Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man

Abstract

Aims: To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral doses of moclobemide, a selective MAO-A inhibitor, and selegiline, a selective MAO-B inhibitor, on mydriatic responses to tyramine.

Methods: Twelve healthy male volunteers participated in three monthly sessions, each associated with ingestion of one capsule (moclobemide 450 mg, selegiline 10 mg, or placebo), according to a double-blind, balanced, cross-over design. Tyramine hydrochloride eye-drops (75 mM, 2 x 10 microl) were instilled three times in the left conjuctival sac at 40 min intervals. Pupil diameter was monitored with a binocular infrared television pupillometer before and for 4.5 h after ingestion of the capsule. The pupillary response to tyramine was expressed as the area under the pupil diameter x time curve (arbitrary units). A blood sample was taken before and 2 h after ingestion of the capsule, for the assay of platelet MAO-B activity, and plasma 3,4-dihydroxyphenylglycol (DHPG) concentration, an index of MAO-A activity. Platelet MAO activity was assayed radiochemically, using [14C]-phenylethylamine as substrate, and plasma DHPG by high performance liquid chromatography (h.p.l.c.). The results were analysed using analysis of variance with repeated measures, followed by Bonferroni's corrected t-test, using a significance criterion of P < 0.05.

Results: Both moclobemide and selegiline, compared with placebo, caused significant miosis in the right (untreated) eye. The changes in pupil diameter (mm +/- s.e. mean) from the pretreatment measurement were: placebo -0.09 +/- 0.07, moclobemide -0.52 +/- 0.09, selegiline -0.26 +/- 0.1. The mydriatic response to tyramine was potentiated by moclobemide, compared with the response recorded in the presence of placebo. The responses to tyramine (arbitrary units +/- s.e. mean) were: placebo 77.08 +/- 11.65, moclobemide 140.25 +/- 18.9, selegiline 72.75 +/- 12.35. Both moclobemide and selegiline significantly reduced platelet MAO activity, compared with placebo. The changes in platelet MAO activity (nmol h(-1) mg(-1) protein +/- s.e. mean) from the pretreatment level were: placebo 0.5 +/- 0.62, moclobemide -6.7 +/- 0.66, selegiline -17.7 +/- 0.87. Moclobemide significantly reduced plasma DHPG concentration, compared with placebo. The changes in plasma DHPG concentration (nmol l(-1) +/- s.e. mean) from the pretreatment level were: placebo -0.01 +/- 0.24, moclobemide -4.98 +/- 0.32, selegiline -0.51 +/- 0.26.

Conclusions: The potentiation of tyramine-evoked mydriasis by moclobemide is likely to reflect the inhibition of MAO-A activity in the iris, consistent with the activity of this enzyme in sympathetic nerve terminals. The lack of effect of selegiline on tyramine-evoked mydriasis argues against a role of MAO-B in terminating the effects of sympathomimetic amines in the iris. The effects of the two drugs on platelet MAO activity and plasma DHPG concentration are in agreement with previous reports and consistent with the relative selectivity of moclobemide for MAO-A and of selegiline for MAO-B. The miosis caused by the two MAO inhibitors is likely to be due to a central sympatholytic action of the drugs.

Figure 1

Design of experimental session. The horizontal line represents running time (min) measured from the end of an initial 10 min rest period (see Procedure). Arrows above the time- base correspond to recordings of pupil diameter (long arrows: in darkness; short arrows: under constant illumination of 32 cd m⁻²). At each time-point, as indicated by the arrows, three 15 s recordings of pupil diameter were taken at 5 s intervals (see text for details). Recordings in darkness at 10, 20 and 30 min, and under illumination at 100, 110 and 120 min, served for the calculation of the presystemic-treatment and pre-eyedrop baselines, respectively. Timings of the administration of systemic (‘capsule’) and local (‘Tyr’) treatments, and of blood sampling is indicated by arrows below the time-base.

Figure 3

Mydriatic response to tyramine. a) Pupil diameter (mm) at different time points following the instillation of tyramine eye-drops. The horizontal axis represents time elapsed since the start of the session. Points correspond to mean (n = 12) values at different time points obtained in the three treatment conditions (circles: placebo; triangles: moclobemide; squares: selegiline). Horizontal broken lines correspond to pre-eyedrop baselines in the placebo (top), selegiline (middle) and moclobemide (bottom) treatment conditions. b) Size of mydriatic response to tyramine in the three treatment conditions (area-under-the-curve, mean±s.e. mean, n = 12). Conventions as in Figure 1.

Figure 2

Change in resting pupil diameter from pretreatment, measured in darkness. Columns correspond to mean±s.e. mean (n = 12) obtained in the three treatment conditions (open column: placebo, hatched column: moclobemide, closed column: selegiline). Asterisk denotes significant difference from placebo (P < 0.05).

Figure 4

Biochemical indices of MAO activity. a) Change in platelet MAO activity (nmol h⁻¹ mg⁻¹ protein) from pretreatment. Conventions as in Figure 1. b) Change in plasma DHPG concentration (nmol l⁻¹) from pretreatment. Conventions as in Figure 1.