Franklin E. Roth

New Class of Antihypertensive Agents

Effective antihypertensive agents of the benzothiadiazine series, devoid of diuretic activity, are described. There follows a method of synthesis and a description of the pharmacological activity of one of these substances

The pharmacology of azatadine, a potential antiallergy drug

Azatadine (6–11-dihydro-11-[1-methyl-4-piperclylidene]-5H{5,6}cyclohepta{1,2-b}pyridine maleate {1∶2}), a nitrogen analog of cyproheptadine has been studied for its antiallergy properties. It was compared in vivo and in vitro to cyproheptadine and seven (7) standard antihistamines: chlorpheniramine, promethazine, diphenhydramine, phenindamine, chloropyriline, tripelennamine and chlorcylizine; an antiserotonin, methysergide; and an anticholinergic, atropine.Azatadine possesses potent antihistaminic, anticholinergic, antiserotinin and antianaphylactic properties. In vitro, azatadines antihistamine potency is equal to chlorpheniramine, cyproheptadine, phenindamine, chloropyrilene and greater than the rest of the antihistamines studied. Its anticholinergic potency is 1/3 that of atropine, equal to promethazine and cyproheptadine and greater than the rest of the antihistamines studied. Its antiserotonin potency is 1/4 that of methysergide, equal to promethazine and greater than the rest of antihistamines studied.In vivo, azatadines ability to protect guinea-pigs from histamine lethality (i.v.) and histamine-induced dyspnea is greater than all of the antihistamines studied. Its ability to protect guinea-pigs from acetylcholine-induced dyspnea is equal to atropine and greater than all of the antihistamines studied. Its ability to protect guinea-pigs from serotonin-induced dyspnea is 1/6 that of cyproheptadine, 1/8 that of methysergide and greater than all of the antihistamines studied.Azatadine is a more potent antianaphylactic agent and has greater therapeutic indices than cyproheptadine in both mice and guinea-pigs.

Comparison of perphenazine and fluphenazine enanthates in rats

Summary1.The enanthate ester of perphenazine, when administered subcutaneously in oil, but not in aqueous solution or suspension, exerted significant conditioned avoidance and locomotor depression in the rat for a substantially longer time than either equipotent or equimolar doses of its free base. The effects were still observable 18–21 days after a single injection of the ester.2.The prolonged action of perphenazine enanthate probably can be attributed to a combination of a tissue oil-depot and hydrolysis of the ester to form the free base.3.Perphenazine enanthate possesses approximately one-third the mg potency of fluphenazine enanthate. In equivalent behavioral dosage, however, perphenazine enanthate exhibits a duration of action equal to that of fluphenazine enanthate.4.Increasing the dose had little additive effect in terms of duration of activity which suggests that lower doses, which presumably could dimmish the incidence of untoward side effects, might be used without significantly diminishing the intensity or duration of therapeutic activity.

A BRIEF REVIEW OF THE DEVELOPMENT OF DIAZOXIDE AS AN ANTIHYPERTENSIVE AGENT

The purpose of this report is to review the historical development of diazoxide as an antihypertensive agent. In so doing, we hope to re-emphasize the potent vasoactive nature of this drug, to recall some of the interest and enthusiasm generated by its antihypertensive potential, and perhaps to stimulate new efforts along similar lines. When we started our investigations, the thiazide diuretics had already been established as drugs of choice in the treatment of mild to moderate hypertension. Their antihypertensive effect was generally attributed to a reduced cardiac output secondary to diuresis and decreased plasma volume.1*2 After awhile, this hypothesis was challenged by reports indicating that during long-term diuretic therapy, plasma volume and cardiac output returned to pretreatment levels despite a sustained antihypertensive effect.3 It was also around this time that chlorothiazide was shown to inhibit the spontaneous contractions of isolated rabbit in te~t ine .~ These experiments raised the possibility that the thiazides might lower blood pressure by directly affecting vascular smooth muscle. In our first series of experiments, we tried to determine whether thiazide diuretics directly affected isolated arterial tissue.5 Using aortic strips from rats and rabbits, we found that thiazides do inhibit aortic contractions. However, the concentrations required to demonstrate inhibition were quite high, generally of the order of 0.5 to 1.0 mglml of bath solution. Nevertheless, we were encouraged by these results, and set out to find a more potent antagonist. If the assumption was correct that the thiazides lower blood pressure by reducing arterial resistance, then the selection of a more potent vasculotropic thiazide need not include one that was also diuretic. In fact, we felt it would strengthen the argument if potent antagonists were found that were not diuretic at all. Consequently, the first group of compounds screened for in vitro activity were not diuretic. Of this group, diazoxide was the second compound to be evaluated.