No abstract

After the oral, intraperitoneal, or intravenous administration of an antihypertensive, antidiuretic benzothiadiazine, diazoxide, to dogs, rabbits, mice, and rats, rapid hyperglycemia is promptly elicited, but of short duration, and reversible. The hyperglycemia is accompanied by increased hepatic glycogenolysis, serum lactate and pyruvate, and blood urea nitrogen (BUN). The hyperglycemia is obtained in depancreatized dogs, alloxanized mice, propylthiouracil treated mice, and nephrectomized mice, suggesting that the pancreas, thyroid and kidneys are not the primary locus of action of diazoxide. Modification of diazoxide hyperglycemia by hypophysectomy suggests that the pituitary plays a role in the hyperglycemic phenomenon. However, this view must be tempered by the realization that hypophysectomy causes partial inanition, perhaps sufficient to prevent hyperglycemia. The partial suppression of diazoxide hyperglycemia by adrenalectomy and BW 61–43 (isopropyl methoxamine), a specific inhibitor of the metabolic effects of epinephrine, suggests that the metabolic effects of diazoxide are mediated, at least in part, by adrenergic hormones. Preliminary experiments wherein diazoxide hyperglycemia was markedly attenuated in adrenalectomized mice treated with a ganglionic blocking agent, chlorisondamine, tend to support this concept. However, some doubt is cast upon this concept since reserpine treated mice respond to diazoxide and differences were observed in the hyperglycemic responses to epinephrine and diazoxide in hypophysectomized mice. Further work is underway to elucidate the mechanism(s) and locus of action of the metabolic effects of diazoxide.

Azatadine (6-11-dibydro-11-[1-methyl-4-piperclyl-idene]-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 ehlorcylizine; an antiserotonin, methysergide; and an anticholinergic, atropine.Azatadine possesses potent antihistaminic, anticholinergie, antiserotinin and antianaphylactic properties. In vitro, azatadine's 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, azatadine's 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 acetylcholi~lr dyspnea is equal to atropine and greater than alOOf the antihistamines studied. Its ability to protect guinea-pigs from serotunininduced dyspnea is 1/6 that of cyproheptadine, 1/s that of methysergide and greater than all of the antihistamines studied.Azatadine is a more potent antianaphylactic agent and has greater therapeutic indices than eyproheptudine in both mice and guinea-pigs.

No abstract

The demonstration of benzothiadiazine diuretic-induced hyperglycemia1-18 preceded the development of diazoxide, a hypotensive, anti-diuretic benzothiadiazine.Ig Diazoxide, combined wi.th a benzothiadiazine diuretic and administered to man20-24 for the treatment of hypertension, or to animal^,^^-^^ elicited varying degrees of hyperglycemia, precluding its use for anti-hypertensive therapy. Later, other investigations showed that diazoxide alone could induce marked hyperglycemia in man30-32 and in a n i m a l~. ~~-~l Drash and W~l f f~~ recognized diazoxide's potential for hypoglycemic states in the human and successfully applied it in the treatment of a leucine-sensitive hypoglycemic child. The use of diazoxide has been extended by other investigators for the treatment of leucine-sensitive h y p~g l y c e m i a~~ as well as hypoglycemias associated with hypopituitary dwarfism,44 i n s u l i n~m a s , *~-~~ non-islet cell t~m o r s ,~~,~~ and glycogen-storage d i s e a~e .~~.~~The mechanism of benzothiadiazine hyperglycemia has presented a provocative and challenging problem; intensive research has revealed several possibilities. Though diazoxide has been shown to inhibit the release of insulin, both in viv020-47d9,51~57-60 and in vitr0,~736~-63 experiments in alloxan-treated m i~e~~,~~ and rats65 and surgically-depancreatized dogs33,38,39 show that diazoxide can elicit a marked elevation of glucose above. the already hyperglycemic levels seen in these diabetic situations, indicating that the pancreas is not essential for the induction of diazoxide hyperglycemia. Thus, at least one other mechanism, an extrapancreatic one, should be involved.The relationship between the secretions of several endocrine organs and glucose metabolism is established, and represents a potentially fruitful area of investigation for the understanding of diazoxide hyperglycemia. The potential roles of the thyroid, pituitary, and adrenals (cortex) have been explored. 33*34,36,38-40,66-70 The involvement of catecholamines, both from the adrenal medulla and from other sources such as nerve endings in diazoxide hyperglycemia, has been proposed and supported by some investigators~3-36~38~O~49~67-69,71 and questioned by others. 59,60,70,72,73 We will consider, therefore, the relationship between diazoxide hyperglycemia and the potential involvement of ( 1 ) several endocrine glands and (2) the catecholamines. Further, we will describe other metabolic consequences of diazoxide's action that may aid in our understanding of the mechanism of diazoxide hyperglycemia.The hyperglycemic action of diazoxide might be a reflection of either the blockade or release of insulin action. The effects of insulin and tolbutamide were evaluated in diazoxide hyperglycemia in mice. As shown in FIGURE 1, when either insulin (20 units/ kg) or tolbutamide ( 160 mg/ kg) was given simuItaneously with diazoxide ( 160 mg/ kg), the usual hyperglycemic effect of diazoxide was not observed, indicating that both insulin and tolbutamide were effective in its presence. Other inv...