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Abstract #8939 Published in IGR 5-2

Inhibition of 11β hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension

Rauz S; Cheung CM; Wood PJ; Coca-Prados M; Walker EA; Murray PI; Stewart PM
Quarterly Journal of Medicine 2003; 96: 481-490


BACKGROUND: Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes (11β-HSD1 activating cortisol from cortisone, 11β-HSD2 inactivating cortisol to cortisone). AIM: To analyse the expression of 11β-HSD in the human eye and investigate its putative role in AH formation. DESIGN: A multipart prospective study, including a randomized controlled clinical trial. METHODS: The expression of 11β-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11β-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11β-HSD) on IOP. RESULTS: ISH defined expression of 11β-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11β-HSD1, with additional GR and MR, but not 11β-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11β-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p < 0.0001). DISCUSSION: CBX lowers IOP in patients with ocular hypertension. These data suggest that this is mediated through inhibition of 11β-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11β-HSD1 could provide a novel treatment for patients with glaucoma.

Dr. S. Rauz, Academic Unit of Ophthalmology, Division of Immunity and Infection, University of Birmingham, Birmingham, UK


Classification:

11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)



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