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1. The activities of a new antispasmodic, N, N-di-methylthymy loxyacetamidine hydrochloride and of its diethyl congener have been compared with the corresponding activities of Trasentine, Trasentine-6H, and atropine sulfate in respect to the following: a. Antagonism of a histamine-induced spasm of the ileum of the guinea pig. b. Antagonism of an acetylcholineinduced spasm of the ileum of the guinea pig. c. Antagonism, of a barium chloride-induced spasm of the small intestine of the rabbit. d. Actions on the feline uterus in vitro and in vivo. e. Actions on the nictitating membrane of the cat and on salivation induced by drugs and by stimulation of the chorda tympani nerve. f. Paralysis of the peripheral cut vagus in the cat. g. Antagonism of Mecholyl-induced hypotension in the cat. h. Intravenous LD50 in white rats. i. Chronic toxicological studies in dogs and rats. 2. The effects of Su-198 upon the intestines of dogs with Thiry-Vella loops and upon the bronchioles of the perfused guinea pig’s lung have been described. 3. Some of the problems have been discussed which must be solved before an objective evaluation of an antispasmodic becomes possible.

Until approximately a decade ago a sympathetic blocking agent was little more than a scientific curiosity but today the picture has been con­ siderably altered; certain sympathetic blocking chemicals have come into their own as valuable therapeutic agents. They have become available to us through the fine cooperation of our research scientists, a group which includes the chemist, the biologist, and the clinical investigator. In the development of these important drugs as available to physicians today is the pharmacologist who early recognized, with the inquisitive clinician, the important role that sympathetic predominance plays in the symptomatology of certain disorders which reflect imbalance of the autonomic nervous system. Some of these include neurogenic hypertension, certain peripheral vascular diseases, especially Raynaud's and probably Buerger's disease, herpes zoster, hyperthyroidism, tachycardia, glaucoma, exophthalmia, migraine headaches (spastic type), neurodermatoses, renal hypertension (in part neurogenic in origin?), vasospastic dysmenorrhea, causalgia, and probably some types of epilepsy. There is little doubt today that the autonomic nervous system plays a very important role, either directly or indirectly in many diseases, in terms of overactivity or underactivity of either portion of the autonomic nervous system, that is, of the parasympathetic or the sympathetic divisions. Our attention at the moment is directed toward suppressing, within desirable physiologic limits, the overactivity of the sympathetic portion of this system in certain undesirable conditions. This goal can be achieved by cer­ tain recently developed chemical compounds which have already established their value as therapeutic agents. Inspection of Fig. 1, a diagram by Hafkenschie1 & Sellers (1), which is an excellent modification of that previously employed (2), reveals various focal points of attack in the establishing of sympathetic or adrenergic blockade. The synonymous or interchanging use of the terms sympathetic and adrener­ gic blockade, a procedure which will be followed throughout this presentation should be noted. Adrenergic refers to that portion of the autonomic nervous system, namely the sympathetic portion, which responds to the action of adrenaline or adrenaline-like substances. These include epinephrine and norepinephrine in particular; any agent that blocks these substances which act in the region of the final arborization or distribution of sympathetic nerve fibers, that is, within the receptive substance of the end organs asso­ ciated with sympathetic innervation, is classified as a sympathetic or adrenergic blocking agent. On the other hand, one must bear in mind that

1. A theoretical explanation for the epinephrine-fast state as a manifestation of imbalance in the histamine-sympathin see-saw is presented (“epinephrine-histamine toxicity”). The experimental observations described lead us to conclude that repeated administrations of epinephrine to such individuals produce an increase in plasma histamine overcoming the effects of the epinephrine. It is theoretically plausible that suitably administered antihistaminic agents might return the see-saw to its normal balance. 2. In eight of a group of ten patients displaying epinephrine-fastness significant improvement followed the use of intravenous tripelennamine hydrochloride or diphenhydramine hydrochloride. Epinephrine, administered subcutaneously or by the aerosol route, appeared to bring relief from acute paroxysmal bronchospasm, whereas previously only the side effects of epinephrine had been observed following its use.

ConclusionsThe compound 2-[N-p′-tolyl-N-(m′-hydroxyphenyl)-aminomethyl] -imidazoline HCl, (C-7337), is a potent adrenolytic agent but much less active as a symptatholytic drug. It is effective orally.6

In the past one has been able to affect the autonomic nervous system to a varying degree in most respects except in depression of the sympathetic or adrenergic nervous system ; but the latter is now becoming a reality in certain respects. The problem of applying adrenergic blockade has been attacked and encouraging results have been obtained so that the medical profession can now treat the varied syndrome of sympathetic predominance. Vasospastic conditions of the vascular tree, including neurogenic or essential hypertension, are peculiarly susceptible in many instances to adrenergic blockade, and it behooves the medical profession to become more aware of the role of sympatholytics and the newer suppressants of sympathetic overflow.