRICD: Pyridostigmine, Special publication, 1998-2001. protective properties of this combination at higher doses of biperiden and HI-6. Correspondence: Ivan Samnaliev Military Medical Academy Soﬁa . Bulgaria

This study was supported by the grant SST. CLG.978337 Received: 11. 10. 2001 '