THE PHARMACOLOGY OF N-BENZYL--CHLOROPROPIONAMIDE (HIBICON), A NEW ANTICONVULSANT

¹ Mead Johnson & Co., Evansville 21, Ind.
² Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

1. Hibicon, N-benzyl--chloropropionamide, is a new anticonvulsant with high efficacy, few side reactions and a wide margin of safety.

2. It is a white crystalline solid with a water solubility of 0.1 per cent at 25°-26°C. and 0.2 per cent at 39°-40°C. Aqueous solutions are neutral to litmus. Hibicon is readily absorbed after oral or intraperitoneal administration.

3. By the maximal electroshock seizure test, the ED₅₀ for Hibicon administered intraperitoneally is 36 mgm./kgm. with 19/20 limits of 32-41 and for Dilantin sodium given by the same route, 23 mgm./kgm. with 19/20 limits of 14-38. Orally the ED₅₀ for Hibicon is 46 mgm./kgm. with 19/20 limits of 26-83 and for Dilantin sodium, 20 mgm./kgm. with 19/20 limits of 12-34. By the Putnam-Merritt electroshock test in cats subjected to a multiple dose procedure, Hibicon is more potent and less toxic than Dilantin. By the Putnam-Merritt test in rats the anticonvulsant action of Hibicon and of Dilantin belongs to the same order. By the intravenous Metrazol test the anti-convulsant potency of Hibicon is greater than that of Dilantin sodium but less than that of Tridione.

4. Hibicon is absorbed satisfactorily after oral administration. In rats anticonvulsant activity can be detected 30 minutes after an oral dose. Maximal activity is attained in two hours and continues through the sixth hour. Anticonvulsant activity is present twelve hours after an asymptomatic oral dose.

5. The liver and also the kidneys are important factors in determining the duration of action of Hibicon.

6. Hibicon is not an analgetic or a sedative. This compound exhibits no anti-spasmodic, oxytocic, miotic or mydriatic action. By the spray chamber technique Hibicon exerts a feeble antihistaminic action. Large intraperitoneal doses of Hibicon produce a moderate decrease in blood pressure in anesthetized animals. However, the vasomotor response to epinephrine, acetylcholine and faradic stimulation of the vagus is essentially unmodified. The E.C.G. in the dogs is unaffected.

7. The intraperitoneal LD₅₀ for Hibicon in rats is 770 mgm./kgm. with 19/20 limits 670-886. For comparison the intraperitoneal LD₅₀ in rats for Dilantin sodium is 475 mgm./kgm. with 19/20 limits 435-518 and for Tridione, 1880 mgm./kgm. with 19/20 limits 1621-2181.

8. If given orally the LD50 for Hibicon in rats is 3200 mgm./kgm. with 19/20 limits of 3098-3306. For comparison the oral LD₅₀ in rats for Dilantin sodium is 4900 mgm./kgm. with 19/20 limits of 4689-5120 and for Tridione, 2290 mgm./kgm. with 19/20 limits 2114-2480.

9. After the intraperitoneal injection of a massive dose, 500-750 mgm./kgm., Hibicon produces in dogs, cats, rabbits, and guinea pigs symptoms which resemble closely those of decerebrate rigidity. Complete recovery from this state is the rule, with few exceptions. Overdosage of Dilantin also produces symptoms of decerebrate rigidity; Tridione does not.

10. The minimal toxic dose (MTD₅₀) of Hibicon administered orally to rats is 350 mgm./kgm., 19/20 limits 282-434; for comparison the MTD₅₀ for Dilantin sodium given orally to rats is 380 mgm./kgm., 19/20 limits 281-513.

11. No evidence of chronic toxicity was observed. For one year the food of 120 rats contained Hibicon at levels to supply 500, 1000 or 1500 mgm./kgm./day.

Eight young dogs were given 300 mgm./kgm./day orally for one year. This was the highest oral dose tolerated by dogs without emesis.