Abstract

The gastric antisecretory action of Pamine bromide has been compared with that of similar parasympatholytic drugs in the pyloric ligation rat. The effective intravenous antisecretory dose of Pamine bromide is very much less than those of methantheline bromide and atropine and slightly less than that of scopolamine. Measurement of volume of secretion over a two-hour period after intravenous dosage gave the following ED₅₀ values: Pamine bromide 0.002, methantheline bromide 0.6, atropine sulfate, 0.07, and scopolamine hydrobromide 0.01 mgm./kgm. By intraduodenal dosage and with a three hour collection period, the ED₅₀ doses are estimated to be 5 to 10, 10 to 20, 0.8 to 1 .6, and 0.3 to 0.6 mgm./kgm., respectively. The activity of Pamine bromide has been shown not to be affected by exposure to either rat or human gastric juice or rat or dog intestinal contents under certain experimental conditions. A higher degree of potency in blocking histamine induced gastric secretion in dogs has been demonstrated for Pamine bromide in comparison with methantheline bromide.

The importance of control of gastric secretion in reducing the incidence of peptic ulceration has been demonstrated in starved rats, in rats with ligated pylorus (Shay rat), and has been suggested in dogs with antral transplants and gastrojejunal anastomoses (Dragstedt dog).

In rats the normal aboral movement of a charcoal-containing mixture is inhibited by both parenteral and oral doses of Pamine bromide. Tolerance did not develop to this spasmolytic action on chronic dosage. In dogs observed radiographically, the movement of a barium meal was markedly delayed by small parenteral and oral doses of Pamine bromide. Similarly, in the upper jejunum of Thiry-Vella dogs, Pamine bromide was notably more potent in achieving spasmolysis than other similar compounds. The antispasmodic activity as observed in vitro in antagonizing acetylcholine induced spasm of rabbit intestine was equal to that of atropine sulfate.

The duration of action of Pamine bromide on gastrointestinal function appears to depend on the mode of administration and on the species of animal. In rats by parenteral dosage Pamine bromide is short acting. By oral dosage, however, effects have been seen to extend over a considerable period. In dogs the activity is prolonged by either route of administration.

In rabbits Pamine bromide was more potent than atropine by parenteral dosage in inhibiting pilocarpine induced salivation. In man, 5 mgm. oral doses had on the average only slight to moderate effects on salivation induced by gum chewing. Profound mydriatic action was demonstrated on application of Pamine bromide to the rabbit's eye. Therapeutic ratios calculated on the basis of a comparison of cardioaccelerator action in dogs with gastric antisecretory action in rats are more favorable for Pamine bromide than for methantheline bromide.

Intravenous doses of Pamine bromide in dogs completely blocked the effects on blood pressure of standard doses of acetylcholine and methacholine chloride for several hours. Intraperitoneal doses protect well against the formation of bloody tears induced by methacholine chloride in rats. Spasmolytic action on rabbit intestine stimulated in vitro with acetylcholine was found to be slightly greater than for methantheline bromide.

CNS stimulation does not occur with Pamine bromide in rats except at very high dosage. Similarly the relatively brief ganglionic and myoneural blocking actions of Pamine bromide, in cats and dogs respectively, are manifest only at very high dosage levels. No local anesthetic action could be demonstrated by the guinea pig wheal. Pamine bromide is not notably active as a bronchodilator on tracheal chains of guinea pigs, or in myoneural blocking action on skeletal muscle of dogs. It is less potent than certain other similar agents in inducing ganglionic blockage and in inhibiting the enzymic hydrolysis of acetylcholine. It has a weak cholinesterase inhibiting action similar to the action of many amines.

In acute toxicity tests in white mice, Pamine bromide has been found to be slightly more toxic than atropine by intraperitoneal dosage and 2.3 times more toxic by intravenous dosage.