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Dorzolamide

Additional clinical investigations were carried out on use of dorzolamide as an adjunctive agent to timolol. At peak, there was an additional IOP drop of 4mm Hg, which decreased to 3.5mm Hg at 8 hours.33 Another study, examining different alternatives for adjunctive therapy, found comparable efficacy between dorzolamide and pilocarpine 2% when added to timolol. Patients tolerated dorzolamide much better and had considerably fewer complaints of decreased vision and induced

myopia.

Considerable attention has been paid to whether three-times-daily application of dorzolamide is significantly better than twice-daily application. Because of the 8- to 10-hour duration of dorzolamide, it does seem that there is a small but definite increase in efficacy with three-times-daily monotherapy compared to twice daily. A prospective clinical trial showed lack of a statistically significant difference in three-times-daily versus twice-daily dorzolamide treatment, but three-times-daily treatment gave approximately 1mm Hg better IOP lowering at 8 to 12 hours (figure 6.4).35 Many ophthalmologists use dorzolamide twice daily as both monotherapy and adjunctive therapy, but there is an occasional patient who benefits from monotherapy administered three times daily. The efficacy of dorzolamide 2% was evaluated in a series of patients who were younger than 6 years of age in a 3-month, controlled, randomized trial. Of the 66 patients who were 2 or more years of age and randomized to dorzolamide 2%, only two patients discontinued treatment due to ocular symptoms. After 3 months of treatment, the mean reduction in IOP compared to baseline was -20.6% among those younger than 2 years of age, and -23.3% among those 2 or more years of age. Thus, when considering patients younger than 6 years of age, dorzolamide is generally effective and well tolerated.36

Careful attempts have been made to document potential ocular and systemic side effects of dorzolamide (table 6.4).37 The ocular effects seem to be principally confined to a 33% incidence of stinging on instillation and a 10% to 15% incidence of punctate keratitis. Incidences of blurred vision, tearing, dryness, and photophobia were all less than 5%. Some of the stinging on instillation is most likely related to

Figure 6.4. Mean IOP for dorzolamide 2% 30

twice daily (7:00 a.m. and 7:00 p.m.) for 5 2g days, followed by three-times-daily dosing ^

(7:00 a.m., 3:00 p.m., and 11:00 p.m.) for 7 e 26 days. Orange circles, prestudy; green circles, 24

day 1; blue circles, day 5; red circles, day 12. — Redrawn with permission from Lippa EA. Carbonic anhydrase inhibitors. In: Ritch R, 20

Shields MB, Krupin T, eds. The Glaucomas. 2nd ed. St Louis, Mo: CV: Mosby Co; 1996:1463-1481.

Hours after morning dose (parallel times prestudy)

the molecule itself, but there is also a potential factor of the slightly low pH (5.8) required to keep the relatively insoluble compound in solution. Periorbital dermatitis has been described in a small case series of patients who were treated with dorzolamide for a mean period of 20.4 weeks. In 8 of the 14 patients described, the dermatitis resolved once the dorzolamide was discontinued.38 After long-term dorzolamide treatment, analysis of both serum and urine chemistries revealed no changes in a group of healthy volunteers.39 There was a decrease in red blood cell carbonic anhydrase II activity, substantiating some systemic absorption, and previous reports have noted that this red blood cell binding is present in detectable amounts for at least 4 months.40 An initial concern during preapproval trials was a small increase in corneal thickness in a dorzolamide-treated group. However, an extensive three-armed, masked, postapproval, phase IV study using endothelial

Table 6.4 Side Effects of Topical Carbonic Anhydrase Inhibitors

Ocular

Burning/stinging eye Punctate keratitis Blurred vision Blepharitis Conjunctivitis Eye discharge Tearing

Foreign-body sensation Corneal erosion Visual disturbance

Systemic

Taste perversion

Source: Reprinted with permission from Adamsons I, Clineschmidt C, Polis A, et al. The efficacy and safety of dorzolamide as adjunctive therapy to ti-molol maleate gellan solution in patients with elevated intraocular pressure. Additivity Study Group. J Glaucoma. 1998;7:253-260.

videokeratography in patients with normal corneas failed to find any increased corneal thickness or significant change in endothelial morphology. It is interesting that, in both the dorzolamide-treated groups and the two beta blocker-treated control groups, there was a trend toward a decrease in overall endothelial cell count.41 However, in patients with severe corneal disease, topical dorzolamide 2% may be problematic. In a series of nine patients with corneal pathology such as Fuch's endothelial dystrophy or surgical trauma, administration of topical dorzolamide for period of 3 to 20 weeks resulted in irreversible corneal decompensation. Seven of the nine eyes subsequently underwent penetrating keratoplasties.42 Some patients have developed urolithiasis during dorzolamide treatment, but the prevalence is low enough to suggest no relationship to the topical medication. Additionally, there have been no reports of Stevens-Johnson syndrome or blood dys-crasias following dorzolamide use, but because of the observed systemic absorption of this drug, continued clinical surveillance is appropriate. The one consistent systemic effect that occurs frequently is a bitter taste following administration, which approximately 25% of patients notice, but which seldom complicates long-term therapy. This side effect is easily reduced by use of punctal occlusion.

Most clinicians have had a positive experience with both the tolerance and the efficacy of dorzolamide, but questions continue to linger regarding equivalence of topical and oral compounds. Although fluorophotometric investigation showed a 17% reduction in aqueous flow following dorzolamide application to nine glau-comatous volunteers, compared with a 30% reduction following acetazolamide,43 most of the long-term dosing trials show equivalence in observed IOP lowering. A 12-week study on 31 patients showed good maintenance of IOP reduction when topical dorzolamide was substituted for oral acetazolamide.44 A larger prospective study has also shown that the oral and topical forms are essentially interchangeable when used as adjunctive therapy (figure 6.5).45 The comparative efficacy of topical CAIs versus the systemic agents may differ on an individual patient basis, and thus clinicians may wish the try various formulations of the drug prior to abandoning this class. The question of whether dorzolamide used topically offers additional IOP lowering when added to oral treatment with acetazolamide was answered by a recent clinical trial that showed lack of such an additive effect. Because it was a three-armed design, the study was also able to substantiate that the group using dorzolamide alone was comparable to the group using acetazolamide alone in IOP

reduction.46

Perhaps because of early impressions that oral CAIs may have an advantageous effect on ocular blood flow, considerable attention has been paid to the effect of dorzolamide on blood flow as measured by several contemporary methodologies. Both optic nerve head blood flow in animals, measured by a laser Doppler flow-meter, and arteriovenous passage time, measured with a scanning laser ophthalmoscope, seemed to be improved following use of topical dorzolamide.47 Recently, Nagel et al.48 assessed the effects of dorzolamide on the autoregulation of major retinal vessels in a series of glaucoma patients. The IOP was elevated to 38mm Hg for 100 seconds. Changes in the diameter of the retinal vessels were measured before, during, and after IOP elevation at baseline, and the measurements were repeated

Figure 6.5. Mean IOP at hour 2 (with 95% confidence intervals) by treatment group. At peak, both dorzolamide and acetazolamide provided additional IOP lowering when added to timolol. At week 12, IOP level at hour 2 in patients receiving acetazolamide was slightly lower (about ImmHg) compared to patients receiving dorzolamide. Orange circles, dorzolamide (n — 53); blue circles, acetazolamide (n — 49). Redrawn with permission from Hutzelmann JE, Polis AB, Michael AJ, Adamsons IA. A comparison of the efficacy and tolerability of dorzolamide and acetazolamide as adjunctive therapy to timolol. Acta Ophthalmol Scand. 1998;76:717-722.

Figure 6.5. Mean IOP at hour 2 (with 95% confidence intervals) by treatment group. At peak, both dorzolamide and acetazolamide provided additional IOP lowering when added to timolol. At week 12, IOP level at hour 2 in patients receiving acetazolamide was slightly lower (about ImmHg) compared to patients receiving dorzolamide. Orange circles, dorzolamide (n — 53); blue circles, acetazolamide (n — 49). Redrawn with permission from Hutzelmann JE, Polis AB, Michael AJ, Adamsons IA. A comparison of the efficacy and tolerability of dorzolamide and acetazolamide as adjunctive therapy to timolol. Acta Ophthalmol Scand. 1998;76:717-722.

4 weeks later following treatment with dorzolamide three times daily. The arterial diameter was greater following treatment with dorzolamide, before and during the elevation of IOP. In the posttreated eyes, the vessel diameter decreased by -1.7% ± 3.0. The researchers concluded that the dilation of the vessels during the IOP elevation may be an indication that dorzolamide may influence the vascular response due to changes in IOP. Whether research such as this small study can show any impact of treatment on the long-term effect on the glaucomatous process remains to be seen. Nevertheless, it seems encouraging that dorzolamide has not been shown to reduce flow in all studies published thus far.

The efficacy and safety of using dorzolamide to prevent the conversion from ocular hypertension to glaucoma were explored in the European Glaucoma Prevention Study (EGPS), a multicenter, randomized, prospective study.49 A total of 1,081 patients 30 or more years of age with IOP at baseline that measured 22 to 29 mm Hg were randomized to either treatment with dorzolamide 2% three times daily or placebo three times daily. Although dorzolamide reduced IOP by 15% to 22% throughout the 5-year follow-up period, there was no statistically significant difference between the two groups of patients. In fact, within the placebo group, the mean IOP reduction ranged from 9% at 6 months to 19% at 5 years. Significant numbers of patients dropped out of both groups by the end of the study. Other factors such as the use of a single agent rather than multiple agents may have contributed to the findings of this study versus the Ocular Hypertension Treatment Study (OHTS),50 which did find a significant difference among those participants who received topical antiglaucoma therapy versus a group of patients who were simply observed. It should be noted that more than one-third of the patients in the treated group in OHTS required more than one medication to achieve of an IOP reduction goal of at least 20% compared to baseline. No such goal was set in the EGPS prior to the initiation of the study. Topical CAIs were among the choices of drugs available to clinicians to achieve the study goal of 20% in OHTS. Thus, clinicians are urged to examine the differences in study design and the demographics of the population before drawing conclusions regarding the role of topical CAIs in the treatment of ocular hypertension.

6.2.5 Brinzolamide. Brinzolamide is available in a 1% concentration (see figure 6.3). Using a formulation similar to that previously employed with betaxolol, brinzola-mide is a suspension that allows buffering to a more neutral pH than does dorzo-lamide. This difference in formulation may be the reason why patients demonstrate less ocular irritation with brinzolamide versus dorzolamide.51 Multicenter studies have been completed comparing both twice-daily brinzolamide and three-times-daily brinzolamide 1% to timolol 0.5%. These results show efficacy similar to that of dorzolamide, but with IOP lowering slightly less than timolol use with either dosing regimen of brinzolamide. Differences between twice-daily and three-times-daily dosing were less than 1mm Hg (figure 6.6).52 A meta-analysis of the IOP-lowering effects of commonly used glaucoma drugs was conducted by van der Valk et al.53 These investigators based their analysis on 27 articles that described 28 randomized clinical trials involving move than 6,000 individuals. Moreover, the analysis was based on 1-month data. When considering the reduction of IOP from baseline, the investigators noted that a peak reduction for dorzolamide of -22% (range, -24% to -20%) and trough of-17% (-19% to -15%) versus brinzolamide, with peak reduction of-17% (range -19% to -15%) and trough of-17% (-19% to -15%). This range is similar to the response of patients to topical dorzolamide in the EGPS and underscores the role of these topical agents as adjunctive therapy rather than monotherapy. In another study, topical and systemic side effects were minimal, with a 2.7% incidence of keratitis and a 0.7% incidence of corneal edema. Systemic plasma levels were detectable in red blood cells at 5 months.54

The most striking difference between brinzolamide and dorzolamide seems to be tolerance. In a 1997 preliminary study involving more than 200 patients, there were significantly more complaints of severe and moderately severe discomfort following masked dorzolamide use compared with masked brinzolamide use.55 Ocular hy-peremia and tearing were also less in the brinzolamide group, but foreign-body sensation and blurred vision were significantly greater in the brinzolamide group. The early clinical use of brinzolamide suggests that patients do occasionally have blurred vision, which is most likely related to the nature of the suspension. Overall, brinzolamide 1% seems to be a safe and effective option with a slightly different tolerance profile compared with dorzolamide for the treatment of glaucoma.

Figure 6.6. Mean change in IOP for each treatment group by visit and time of day during 3-month treatment period. Values reported are least-squares means of change from corresponding baseline diurnal IOP. All changes from baseline were statistically significant (P < .0001). Green squares, brinzolamide 1% twice daily; orange circles, brinzolamide 1% three times daily; blue triangles, dorzolamide 2% three times daily; red circles, timolol 0; 5% twice daily. Redrawn from Silver LH. Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Brinzolamide Primary Therapy Study Group. Am J Ophthalmol. 1998;126:400-408. Copyright 1998, with permission from Elsevier Science.

Figure 6.6. Mean change in IOP for each treatment group by visit and time of day during 3-month treatment period. Values reported are least-squares means of change from corresponding baseline diurnal IOP. All changes from baseline were statistically significant (P < .0001). Green squares, brinzolamide 1% twice daily; orange circles, brinzolamide 1% three times daily; blue triangles, dorzolamide 2% three times daily; red circles, timolol 0; 5% twice daily. Redrawn from Silver LH. Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Brinzolamide Primary Therapy Study Group. Am J Ophthalmol. 1998;126:400-408. Copyright 1998, with permission from Elsevier Science.

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