Clinicopathologic and ultrastructural studies of L asparaginase induced hypocalcemia in rabbits. An experimental animal model of acute hypoparathyroidism

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The intravenous administration of E. coli L asparaginase (Asnase) to rabbits at a dose schedule of 1000 IU per kg. per day for 3 days resulted in an incidence of hypocalcemia of 100% and tetany of 70%. In addition, the majority of the rabbits had hyperphosphatemia, hypomagnesemia, hyperkalemia, and azotemia. These alterations correlated well with histopathologic and ultrastructural findings of degenerating chief cells, degranulation, autophagy, and deficiency of subcellular organelles associated with protein synthesis in parathyroid glands. Additional studies were designed to contribute to a further understanding of the Asnase induced parathyropathy. Rabbits receiving Asnase derived from the bacterium Erwinia carotovora developed clinicopathologic manifestations and morphologic alterations in parathyroid glands similar to E. coli Asnase treated rabbits. Other rabbits administered E. coli endotoxin failed to develop a significant hypocalcemia or parathyroid alteration. The majority of rabbits receiving prophylactic and therapeutic treatments designed to alleviate the fatal hypocalcemic tetany induced by Asnase responded favorably. Rabbits surgically thyroparathyroidectomized developed overt signs and clinicopathologic alterations similar to Asnase treated rabbits and died within 24 hours after surgery. The performance of bilateral ureterectomies in additional rabbits resulted in an increase in blood urea nitrogen levels up to 5 fold greater than those occurring in Asnase treated rabbits but failed to produce a hypocalcemia of a degree sufficient to induce tetany. These findings offer support for the hypothesis that the parathyroid alteration associated with Asnase administration is related to the cause, rather than the effect, of the hypocalcemia. In addition, the results indicate that neither endotoxin nor the uremic effects of Asnase are etiologic in the development of the experimentally induced hypocalcemia and tetany. The rabbit Asnase system is presented as an experimental animal model of drug induced hypoparathyroidism characterized by drug endocrine cell interactions somewhat analogous to the lethal selectivity of alloxan for pancreatic β cells in the production of experimental diabetes.

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Laboratory Investigation

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