The effect of MK-927, a topical carbonic anhydrase inhibitor, on IOP in glaucomatous monkeys

MK-927 is a water soluble, potent inhibitor of human carbonic anhydrase (CA) II in vitro. Topical administration of MK-927 reduces intraocular pressure (IOP) in rabbits. Elevated IOP was produced in cynomolgus monkey eyes by argon laser photocoagulation of the trabecular meshwork. IOP was measured at 0 hr, 0.5 hr and hourly for 8 hrs in 8 eyes for two baseline days, one day on vehicle and five days of therapy with 2% MK-927 b.i.d., after initial single-dose trials of various concentrations. IOP was not significantly different comparing baseline and vehicle treated days. Significant (p less than 0.05) reductions of IOP occurred for five days lasting at least 8 hrs after each dosing. At 3 hrs after treatment with vehicle the IOP was 31.6 +/- 3.4 (SE) mm Hg. Maximum reduction of IOP occurred at 3 hrs after application of MK-927, the IOP decreasing from day 1 (19.9 +/- 1.0 mm Hg) to day 5 (16.5 +/- 1.6 mm Hg). MK-927 appears to have great clinical potential.     

Comparative tolerability of topical carbonic anhydrase inhibitor MK-927 and its S-enantiomer MK-417

A single-dose, randomised, double-masked, placebo-controlled, five-period cross-over comparative ocular tolerance study was undertaken with the topical carbonic anhydrase inhibitor (CAI) MK-927 (1% and 2% concentrations) and its S-enantiomer MK-417 (1 and 1.8% concentrations) in 20 healthy, normal volunteers. Subjects received one drop of placebo (common vehicle) or CAI in each eye on five different days that were separated by washout intervals of 1 week. The incidence of burning increased significantly after treatment with 2% MK-927 (P<0.01) and 1.8% MK-417 (P < 0.05) as compared with placebo. The mean duration of burning following placebo was 16.8 s, somewhat less than that following CAI application (23–37.1 s). The duration of tearing following CAI treatment was also significantly prolonged (P < 0.05). Pupil size was not changed by CAIs. No other side effects were observed. At 3 h after instillation, intraocular pressure (IOP) was found to be decreased following all four CAI treatments, significantly so with 1% and 1.8% MK-417. The reasonable single-dose tolerability of MK-927 and MK-417 in this sensitive normal-volunteer model supports their potential as topical glaucoma medications. This study suggests that MK-417 may possess greater IOP-lowering activity than MK-927 in man.E.A. Lippa (Director, Clinical Research), F.L. Brunner-Ferber (Assistant Director, Clinical Pharmacology) and D. Panebianco (statistician) are employes of Merck & Co., Inc.; N. Pfeiffer, J. Gerling and F. Grehn have no commercial or proprietary interest in the drugs investigated Offprint requests to: N. Pfeiffer     

Chemical and pharmacological properties of MK-927, a sulfonamide carbonic anhydrase inhibitor that lowers intraocular pressure by the topical route

A large number of sulfonamides have now been tested by the topical route for the lowering of intraocular pressure in the normal albino rabbit. Certain compounds with favorable balance between lipid and water solubility, and high activity against carbonic anhydrase, do lower pressure as much as 3 mmHg. MK-927, a thienothiopyrane-2-sulfonamide carrying an alkylamino group of pK 5.8, has desirable physicochemical properties: good water solubility below pH 5.8, a CHCl3/buffer ratio of 0.6 at pH 5.4, and a KI value against carbonic anhydrase of 2-7 nM, depending on assay conditions. Inhibition of CO2 hydration is non-competitive. By comparison with other candidate topically active sulfonamides, it is the most effective in terms of pressure lowering times duration of action. There are no apparent systemic effects or ocular toxicity. The concentration of drug reaching the ciliary process and aqueous humor is of the same order as that following parenteral sulfonamides, so that inhibition of the enzyme exceeds 99%. MK-927 is therefore a candidate for the clinical treatment of glaucoma.     

Blurred vision after instillation of topical carbonic anhydrase inhibitor

PURPOSE: The aim of this study was to compare brinzolamide with dorzolamide in regard to blurred vision after instillation. We also compared saline with two topical carbonic anhydrase inhibitor drugs. SUBJECTS AND METHODS: The study population comprised 21 healthy volunteers whose best corrected visual acuity was 1.0 or better. Brinzolamide 1% or dorzolamide 1% was applied to one eye the contralateral eye was exposed to the other drug. At 30 sec after instillation, visual acuity was measured every 30 sec until best visual acuity was recovered. Because visual acuity can fluctuate widely with blinking, subjects blinked for 5 sec before visual acuity measurement. As control, we applied saline alone to both eyes of 14 subjects and measured the change in visual acuity in the same way. Subjective sensations in each eye were recorded after measurement. RESULTS: Average visual acuity every 30 sec for 5 min was 0.41, 0.56, 0.68, 0.86, 0.87, 0.96, 1.04, 1.08, 1.11, and 1.12 after dorzolamide instillation, and 0.28, 0.42, 0.60, 0.69, 0.81, 0.91, 0.93, 0.99, 1.06, and 1.10 after brinzolamide instillation. In contrast, the average visual acuity after saline instillation for 2 min was 1.09, 1.13, 1.16 and 1.16. Of the 21 subjects, 15 (71.4%) felt moderate or severe irritation when dorzolamide was instilled; 2 (9.5%) felt moderate or severe irritation when brinzolamide was instilled. CONCLUSIONS: Both brinzolamide and dorzolamide caused significantly prolonged blurring of vision, from 30 sec to 2 or 3 min after instillation, as compared with saline only. The average visual acuity after brinzolamide instillation was lower than after dorzolamide for 5 min after instillation, although there was no significant difference. Judging from the subjects' sensations, it is suggested that with dorzolamide the prolonged blurred vision was due to reflex tearing from irritation, as explained above, whereas with brinzolamide it was due to opaque tears on the ocular surface.     

Relations among IOP reduction, ocular disposition and pharmacology of the carbonic anhydrase inhibitor ethoxzolamide.

We have measured sequentially the concentrations of ethoxzolamide (6-ethoxybenzothiazole-2-sulfonamide) in ocular tissues following its intravenous or topical administration to normal albino rabbits. This was done in parallel with determinations of intraocular pressure (IOP) measured by tonometer or direct manometry. Ethoxzolamide was used because of its very high activity against carbonic anhydrase and experience showing that there is little or no other receptor in tissues. During the course of these experiments it was discovered that the lipid-soluble ethoxzolamide is converted in vivo to a water-soluble metabolite, while retaining high activity against the enzyme. Presumably this is the 6-O-glucuronide adduct. At the minimal dose for maximal effect (4 mg kg-1 i.v. at 45 min) the IOP lowering was 4.2 mmHg, the concentration in anterior uvea was 2.5 mumol kg-1, and the fractional inhibition of the enzyme (i) was 0.9995. The effect of free drug in the anterior uvea and other tissues. Following topical administration i was measured as a function of drug and enzyme in ciliary process. IOP lowering at 1 hr was -1.9 mmHg and i = 0.9993. By 4 hr i = 0.9980 and the pharmacological effect disappeared. At 8 hr the concentration of ethoxzolamide in the ciliary process is 0.4 mumol kg-1, essentially that of enzyme, with no free drug present: drug is now a marker for enzyme. Ethoxzolamide also labels the red cell carbonic anhydrases in the rabbit as well as other species including man. There appears to be no ethoxzolamide receptor other than carbonic anhydrase.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of L-671,152 and MK-927, two topically effective ocular hypotensive carbonic anhydrase inhibitors, in experimental animals

L-671,152 is a water-soluble, carbonic anhydrase inhibitor structurally similar to MK-927, a carbonic anhydrase inhibitor that, on topical administration, lowers the intraocular pressure (IOP) of experimental animals and humans. L-671,152 was more potent than MK-927 at inhibiting purified, human erythrocyte carbonic anhydrase II in vitro, as reflected in their respective IC50 values of 0.16 nM and 1.19 nM. Both compounds were compared for topical, ocular hypotensive activity in pigmented rabbits and cynomolgus monkeys. Ocular hypertension was induced in the latter by argon laser photocoagulation of the trabecular meshwork. A 2% solution of L-671,152 was more potent than 2% MK-927 in lowering the IOP of ocular hypertensive monkeys, the maximum reductions being 13.8 mm Hg (37%) and 9.6 mm Hg (27%) at 5 hr and 4 hr, respectively. Moreover, the duration of action of L-671,152 was superior to that of MK-927. The ocular hypotensive effect of L-671,152 was greater than that of MK-927 over a range of concentrations (0.5%-2%) in pigmented rabbits whose IOP was inherently elevated. The peak declines in the IOP of these rabbits after the instillation of 2% solutions of L-671,152 and MK-927 were 6.1 mm Hg and 4.8 mm Hg, respectively. L-671,152 was very effective in lowering the elevated IOP of alpha-chymotrypsinized rabbits and the unilateral instillation of 0.5% L-671,152 into the contralateral eye failed to decrease the elevated IOP of the alpha-chymotrypsinized eye. This finding indicates that the site of action of topically applied L-671,152 is local. The enhancement in the potency of L-671,152 over MK-927 is attributed to a greater inhibition of carbonic anhydrase activity.     

A topical or oral carbonic anhydrase inhibitor to control ocular hypertension after cataract surgery

PURPOSE: To compare the effects of oral acetozolamide and topical 2% dorzolamide to prevent ocular hypertension after cataract surgery. METHODS: This prospective, randomized study comprised 62 consecutive patients who had extracapsular cataract extraction and posterior chamber intraocular lens implantation. Patients received either oral acetozolamide (Diazomide) 250 mg three times daily or topical dorzolamide 2% (Trusopt) three times daily, for three days. Intraocular pressures (IOP) were measured by Goldmann applanation tonometry preoperatively and 16, 40, 64 hours postoperatively. RESULTS: IOP in the dorzolamide group peaked at 16 hours and had returned to preoperative values by 40 hours. In the acetozolamide group mean IOP was significantly higher than preoperative values at 16, 40 and 64 hours (p<0.05). At all three postoperative measurement times, mean IOP was significantly higher in the acetozolamide group (p<0.05). CONCLUSIONS: Topical dorzolamide 2% offers better IOP control than oral acetozolamide to prevent ocular hypertension after cataract surgery.     

最新型局部碳酸酐酶抑制剂派立明的临床前及临床研究

派立明是一种最新型的局部碳酸酐酶抑制剂。此药可选择性、高亲和力及明显地抑制碳酸酐酶同功酶Ⅱ的活性,有效地降低眼压。本品滴眼后可快速进入眼组织,在虹膜、睫状体、脉络膜、视网膜、晶状体和血液中有较长的半衰期(数天)。虽然用派立明滴眼后,可在全血中测出药物浓度,提示陔药可全身吸收,但主药和其代谢产物的血浆浓度非常低,在稳定状态下药物与红细胞内碳酸酐酶的结合达不到完全饱和。因此,不会出现全身酸中毒或其他与口服碳酸酐酶抑制剂有关的副作用。对兔眼滴用派立明还町增加视乳头血流量,而对全身酸碱平衡的影响极小。如这一作用在人眼被证实,将对有视神经病变的青光眼患者十分有益。1％派立明每日滴眼2次的降眼压效果最好,且患者的耐受性较多佐胺好,这可提高患者长期用药的依从性。滴眼后最常见的剐作用是视物模糊(6％)及口苦、口酸等味觉异常(6％),总之,派立明的降眼压作用强,副作用小,滴眼舒适,患者耐受性好,是一种非常有价值的抗青光眼新药。     

Hyperkalaemia induced by carbonic anhydrase inhibitor.

An 81-year-old man developed hyperkalaemic and hyperchloraemic metabolic acidosis following treatment with a carbonic anhydrase inhibitor for his glaucoma. He had mild renal failure and selective aldosterone deficiency was confirmed. In this case the treatment did not lead to hypokalaemia because of the limited potassium secretory capacity in the renal tubules from selective aldosterone deficiency; rather, it may have led to hyperkalaemia because metabolic acidosis induced by the carbonic anhydrase inhibitor caused transcellular movement of potassium.     

碳酸酐酶抑制剂的局部应用对大鼠角膜新生血管形成过程中水通道蛋白1表达的影响

背景研究表明,水通道蛋白1（AQP1）与大鼠碱烧伤后角膜新生血管（CNV）的形成密切相关,碳酸酐酶抑制剂具有抑制AQP1的作用,从而可间接抑制CNV,但其全身应用不良反应较重,因此局部碳酸酐酶抑制剂布林佐胺滴眼液对CNV的作用受到关注。目的研究局部应用布林佐胺滴眼液对大鼠碱烧伤后CNV形成过程中AQP1表达的影响。方法健康SD大鼠35只按随机数字表法随机分为正常对照组5只10只眼、模型组15只30只眼和布林佐胺组15只30只眼。模型组和布林佐胺组大鼠用浸有1mol／LNaOH溶液的滤纸贴附于角膜40s建立角膜碱烧伤大鼠模型,布林佐胺组大鼠在造模后用布林佐胺滴眼液点眼,正常对照组和模型组大鼠用生理盐水点眼。造模后3d裂隙灯下对角膜烧伤程度进行分级;造模后3、5、7、10d对大鼠角膜混浊度进行评分,同时测量CNV的生长面积。造模后第10天获取大鼠角膜组织并行苏木精-伊红染色观察大鼠角膜的组织病理学改变,透射电子显微镜下观察各组角膜超微结构的改变。应用免疫组织化学法检测AQP1及血管内皮生长因子（VEGF）在各组大鼠角膜中的表达。结果裂隙灯下模型组与布林佐胺组大鼠角膜碱烧伤的评分差异无统计学意义（t=0．97,P〉0．05）。正常对照组大鼠角膜无水肿、无混浊,无CNV生成;造模后5d布林佐胺组大鼠角膜水肿、混浊评分低于模型组（t=2．18,P〈0．05）,CNV面积小于模型组（t=6．58,P〈0．01）。角膜组织病理学检查显示,布林佐胺组大鼠较模型组大鼠CNV及炎性细胞少。透射电子显微镜检查显示,模型组大鼠CNV旺盛,布林佐胺组大鼠角膜较模型组大鼠角膜血管腔少见。免疫组织化学检测表明,正常对照组大鼠角膜组织中可见AQP1和VEGF呈弱表达;模型组及布林佐胺组大鼠角膜碱烧伤后角膜组织中VEGF灰度值分别为84．92±9．49和78．18±11．41,差异有统计学意义（t=2．48,P=0．02）,2个组AQP1灰度值分别为88．01±11．03和58．10±12．14,差异有统计学意义（t=9．99,P=0．00）。结论布林佐胺滴眼液能抑制大鼠角膜碱烧伤后CNV形成过程中AQP1的高表达,从而间接影响VEGF的表达,抑制或延缓CNV的形成。     

Electroretinal changes in the presence of a carbonic anhydrase inhibitor

A specific carbonic anhydrase activity inhibitor (methazolamide) was injected into one vitreous body each of 4 New Zealand White rabbits. Electroretinograms (ERG) were recorded before and several times after the methazolamide injection. The stimulus levels maximized the rod and cone response characteristics of the rabbit ERG. The effects of methazolamide were followed over 5 h. During this time, the electroretinograms showed a decline in amplitude of both a and b waves at both stimulus levels. The data support the involvement of carbonic anhydrase in the excitatory physiological events in the retina. Preliminary evidence indicates a slow recovery of the carbonic-anhydrase-inhibited ERG.     

MK-507 versus sezolamide. Comparative efficacy of two topically active carbonic anhydrase inhibitors

Topical carbonic anhydrase inhibitors MK-507 and sezolamide hydrochloride (previously known as MK-417) were compared in a double-masked, randomized, placebo-controlled study in 82 patients with bilateral primary open-angle glaucoma or ocular hypertension. MK-507 was given every 8 or 12 hours, sezolamide every 8 hours, or placebo every 8 or 12 hours for 4 days. Both drugs lowered intraocular pressure (IOP) substantially. MK-507 was somewhat more active than sezolamide, with a peak mean IOP reduction of 26.2% for MK-507 versus 22.5% for sezolamide, although the difference between the treatments was not statistically significant. These drugs may have potential in the treatment of glaucoma.     

Decreased libido--a side effect of carbonic anhydrase inhibitor

Thirty-nine cases of decreased libido in glaucoma patients on carbonic anhydrase inhibitors are reported. This symptom completely reversed or markedly improved after discontinuation of the drug in all cases. Twelve of these patients restarted their carbonic anhydrase inhibitor medication which resulted in a recurrence of decreased libido symptoms. There were 3 cases of impotency which reversed after discontinuation of the drug. Most likely, these symptoms are a result of the malaise and depression occurring in some patients on carbonic anhydrase inhibitor therapy.     

Inhibition of membrane-bound carbonic anhydrase decreases subretinal pH and volume

Purpose: The lipophilic carbonic anhydrase (CA) inhibitor acetazolamide has been shown to enhance subretinal fluid resorption, reduce subretinal pH, and can improve cystoid macular edema, but its clinical use is limited by systemic side effects. While these are most likely a result of inhibiting intracellular CA isoenzymes, retinal pigment epithelial (RPE) transport is thought to be modulated via membrane-bound CA. This study investigates whether benzolamide, a hydrophilic CA inhibitor that does not readily penetrate cell membranes, is sufficient to modulate subretinal volume and pH. Methods: Volume and pH were assessed in the subretinal space (SRS) of the perfused chick retina–RPE-choroid preparation by calculating these variables from data obtained with two different double-barreled, ion-selective electrodes (H⁺ for pH and the extracellular space marker tetramethylammonium (TMA⁺) for SRS volume). Light induced variations and changes in baseline measurements were recorded before and after addition of 10^-4M acetazolamide or benzolamide to the basal perfusion. Results: Basal perfusion with either drug induced both an acidification of the SRS by 0.02–0.04 pH units, which occured within 60 s, as well as an increase in the amplitude of the light-induced alkalinisation of the SRS. TMA⁺ concentration in the SRS increased steadily over a period of several minutes after basal perfusion with either of the CA inhibitors, and the calculated SRS volume was reduced by 40% within 8–10 min. Conclusion: The observation that benzolamide had effects equal to acetazolamide suggests that inhibition of membrane-bound CA at the basolateral membrane of the RPE is sufficient to decrease subretinal pH and volume. This may represent a clinically important mechanism for the resorption of sub- and intraretinal fluid. This revised version was published online in July 2006 with corrections to the Cover Date.     

Ocular hypertension. II. A carbonic anhydrase inhibitor test for early detection of glaucoma

The intraocular pressure before and three h after oral administration of a carbonic anhydrase inhibitor was measured in one normotensive, one hypertensive as well as two glaucoma groups. The ratio between the outflow pressure after and before this treatment was estimated. The percentage outflow pressure was found to be about 50% in the normotensive group and in the two glaucoma groups, but in the hypertensive group 68%. This carbonic anhydrase inhibitor test (CAI-test) seems to give additional information which can improve the possibility of differentiating between high normative pressure and early glaucoma prior to glaucomatous lesions.     

6-amino-2-benzothiazole-sulfonamide. The effect of a topical carbonic anhydrase inhibitor on aqueous humor formation in the normal human eye

The carbonic anhydrase inhibitor, 6-amino-2-benzothiazolesulfonamide, formulated as a 3% suspension in a gel vehicle was instilled in one eye of 21 human subjects in a single dose study to determine its effect on aqueous dynamics. A small but statistically significant effect on aqueous humor flow was observed 2 to 7 hours after application. By 8 hours, the effect had disappeared, and intraocular pressure (IOP) measured 8 hours after application of a single dose was unchanged in these normal volunteers. The drug and its vehicle caused local side effects including irritation, hyperemia, and blurred vision. The authors wondered if multiple doses would produce a greater effect. Four subjects received up to four doses of the drug over 2 days and were restudied. Marked bulbar injection and follicular conjunctivitis, attributable to either the drug or the vehicle, developed in two of the subjects, both contact lens wearers. A milder form of bulbar injection and follicular conjunctivitis developed in a third subject, who received three doses of the drug and was not a contact lens wearer. These side effects precluded additional multiple-dose testing of this formulation of the drug, and no conclusions about the effect of the drug on aqueous flow can be drawn from this portion of the study.     

Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors

There was a time gap of over 40 years between the demonstrated oral effectiveness of acetazolamide in lowering the intraocular pressure (IOP) of glaucoma patients and the introduction of a topical carbonic anhydrase (CA) inhibitor. This is due to the fact that CA-II, the isoenzyme which most likely plays an important role in the production of aqueous humor in humans, must be essentially inhibited by 100% to elicit a pharmacological response. The lack of success with earlier attempts to obtain a topical agent stems from an inability to attain and maintain a sufficiently high intraocular concentration of drug to achieve the required inhibition of CA. Dorzolamide and brinzolamide are two topical CA inhibitors which are currently available to treat ocular hypertension and/or glaucoma. Dorzolamide is a very potent inhibitor of CA-II and its site of action is local within the eye. Like oral CA inhibitors, topically applied dorzolamide lowers IOP by decreasing the production of aqueous humor. The drug is used in monotherapy as a 2% solution administered three times daily. Its ocular hypotensive effect is comparable to that of timolol at peak but is somewhat less at trough. The IOP lowering effect of timolol is enhanced by the twice daily administration of 2% dorzolamide either concomitantly or in combination. Topically applied dorzolamide is generally well tolerated and had a low drop-out rate in clinical studies. The most frequent ocular adverse experience is burning and/or stinging. Corneal and lenticular problems have generally not been encountered with long-term therapy with dorzolamide. Topically applied dorzolamide penetrates directly to the posterior segment of the eye and its presence is consistent with the initial report that dorzolamide increases retinal blood flow velocity in patients with normal tension glaucoma. The most frequent systemic adverse experience is a transient bitter taste. Biochemical changes indicative of the systemic inhibition of CA have not been observed in monotherapy studies lasting up to 2 years. This is in harmony with the inability of dorzolamide at steady-state to saturate CA in the red blood cell and the failure to detect its presence in plasma. A 1% suspension of brinzolamide is comparable to 2% dorzolamide in lowering IOP, both drugs being administered three times daily. Although brinzolamide has a lower incidence of burning/ stinging, it elicits more blurred vision.     

Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma.

PURPOSE:Our purpose was to compare, in a crossover design,the hypotensive effect of oral acetazolamide (Diamox) and topical dorzolamide (Trusopt) in patients with pediatric glaucoma. METHODS: All patients less than 18 years old who were switched from acetazolamide to dorzolamide without other intervention were reviewed. Intraocular pressures were obtained with either a Tono-Pen (Mentor Ophthalmics, Santa Barbara, Calif.) or applanation tonometer. Minimum follow-up times on acetazolamide and on dorzolamide were 1 month (mean 12.2 +/- 19.7 months) and 2 months (mean 8.2 +/- 5.1 months), respectively. The average dose of acetazolamide was 9.9 +/- 1.8 mg/kg/day. RESULTS: Eleven eyes (11 patients) were included. Indications for crossover from oral to topical carbonic anhydrase inhibitor (CAI) therapy were intolerance to acetazolamide (6 eyes) and surgical intervention in the fellow eye (5 eyes). The mean age at the time of crossover was 7.4 +/- 3.0 years. A comparison of intraocular pressure (IOP) before addition of a CAI was made in 8 eyes. The mean IOP off of a CAI was 27.8 +/- 4.9 mm Hg. The mean 10P was reduced to 18.5 +/- 4.3 mm Hg on acetazolamide (mean percent IOP reduction 35.7% +/- 15.6%, p < 0.01) and to 22.2 +/- 5.4 mm Hg on dorzolamide (mean percent IOP reduction 27.4% +/- 17.1%, p < 0.01). All 11 eyes showed an increase in IOP when switched from acetazolamide to dorzolamide, with a mean increase of 3.7 +/- 2.5 mm Hg (20.2% -/+ 13.7%, p < 0.01). Five eyes have remained controlled on dorzolamide and a topical beta-blocker. Five eyes required further intervention for the control of glaucoma. One eye was switched back to acetazolamide for better IOP control. CONCLUSION: Although not as effective as oral acetazolamide, topical dorzolamide causes a significant IOP reduction in this group of pediatric glaucoma patients and appears to be well tolerated.     

Comparison of intraocular pressure lowering by topical and systemic carbonic anhydrase inhibitors in the rabbit.

We compared the effect on intraocular pressure (IOP) of maximal doses of a topical carbonic anhydrase inhibitor (CAI) at acidic and alkaline pH where it is maximally effective with full systemic CA inhibition in ocular normotensive New Zealand Albino rabbits. Tonometric IOP levels were measured hourly during 3 hour control period. Topical MK-417 (pKa 5.8, 8.3), a close congener of MK-507 (Dorzolamide) was given as a 1.4% solution at pH 4.5 (n=6) and pH 9.2 (n=6). MK-417 was instilled to the left eye with the right eye used as an untreated control. One hour later methazolamide was given intravenously at 10 mg/kg, a dose known to give full inhibition of the enzyme. Control IOP (mm Hg) was 19.12+/-0.50. One hour following MK-417, the left eye IOP was 13.40 +/-0.70 (pH 4.5) and 13.25+/-0.70 (pH 9.2). The right eye pressure was unchanged. Methazolamide injection at this time gave no further drop in the left eye IOP at either pH. IOP in the right eye fell to 14.00+/-0.70 so that 2 hours after methazolamide injection, the 2 eyes had the same pressure. In conclusion, topical CAI in sufficient dose and correct pH yields IOP lowering equivalent to a maximally effective dose of systemic CAI in rabbits.