A. J. Plummer

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.

Distribution and elimination of methylphenidate-C14

Abstract Methylphenidate labeled with C14 in the carboxyl carbon was administered intraperitoneally to guinea pigs and its distribution studied. The concentration of C14 in the brain and other tissues was higher when increased motor activity was evident than when no such drug effects could be noted. The C14 in the tissues was found to be distributed in several chemical forms including the intact drug, its product of hydrolysis, and a water-soluble conjugate. Most of this C14, however, was associated with the metabolic products rather than the unaltered drug. Over a 24-hour collection period, approximately 70% of the injected dose appeared in the urine while only 2% appeared in the feces. Most of the C14 in the excreta was composed of degradation products similar in certain respects to those found in the tissues.

Distribution and fate of hydrochlorothiazide-H3

Abstract Hydrochlorothiazide was labeled with tritium by the reduction of chlorothiazide with tritium-labeled sodium borohydride. Its distribution and metabolism were studied in saline-loaded, fasted rats. The drug was rapidly absorbed and 43 and 69% was excreted into the urine in 48 hours with doses of 4.7 and 0.15 mg/kg, respectively. No evidence could be found for the metabolic alteration of hydrochlorothiazide by the rat.

Studies with the Ganglionic Blocking Agent, Chlorisondamine Chloride in Unanesthetized and Anesthetized Dogs

The normotensive unanesthetized dog receiving chlorisondamine chloride, pentapyrrolidinium, or hexamethonium exhibits a drop in systolic blood pressure, narrowing of pulse pressure, tachycardia and relaxation of nictitating membranes. The relative potencies of these compounds are in the ratio 8:3:1 respectively. While these compounds are apparently equally well absorbed, the activity of chlorisondamine chloride is markedly prolonged. This prolonged activity of chlorisondamine chloride after oral administration is probably due, in large part, to its persistence in the tissues. Chlorisondamine chloride and hexamethonium can suppress the pressor response induced in neurogenic hypertensive dogs by application of annoying stimuli.

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.

Effects of Reserpine on Urinary Bladder Tension

Summary Reserpine will produce a gradual increase in bladder tension which is initiated within five minutes after intravenous injection. This response is not blocked by ganglionic blocking agents. Atropine has a slight to moderate antagonizing effect on this response. The adrenergic blocking agent, phentolamine, has a marked antagonizing effect on this response. Reserpine can potentiate the response of the bladder to mecholyl and carbamylcholine. The significance of these facts is discussed.

Hypotensive activity ofcis-cinnamyl guanidine sulfate

Es wird die Synthese und Pharmakologie eines neuen blutdrucksenkenden Mittels,cis-Cinnamyl-guanidinsulfat, beschrieben.

Influence of Adrenergic Blockade and an Amine Oxidase Inhibitor on Reserpine Hypotension

Summary In proper doses administration of reserpine phosphate subsequent to adrenergic blockade with phentolamine will produce a more rapid decline in blood pressure than is commonly obtained by administration of reserpine alone. After pretreatment with amine oxidase inhibitor, choline p-tolyl ether, reserpine will produce pressor responses. These data are interpreted as supporting the hypothesis that reserpine releases sympathomimetic humoral agents which mask the early onset of the cardiovascular actions commonly attributed to reserpine.

Rauwolfia alkaloids XXXV. potent, fast-acting sedatives derived from methyl reserpate

Durch Umsetzung des Methyl-Reserpates (Ic) mit Diazomethan in Gegenwart von Fluoborsäure wird 18-O-Methylreserpsäure-methylester (Id) gewonnen. Reaktion des 18-O-p-Brombenzolsulfonylreserpsäure-methylesters (Ie) mit Methanol und Triäthylamin führt dagegen zum isomeren 18-epi-Methyläther (IIa). Diese Produkte, und besonders ihre wasserlöslichen Hydrochloride, besitzen ausgeprägte sedative Eigenschaften mit schnellem Wirkungseintritt; sie sind aber nicht hypotensiv wirksam.

Effect of ganglionic blocking agents on pressor responses induced by splanchnic faradization.

Summary The effects of the ganglionic blocking agents, TEA, hexamethonium, pentapyrrolidinium and chlorisondamine chloride on the pressor responses induced by peripheral splanchnic faradization have been determined in 16 cats. These agents did not antagonize the pressor responses when the ipsi-lateral adrenal gland was present or after it had been ablated. The significance of these findings is discussed.