Walter Barrett

The pharmacology of hydrochlorothiazide (Esidrix™), a new, orally effective sulfonamide diuretic

Abstract 1. 1. On the basis of comparative minimally effective diuretic doses, hydrochlorothiazide was eight times as active as chlorothiazide, and on the basis of doseresponse effects, it was 6.3 times more potent. In terms of the relative potencies for influencing each of the four parameters selected, the excretion of water, sodium, potassium, and chloride, hydrochlorothiazide was found to predominate over chlorothiazide. In addition, this drug is characterized by a long duration of action. 2. 2. The major anion excreted by the dogs under the influence of hydrochlorothiazide was chloride rather than bicarbonate, thus yielding a less alkaline urine. 3. 3. It was found that hydrochlorothiazide increased or potentiated the activity of the antihypertensive drug, hydralazine, which in turn augmented the antihypertensive properties of hydrochlorothiazide. The hypotensive response elicited by histamine was also enhanced by hydrochlorothiazide in 50% of the experiments. 4. 4. Hydrochlorothiazide did not stimulate the small intestine of the dog, nor did it produce a stimulation of gastric secretion, but rather tended to reduce the gastric secretory response produced by histamine. 5. 5. In acute toxicity studies in rats, hydrochlorothiazide was found to be less toxic than chlorothiazide. 6. 6. It has been suggested that hydrochlorothiazide may increase the responsiveness of dogs to endogenous histamine. This activity could account in part for its circulatory effects.

A pharmacologic investigation of dimethpyrindene maleate (forhistal

Dimethpyrindene is intrinsically a potent, long lasting, orally effective antihistaminic, antiallergic drug. The specific antihistaminic activity of dimethpyrindene and its low oral toxicity have resulted in the highest therapeutic ratio reported for an antihistaminic drug. Dimethpyrindene does not possess marked anticholinergic activity nor did it potentiate the pressor action of l-epinephrine or l-norepinephrine. Dimethpyrindene was found to have a mild natriuretic and diuretic action when administered orally to unanesthetized dogs. Dimethpyrindene was found to inhibit the in vivo effects of histamine on the intestine of the anesthetized dog. In addition to its increased potency, dimethpyrindene has a significantly longer duration of action, both in vitro and in vivo, than the other antihistaminic drugs employed in this study.

The action of reserpine on the motility of the digestive tract.

1. Studies have been designed to determine the cause of the increased motor activity of the intestine caused by reserpine in animals. When reserpine was tested on the isolated ileum of various species of animals, it was found to possess moderate anticholinergic activity and some direct relaxant activity. Cholinergiclikc-like or stimulatory effects were completely absent. Essentially the same results were obtained with the isolated colon of the various species. 2. In the anesthetized dog, on the other hand, with or without cervical vagotomy, reserpine elicited a stimulation of the small intestine. In dogs with a cervical vagotomy, hexamethonium in an intravenous dose of 2 mgm./kgm. decreased the stimulation evoked by reserpine. 3. In the anesthetized dog subjected to both a transection of the spinal cord at C-6 and a cervical vagotomy, reserpine caused a stimulation of the small intestine which was largely inhibited by the administration of hexamethonium in a dose of 2 mgm./kgm, intravenously. 4. A mechanism has been suggested to explain the stimulation of the small intestine evoked by reserpine; an action on the parasympathetic ganglia which augments the effect of a reduced central sympathetic inhibitory influence. Increased intestinal and colonic activity is the most likely cause of the diarrhea caused by reserpine in certain animals.

A method of sensitizing guinea pigs to horse serum that eventuates in 100 per cent mortality after challenging

Abstract Various methods of sensitizing guinea pigs to horse serum were employed in the hope of finding one that would invariably produce a potentially fatal level of antibody in 100 per cent of the animals. The only successful method involved intrahepatic or intraperitoneal injections of 2 × 0.05 ml. of horse serum alone, or with killed tubercle organisms. The details of this new method have been described. Even large doses of antihistaminics offered but partial protection against anaphylactic shock to animals so sensitized. This might be additional evidence that released histamine does not alone account for the symptoms of anaphylactic shock, but the possibility was not excluded that so much histamine was liberated that cardiovascular collapse resulted, since it is known that antihistamines only partially antagonize the hypotensive actions of higher doses of histamine.

Pharmacological properties of a new antispasmodic N, N-Dimethylthymyloxyacetamidine hydrochloride

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.

Responses of the guinea pig's ileum to histamine, acetylcholine, antigen, and electrical stimulation as influenced by progressive decreases in the concentrations of calcium, magnesium or potassium separately or in pairs.

The normal responses of strips of ileum from the guinea pig to histamine, acetylcholine, electrical stimulation, and to added antigen (horse serum) were determined. A perfusion of the tissue was then initiated with a Lockes solution lacking one of three ions : potassium, calcium, or magnesium. The progressive effect of this increasing lack upon the responses to the initially tried four stimuli was then investigated. In other experiments a pair of ions was removed from the normal Lockes solution. It has been suggested that a chain of enzymatic reactions exists within the cell and terminates in the final link of the reversible change in the actomyosin molecule. Since the response to electrical stimulation was the first to disappear in the absence of potassium or calcium ions from the Lockes solution, it is suggested that this stimulus must act at a link more distant from the final link than do either histamine or acetylcholine. Since the responses to histamine and acetylcholine disappeared pari passu in the absence of either potassium or calcium, it is suggested that they have a similar focus of attack. Added antigen was without effect in the absence of calcium ions but the moment the calcium ions were added to the bath the response promptly occurred even though many minutes might have elapsed between the two additions. It is suggested on this basis that the antigen-antibody reaction leads to a release of a substance within the cell which is reasonably stable and persists for some time.

The effects of variable intervals of cooling upon the responses of the lapin intestine and uterus and the feline intestine to histamine, acetylcholine pituitrin and barium chloride

A study was made of the effects of cooling upon the response of the isolated uterus of the rabbit to acetylcholine, histamine, Pituitrin, and barium chloride. Since the responses of the tissues to the last spasmogenic agent were characterized by marked tachyphylaxis and an earlier loss than were the responses to the first two, it has been suggested that the focus of the barium ion’s action is relatively far removed from the final contractile response. It may lead to an alteration in the local concentration of some other cation such as potassium.