Restoring Sensitivity to Timolol After Long-Term Drift in Primary Open-Angle Glaucoma

Transcription

1 Investigative Ophthalmology & Visual Science, Vol., No. 2, February 90 Copyright Association for esearch in Vision and Ophthalmology estoring Sensitivity to Timolol After ong-term Drift in Primary Open-Angle Glaucoma Stefano A. Gandolfi In a prospective randomized single-masked study lasting 6 months, 39 eyes with primary open-angle glaucoma showing a long-term drift with 0.5% timolol were put on a "timolol holiday" lasting or days. Twenty-three of them were enrolled with dipivefrin 0.1% twice daily during the holiday. When timolol therapy was restored, the dipivefrin-treated group showed a more pronounced decrease of intraocular pressure (IOP) (8.2 ± 1.5), whereas the IOP decrease in the nondipivefrin-treated group was lower (3.9 ± 1.2) and of shorter duration (< days). Among the dipivefrin-treated group, the response to timolol was more prolonged in the eyes treated for days: the IOP of these eyes was < mmhg throughout the follow-up. Invest Ophthalmol Vis Sci :354-3, 90 Since the successful introduction of timolol as an agent in lowering intraocular pressure (IOP), some concern has been raised concerning its long-term efficacy. Krieglstein, in 78, published a follow-up study on the IOP response of timolol eye drops and demonstrated a long-term drift. 1 Other reports have agreed with Krieglstein's results. In reviewing these reports, Boger 2 speculated that the dissipation of the timolol efficacy could be the result of changes in the number or affinity of the beta-receptors during continuous adrenergic blockade. He also suggested that individuals successfully treated with timolol over a long period of time might benefit from a timolol "holiday" if they developed a long-term drift. 2 This hypothesis has been tested in the current pilot study designed to explore the possibility that either a timolol withdrawal alone or a timolol withdrawal accompanied by concurrent therapy with the prodrug of epinephrine dipivefrine could overcome the longterm drift. Dipivefrin was chosen instead of epinephrine, since dipivefrin appears to have a lower incidence of side effects. 3 " 5 Materials and Methods A total of 42 eyes of consecutive patients suffering from chronic open-angle glaucoma and meeting the eligibility criteria were selected for the study in the From the Istituto di Oftalmologia, Universita di Parma, Parma, Italy. Submitted for publication: January 12, 89; accepted July 7, 89. eprint requests: Stefano A. Gandolfi, Istituto di Oftalmologia, Via Gramsci, 14, 400 Parma, Italy. period February-June 87. The patients' age ranged from yr (average, yr). The criteria for selection were as follows: applanation tension > mmhg on two consecutive determinations at a 48-hr interval glaucoma open angle by gonioscopy stable visual field optic nerve healthy enough to be safe without treatment for 1 or 2 months absence of any previous therapy with adrenergic drugs, except for timolol eye drops All of the enrolled eyes had been treated successfully (ie, IOP < mmhg) with 0.5% timolol eye drops twice daily alone for a period ranging from 1 to 4 yr (Table 1) before developing a drift. The initial hypotensive effect of 0.5% timolol twice daily (Table 2) was not significantly different among the groups assigned to the four treatment schedules (ie, the patients were equally responsive to the beta-blocker). The treatment protocol of the current study is summarized as follows. After entering the study, timolol was withdrawn and randomly replaced with either 0.1 % dipivefrin eye drops twice daily ( eyes) or with artificial tears (16 eyes). The timolol holiday lasted ( eyes) or ( eyes) days. Afterwards, timolol therapy was reinitiated. IOP was checked the day before restoring timolol, and 7,, 1, and 0 days after, by a masked observer. The first IOP control after the holiday was set up at after withdrawal of dipivefrin to allow a proper washout of the adrenergic agonist in order to avoid the occurrence of any additive effect with timolol. 6 ' 7 For ethical reasons, when the IOP was found > mmhg during any of these control visits, the affected eye was treated immediately with stronger hypotensive agents to avoid 354 Downloaded From: on 12//

2 No. 2 ONG-TEM DIFT DUING TIMOO THEAPY IN PO / Gondolfi 355 any damage to the optic nerve, and the patient was considered to have completed the study (ie, the follow-up was interrupted). This happened to be the case in each of the nondipivefrin-treated eyes at the day follow-up visit and in each of the -day dipivefrin-treated eyes at the day 1 follow-up visit. Two patients (three eyes) did not come back at the end of the timolol holiday and therefore were lost to follow-up. The number of subjects at the end of the study then was reduced to (39 eyes). IOP measurements were performed by applanation tonometry at approximately the same time of the day on each visit to avoid the influence of diurnal variations. All patients received open-label timolol and open-label dipivefrin. Before entering the study, informed consent was obtained from each patient. esults The IOP changes induced by the timolol holiday in each patient are summarized in Figure 1 and displayed in detail in Tables 3-6. The sample size of each group was designed with a type I error = 0.01, type II error = 0.05, and a 1-/8 coefficient = Analysis of significance was performed by counting patients and not eyes. (However, separate data for the left and right eyes are provided in Tables 3-6.) When both eyes of a patient were analyzed, the average of the two IOP values was used for calculation with the paired student t-test. 8 The eyes in which timolol was withdrawn without replacement with dipivefrin showed a low but significant recovery of sensitivity to the beta-blocker: the mean decrease was 3.5 ± 1.2 and 3.7 ± 1.6 for a - and -day holiday, respectively (paired samples student t-test = 7. and 5.72, P < 0.01). This sensitivity was no longer maintained, since 2 months later, the IOP had returned to the prewithdrawal value. It is noteworthy that in only 3 of 16 tested eyes did the IOP decrease to below mmhg. A different situation is depicted when considering the dipivefrin-treated eyes. A significant and more Table 2. Initial hypotensive effect of timolol Duration of timolol holiday (days) + dipivefrin + dipivefrin IOP at diagnosis (mmhg).3 ± ± ± ± 1.8 IOP with timolol 0.5% twice dait\>* (mmhg).5 ±3.7.0 ±2.8.9 ±2.1.3 ±2.9 Values represent the mean ± SD of the IOP readings taken in each patient enrolled in the study, at the same time of the day. When both eyes of a patient were analyzed, the average of the two IOP values was considered, according to Ederer. 8 * IOP was checked within 3-4 weeks after the therapy with timolol was initiated. pronounced recovery of sensitivity to timolol was obtained after both a - and -day dipivefrin treatment: the mean IOP decrease ± SD was 7.7 ± 1.2 and 8.5 ± 1.5, respectively (paired samples student t-test =.37 and 14.03, P < ). In the -day dipivefrin-treated eyes, however, the IOP, although remaining roughly unchanged after 2 months, increased up to the prewithdrawal value at the 4-month control. In contrast, the -day treated eyes maintained a low IOP at all time points during the follow-up. The follow-up of the nondipivefrin-treated and of the -day dipivefrin-treated eyes is shorter because these eyes were treated immediately as soon as the IOP was found to be mmhg or higher during the follow-up. en Q_ O Table 1. Previous timolol treatment of the enrolled eyes Duration of timolol holiday (days) Duration ofprevious timolol treatment* (months) + dipivefrin + dipivefrin.8 ± ± ± ±8.2 * Values represent the mean ± SD of the duration of previous treatment with timolol (0.5% twice daily) obtained from each patient enrolled in the study. Durations were calculated from the month the timolol treatment was initiated to the month the patient was recruited for the study. U Follow up time (months) Fig. 1. IOP variations during the follow up. The break on the x-axis represents the timolol holiday. The symbols represent the mean ± SD of the single values detailed in Tables = days; O = days; = days + dipivefrin; = days + dipivefrin. Downloaded From: on 12//

3 356 INVESTIGATIVE OPHTHAMOOGY b VISUA SCIENCE / February 90 Vol. Table 3. -day timolol holiday days AF AF PG PG A MC F Discussion Several reports have demonstrated the occurrence of dissipation phenomena in which initial hypotensive effect of timolol diminishes with continuous administration. 910 The terms short-term "escape" and long-term "drift" have been used to describe the reduction in the effectiveness of timolol over a few days or over years, respectively. 2 Steinert and co-workers reported that withdrawal of timolol in glaucomatous patients who developed a long-term drift induced a mean IOP increase of 6 mmhg. A detailed analysis of the data collected in the saline-treated patients (Tables 3-6) showed that withdrawal of timolol led to mean IOP increases of 2.6 ± 1.9 (0.01 < P < 0.1) and 1.3 ± 1.6 (0.1 < P 0.2) in the - and -day treatment schedules, respectively. The relatively small difference in these increases, taken together with the very moderate statistical significance, therefore makes it possible to assume that the IOP of the patients enrolled in the study was indeed no longer responsive to timolol. The molecular mechanisms underlying the longterm drift to the beta-blockade are yet to be elucidated. However, in vitro experiments have shown that the density of beta-receptors can change in the presence of continued adrenergic treatment in several tissues of the human body." In particular, the number of beta-receptors in ocular tissues increases after prolonged timolol therapy. 12 In contrast, down regulation of the beta-receptor is observed after betaadrenergic agonist stimulation. 13 Either a real loss of the beta-receptors from the plasma membrane 14 or a functional uncoupling of the beta-receptor from the adenylate cyclase may account for this phenomenon ecently, an in vitro adrenergic stimulation of ciliary process epithelium has been shown to induce a surface membrane internalization, which may represent the morphologic counterpart for the mechanisms of the adrenergic-induced beta-receptor desensitization. In view of this proposed molecular mechanism, one may speculate that a timolol holiday and a concomitant adrenergic therapy exerts an additive effect in reducing the number of beta-receptors in the ocular tissues and possibly in restoring sensitivity to the beta-blockade. A timolol holiday alone has been tested by Steinert and co-workers, but the reapplication of the beta-blocker did not lower the IOP to below the prewithdrawal level. However, Boger reported some cases in which a more prolonged timolol withdrawal, with concurrent administration of car- Table 4. -day timolol holiday days PT A A MT A F Downloaded From: on 12//

4 No. 2 ONG-TEM DIFT DUING TIMOO THEAPY IN PO / Gondolfi 357 Table 5. -day timolol holiday + dipivefrin IOP(mmHg) days 1 days F F T T AB AB FM FM BC F PM Table 6. -day timolol holiday + dipivefrin days 1 days 0 days F F N N AS AS PF PF GG bonic anhydrase inhibitors, was effective in restoring eye sensitivity to the beta-blocker. The striking importance of the duration of the timolol holiday is confirmed by the results reported in this paper. Provided that a timolol holiday alone did not give appreciable results with time, only the eyes treated with dipivefrin for at least days showed a significant IOP response; a 10-day period was ineffective (data not shown). Moreover, a more prolonged restoration of sensitivity to timolol was observed in the -day dipivefrin-treated group. Neufeld and co-workers 12 noticed that 4-day epinephrine therapy reduced the number of beta-receptors in rabbit corneas while leaving unaffected the number of beta-receptors in the iris-ciliary body complex. They interpreted this result by speculating a time-dependence due to the penetration rate of the compound into the intact eye. They suggested further 12 that a more prolonged treatment with epinephrine may be necessary to obtain a detectable reduction in the number of beta-receptors in the iris-ciliary body complex. In conclusion, the results reported in this pilot study, although collected on a limited number of eyes, support the hypothesis of the usefulness of a timolol holiday paralleled by therapy with adrenergic agonists in restoring the sensitivity to the beta-blockade in eyes affected by chronic open-angle glaucoma. Further studies must evaluate the duration of the holiday necessary to restore sensitivity to timolol and long enough to allow a safe and reliable reinstillation of the beta-blocker. Key words: timolol, open-angle glaucoma, dipivefrin, betablockers, beta receptors Acknowledgments The author thanks Prof. Giovanni Maraini, MD, for helpful discussions and criticisms in revising the manuscript. The author is indebted also to Dr. orenza Bertoncini for English language supervision. eferences 1. Krieglstein GK: ongzeituntersuchungen zur augendruksenkendedn wiekung von timolol augentropfen. Klin Monatsbl Augenheilkd 5:6, 78. Downloaded From: on 12//

5 3 INVESTIGATIVE OPHTHAMOOGY & VISUA SCIENCE / Februory 90 Vol. 2. Boger WP, III: Short-term escape and long-term drift: The dissipation effect of the beta-adrenergic blocking agents. Surv Ophthalmol :5, Mandell AI, Stentz F, and Kitabachi AE: Dipivalyl epinephrine: A new prodrug in the treatment of glaucoma. Ophthalmology 85:8, Wei C, Anderson JA, and eopold I: Ocular absorption and metabolism of topically applied epinephrine and a dipivalyl ester of epinephrine. Invest Ophthalmol Vis Sci :5, Yablonski ME, Shin DH, Kolker AE, Kass M, and Becker B: Dipivefrin use in patients with intolerance to topically applied epinephrine. Arch Ophthalmol 95:57, Keats MD and Stone A: Safety and effectiveness of concomitant administration of dipivefrin and timolol maleate. Am J Ophthalmol 91:3, Thomas V and Epstein D: Timolol and epinephrine in primary open angle glaucoma. Arch Ophthalmol 99:91, Ederer F: Shall we count number of eyes or number of subjects? Arch Ophthalmol 89:1, Krieglstein GK: Die wirkung von timolol augentropfen auf den augeninnendruck bei glaucoma simplex. Klin Monatsbl Augenheilkd 2:677, Krieglstein GK: Zur tachyphylaxie von beta-rezeptoren blochern amr glaukomauge. Ber Dtsch Ophthalmol Gesell 75:357, Stiles G, Caron HG, and efkowitz J: Betaadrenergic receptors: Biochemical mechanisms of physiological regulation. Physiol ev 64:6, Neufeld AH, Zawistowski KA, Page ED, and Bromberg BB: Influence on the density of beta adrenergic receptors in the cornea and iris-ciliary body in the rabbit. Invest Ophthalmol Vis Sci :1069, Galant SP, Duriseti, and Underwood S: Decreased betaadrenergic receptors on polymorphonuclear leukocytes after adrenergic therapy. New Engl J Med 9:933, Harden TK: Agonist induced desensitization of the beta adrenergic receptor linked adenylate cyclase. Pharmacol ev 35:5, Mittag T and Tormay A: Desensitization of the beta adrenergic receptor adenylate cyclase complex in rabbit iris-ciliary body induced by topical epinephrine. Exp es 33:497, Sibley D and efkowitz J: Molecular mechanisms of receptor desensitization using a beta adrenergic receptor coupled adenylate cyclase system as a model. Nature 7:1, 85.. Brandt JD, Bartels SP, and Neufeld AH: Adrenergic stimulation of ciliary process epithelium causes surface membrane internalization. Invest Ophthalmol Vis Sci :4, 87.. Steinert F, Thomas JV, and Boger WP, III: ong-term drift and continued efficacy after multiyear timolol therapy. Arch Ophthalmol 99:100, 81.. Boger WP, III: Discussion of "Short-term escape and longterm drift: The dissipation effect of beta adrenergic blocking agents." Surv Ophthalmol :2, 83. Downloaded From: on 12//