Evidence for ototopical glucocorticoid-induced decrease in hypothalamic-pituitary-adrenal axis response and liver function.
To clarify whether ototopical glucocorticoid treatment is associated with impaired hypothalamic-pituitary-adrenal axis (HPA) activity and altered hepatic metabolism, one commercially available dexamethasone-containing ointment was tested. At present, very little is known about the effects of ototopical glucocorticoid treatment on HPA and liver function. Ten beagle dogs received two daily therapeutic doses of dexamethasone (0.6 mg/ear) in the outer auditory canal for 21 d in a single-blind, placebo-controlled study. Resting cortisol concentrations were assessed before, during, and after treatment using an RIA system. Adrenal function and HPA feedback sensitivity were measured by a standard dose (250 microg) ACTH stimulation test. Serum biochemical and hematological parameters were measured, whether ototopical glucocorticoids affect hepatic function was studied, and blood cell counts were made. Ototopical dexamethasone treatment induced a marked suppression (to about 100%) of resting plasma cortisol concentrations below the placebo effect (P < 0.0001) within the first 11 d, and these remained reduced during the entire treatment period up to d 19. As well, an ACTH stimulation test found a markedly reduced rise in plasma cortisol concentrations (P = 0.0004). Concomitantly, significant increases in serum activities of alkaline phosphatase, gamma-glutamyl transferase, alanine transaminase, and aspartate transaminase were detected. Moreover, we found a significant reduction in differential leukocyte counts of eosinophils and lymphocytes, whereas neutrophils increased. Although cortisol levels and hematological parameters returned to baseline 7 d after treatment cessation, liver enzyme activities remained elevated. In conclusion, these findings suggest that after ototopical application, dexamethasone is sufficiently absorbed from the auditory canal to suppress HPA function as well as to alter metabolic and hemopoietic profiles. Thus, in long-term treatment of otitis externa or media, the systemic adverse suppression of HPA has to be considered in relation to stress exposure, whereas changes in serum enzyme activities may not be interpreted as hepathopathy.
Abraham
Getu
G
Leipzig University, Institute of Pharmacology, Pharmacy, and Toxicology, An den Tierkliniken 15, D-04103 Leipzig, Germany. gabraham@rz.uni-leipzig.de
Gottschalk
Jutta
J
Ungemach
Fritz Rupert
FR
D000287:Administration, Topical; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001769:Blood / Q000187:drug effects; D001772:Blood Cell Count; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology; D004285:Dogs; D004424:Ear Canal; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000097:blood
D005938:Glucocorticoids; D003907:Dexamethasone; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D006854:Hydrocortisone