In vivo and in vitro effects of the azidothymidine analog dideoxyinosine on the exocrine pancreas of the rat

T. Grady, Ashok Saluja, M. L. Steer, M. M. Lerch, I. M. Modlin, R. E. Powers

Research output: Contribution to journalArticle

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Abstract

Phase I clinical trials of the purine analog 2',3'-dideoxyinosine (ddl) revealed that 10% of the patients developed pancreatitis, yet there was no clear relationship between increasing doses of ddl and the development of pancreatitis. To test the effects of chronic ddl administration on the structure and function of the rat pancreas, male Wistar rats were given ddl at 100 mg/kg/day i.p. for 35 days or 1400 mg/kg/day for 30 days, in two divided doses. Serum amylase levels, pancreatic tissue water content (edema) and pancreatic morphology by light and electron microscopic examination of pancreata from ddl-treated rats were similar to those of rats receiving saline injections only (controls). 2',3'-Dideoxyinosine administration did not alter the subcellular distribution of the lysosomal enzyme cathepsin B, whose redistribution to a more dense zymogen granule-enriched subcellular fraction is an early indicator of acute pancreatitis. Dispersed pancreatic acinl from rats receiving ddl (100 mg/kg/day for 30 days) were incubated in vitro for 15 min with either caerulein or carbamylcholine as secretory stimuli. There was no detectable difference in the stimulatable amylase secretion from ddl-treated animals compared to the control group. Based on these findings, we conclude that ddl has no direct toxic effect on the rat pancreas. 2',3'-Dideoxyinosine may be contributing to pancreatitis in acquired immunodeficiency syndrome patients by potentiating other pancreatotoxic agents or by its action on a pancreas that is already altered by the human immunodeficiency virus infection.

Original languageEnglish (US)
Pages (from-to)445-449
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number1
StatePublished - Jan 1 1992
Externally publishedYes

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Didanosine
Exocrine Pancreas
Zidovudine
Pancreatitis
Pancreas
Amylases
Ceruletide
Cathepsin B
Clinical Trials, Phase I
Subcellular Fractions
Poisons
Secretory Vesicles
Carbachol
Virus Diseases
Wistar Rats
Edema
Acquired Immunodeficiency Syndrome
In Vitro Techniques
HIV
Electrons

ASJC Scopus subject areas

  • Pharmacology

Cite this

In vivo and in vitro effects of the azidothymidine analog dideoxyinosine on the exocrine pancreas of the rat. / Grady, T.; Saluja, Ashok; Steer, M. L.; Lerch, M. M.; Modlin, I. M.; Powers, R. E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 1, 01.01.1992, p. 445-449.

Research output: Contribution to journalArticle

Grady, T. ; Saluja, Ashok ; Steer, M. L. ; Lerch, M. M. ; Modlin, I. M. ; Powers, R. E. / In vivo and in vitro effects of the azidothymidine analog dideoxyinosine on the exocrine pancreas of the rat. In: Journal of Pharmacology and Experimental Therapeutics. 1992 ; Vol. 262, No. 1. pp. 445-449.
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