Br. J. clin. Pharmac. (1992), 34, 269-271

Ocular hypotensive effects of medifoxamine S. SALEH & P. TURNER Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE

Medifoxamine is a novel monoamine re-uptake inhibiting antidepressive drug which preferentially inhibits dopamine reuptake. In human volunteer studies it has been found to reduce significantly intraocular pressure after single oral doses of 300-1000 mg, and to produce a small but statistically significant miosis. Its maximal ocular hypotensive action was less than that of oral timolol 20 mg.

Keywords medifoxamine non-contact tonometer

dopamine agonism

intraocular pressure

Introduction

IOP was measured (mean of three readings) by noncontact tonometry (Grolman, 1972), and pupil diameter

There is considerable evidence that stimulation -of peripheral dopamine-2-receptors reduces intraocular pressure (IOP) in man. Single oral doses of bromocriptine (Al-Sereiti & Turner, 1989; Mekki et al., 1984), lisuride (Al-Sereiti & Turner 1989), and pergolide (AlSereiti et al., 1989) produce a significant reduction in IOP in normal human volunteers, which is antagonised by metoclopramide (Mekki & Turner, 1985) and domperidone (Al-Sereiti et al., 1990). Medifoxamine is a monoamine re-uptake inhibiting antidepressant drug which appears to act by preferentially inhibiting dopamine re-uptake presynaptically (Bessiri et al., 1986; Ferreri, et al., 1987, Morou, 1989; Scharbach et al., 1986). In a preliminary study in eight normal subjects, we found that single oral doses of medifoxamine 300 and 600 mg produced a significant reduction in IOP when compared with placebo and medifoxamine 150 mg (P < 0.002), and a significant reduction in pupil diameter (P < 0.001). We have, therefore, carried out a study to investigate the effects of larger doses of medifoxamine and compared them with those of timolol, an established agent in the treatment of glaucoma.

by entopic pupillometry (Cogan, 1941), immediately before and at 0, 1, 2, 3, 4, 6 and 8 h after administration of the treatment. Changes in IOP and pupil diameter after drug treatment were compared with those after placebo, using multiple linear regression analysis, with the baseline values included as continuous independent variables and those of treatment, time of measurement and subjects as discrete independent variables.

Results

Means and s.e. mean of the eight subjects IOP and pupil diameter data at different time points after different treatments in each eye are presented graphically in Figures 1 and 2. Considering all post-dosing measurements, medifoxamine and timolol both reduced IOP in both eyes when compared with placebo (P < 0.005). There was no significant difference between the response to the two doses of medifoxamine, but timolol was significantly more effective than medifoxamine in reducing IOP (P < 0.001). Medifoxamine significantly reduced pupil diameter in both eyes compared with placebo and timolol (P < 0.001), but timolol had no significant effect.

Methods

Eight healthy volunteers (four males, aged 19-29 years, mean age 23 years) were given single oral doses of either 750 mg and 1000 mg medifoxamine, 20 mg timolol or matched placebo capsules on four occasions, 1 week apart, in a randomised, double-blind, cross-over and balanced design based on two 4 x 4 latin sequences. They arrived fasting and abstained from smoking for at least 12 h. No medication was taken for 1 week before

Discussion

This study confirms our preliminary observation that medifoxamine has ocular hypotensive and miotic effects in healthy human volunteers. The effects on IOP appear to occur at oral doses of 300 mg and above, but the effect

the study and throughout the period of the study. They abstained from alcoholic beverages, caffeine containing substances, and smoking on each study day.

Correspondence: Professor P. Turner, Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE

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Short report (Randhawa et al., 1988). Rather, in vitro animal studies (personal communication, laboratories Anphar-Rolland) have suggested that medifoxamine has very weak affinity for muscarinic-M-receptors, and it may be that its effects on IOP and pupil diameter results from this. However, its miotic effect was small compared with that of established cholinergic drugs used in the treatment of glaucoma, such as pilocarpine, and it demonstrates no other cholinergic effects (Randhawa et al., 1988). Finally, it is possible that its effects on IOP are due, at least in part, to its enhancement of dopaminergic activity though inhibition of presynaptic dopamine re-uptake. It is of interest that while dopamine-2-receptor agonist activity reduces human IOP, dopamine-1-receptor stimulation with fenoldopam increases it (Elliott et al., 1991).

271

These opposing actions of selective dopamine receptor stimulation may explain the lower efficacy of dopaminergic agonists in reducing IOP compared with other agents such as timolol. While it is unlikely, therefore, that the ocular hypotensive action of medifoxamine is sufficient for therapeutic purposes, the possession of a weak cholinergic action rather than the anticholinergic activity found with many monoamine re-uptake inhibiting drugs represents a potentially important property for an antidepressant agent. S. Saleh was sponsored by Al-Fatah University, Tripoli, Libya. We thank Laboratories Anphar-Rolland for supplying medifoxamine and financial support for the study.

References Al-Sereiti, M. R. & Turner, P. (1989). The effect of lisuride, terguride and bromocriptine on intraocular pressure. Br. J. clin. Pharmac., 27, 159-163. Al-Sereiti, M. R., Coakes, R. L., O'Sullivan, P. D. & Turner, P. (1989). A comparison of the ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops in normal human volunteers. Br. J. clin. Pharmac., 28, 443447. Al-Sereiti, M. R., Quik, R. F. P., Hedges, A. & Turner, P. (1990). Antagonism by domperidone of the ocular hypotensive effect of pergolide. Eur. J. clin. Pharmac., 38, 461463. Al-Sereiti, M. R., Quik, R. F. P. & Turner, P. (1989). The effect of a single oral dose of pergolide on intraocular pressure and pupil diameter. Br. J. clin. Pharmac., 28, 2643-2648. Bessin, P., Labaurne, J. & Levy, J. (1986). Approache du mecanism d'action d'un antidepresseur, la medifoxamine: relation le system dopaminergique. Association Francaise de Pharmacologistes. Congres de Pharmacologie Francophone, Rouen. Abstract D06. Cogan, D. G. (1941). A simple entopic pupillometer. Am. J. Ophthalmol., 24, 1431-1433. Elliott, W. J., Karneziz, T. A., Silverman, R. A., Geanon, J., Tripathi, R. C. & Murphy, M. B. (1991). Intraocular pressure increases with fenoldopam, but not nitroprusside, in hypertensive humans. Clin. Pharmac. Ther., 49, 285-

293. Ferreri, M., Potez, H. & Alby, J. (1987). Double-blind comparitive trial in depressions: medifoxamine versus amineptine. Psychologie Medicale, 19, 39-55. Grolman, B. A. (1972). A new tonometer system. Am. J. Ophthalmol., 49, 646-660. Mekki, Q. A. & Turner, P. (1985). Stimulation of dopamine receptors (type 2) lowers human intraocular pressure. Br. J. Ophthalmol., 69, 909-910. Mekki, Q. A., Warrington, S. J. & Turner, P. (1984). Bromocriptine eye drops lower intraocular pressure without affecting prolactin levels. Lancet, i, 287-288. Morou, P. (1989). Efficacy and tolerability of long-term treatment with medifoxamine. Psychologie Medicale, 21, 1831-1845. Randhawa, A., Hedges, A., Johnston, A. & Turner, P. (1988). A psychopharmacological study to assess antimuscarinic and central nervous effects of medifoxamine in normal volunteers. Human Psychopharmac., 3, 195-200. Scharbach, H., Blanchard, C. H., Grivel, A., Houri, Z. & Lachaud, J. D. (1986). Double-blind trial comparing medifoxamine versus clomipramine in neurotic reactive depression. Psychologie Medicale, 18, 1486-1493.

(Received 2 January 1992, accepted 22 April 1992)