betadex and Hypervitaminosis-A

Post-treatment data were collected on a patient who received intravenous hydroxypropyl beta-cyclodextrin in a dose of 1.5 g/kg in 1985. Although no untoward effects were observed in this patient, rarely occurring agitation and pulmonary edema have been noted after injections into rabbits and dogs, respectively. These complications are analyzed here on the basis of symptoms and on the effects of hydroxypropyl beta-cyclodextrin on the biochemistry of a representative lipid, cholesterol, which were studied in rats. It is hypothesized that these untoward effects of parenteral hydroxypropyl beta-cyclodextrin are due to complex formation, with lipid mediators of pathological responses, of which prostaglandins are one example. These mediators normally have brief and localized functions; if hydroxypropyl beta-cyclodextrin happens to be injected when these mediator systems are activated, their influence and the responses of the organism may be increased.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Child; Cholesterol; Cholesterol Esters; Cyclodextrins; Female; Humans; Hypervitaminosis A; Injections, Intravenous; Kidney Function Tests; Male; Phosphatidylcholine-Sterol O-Acyltransferase; Rats; Rats, Sprague-Dawley

Hydroxypropyl ethers of cyclodextrins, after parenteral administration, come into contact with lipids in tissues and in circulation and form water-soluble inclusion complexes with these lipids. A single intravenous administration of hydroxypropyl-beta-cyclodextrin to a hereditary hyperlipidemic Watanabe rabbit slightly and temporarily decreased the level of total cholesterol in serum. Single injections of hydroxypropyl-alpha-cyclodextrin and of the corresponding gamma-homologue, both of which are less potent solubilizers of cholesterol, had lesser effects. Repeated administration of hydroxypropyl-beta-cyclodextrin to rabbits led to a gradual increase in total cholesterol in circulation and eventually to a slight relief of atherosclerotic lesions in the thoracic aorta. The only untoward effects of repeated treatments (total doses of up to 40 g/kg) were vacuoles in cells of proximal convoluted tubules in the kidneys. Repeated administration also strongly increased cholesterol in urine, probably because of excretion of the soluble cholesterol-hydroxypropyl-beta-cyclodextrin complex. Proteins in urine increased significantly, whereas triglycerides increased only moderately after repeated administrations. Intravenous infusion of hydroxypropyl-beta-cyclodextrin into a patient with hypervitaminosis A led to a release of liver-stored retinoids into serum in quantities much higher than those that could be directly solubilized by hydroxypropyl-beta-cyclodextrin. Levels of total cholesterol in the circulation of this patient decreased during the infusion. Thus, hydroxypropylcyclodextrins may serve as artificial lipid carriers in the circulation, and because the exchanges that involve inclusion complexation occur very quickly, the presence of hydroxypropylcyclodextrins in organisms may catalytically augment the establishment of equilibria in lipid distribution.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Cyclodextrins; gamma-Cyclodextrins; Humans; Hypervitaminosis A; Hypolipidemic Agents; Injections, Intravenous; Lipids; Lipoproteins; Rabbits; Retinoids

A 2-year-old boy had signs and symptoms of chronic hypervitaminosis A. A course of increasing severity led to eventual death. A younger brother later had similar clinical features. Chicken liver spread containing up to 420 IU/g vitamin A was the likely source of intoxication. Markedly elevated circulating retinyl ester levels have persisted in the surviving sibling for 3 subsequent years despite severe restriction of vitamin A intake. A therapeutic trial of the carbohydrate-derived complexing agent 2-hydroxypropyl-beta-cyclodextrin was initiated. Circulating retinyl esters transiently increased during the infusion (from 407 to 4791 micrograms/dL), and urinary total vitamin A excretion, undetectable before infusion, increased to 23 micrograms/dL after infusion. The frequency of hypervitaminotic episodes has decreased somewhat in the 2 years since the infusion, probably related to dietary vitamin A restriction. The occurrence of this syndrome in two brothers, while a sister ingesting the same diet remains completely healthy, suggests an inherited variance in tolerance to vitamin A intake.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Carboxylic Ester Hydrolases; Child, Preschool; Cyclodextrins; Esters; Humans; Hypervitaminosis A; Infusions, Intravenous; Male; Retinoids; Vitamin A