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.     

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.     

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     

A single dose of the topical carbonic anhydrase inhibitor MK-927 decreases IOP in patients.

MK-927 is a novel topical carbonic anhydrase inhibitor (CAI). We present the first single-dose clinical trial of MK-927 in 24 patients with bilateral primary open-angle glaucoma or ocular hypertension. This investigation was conducted as a two-centre, double-masked, randomised, placebo controlled study. Patients received one drop of 2% MK-927 in one eye and placebo in the other eye. Modified diurnal intraocular pressure (IOP) curves were performed before the study and on one treatment day. A single dose of 2% MK-927 induced a peak mean IOP decrease of 10.5 mmHg at 4.5 hours postdose. With compensation for diurnal variation, as determined by the prestudy diurnal pressure curve, the net peak mean reduction of IOP caused by MK-927 was 7.5 mmHg versus a corresponding net change of 1.4 mmHg in the contralateral placebo treated eye. Thus a single dose of MK-927 gave a clinically significant IOP reduction in patients.     

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.     

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.     

Fluorophotometric study of intravenous carbonic anhydrase inhibitors in rabbits

The ability of fluorophotometry to measure the time course of changes in aqueous humor flow in rabbits was evaluated by measuring the effect of intravenous carbonic anhydrase inhibitors on aqueous humor flow determinations. The abrupt changes in aqueous humor flow which were found by fluorophotometry agreed well with the expected changes in aqueous humor flow calculated from the time course of the intraocular pressure. Therefore, it was concluded that fluorophotometry could measure the time course of changes in aqueous humor flow in rabbits. Furthermore, it was suggested that the initial abrupt changes in aqueous humor flow after the administration of a carbonic anhydrase inhibitor were induced by the base content of the drug, followed by a more gradual decrease in aqueous humor flow caused by the direct effect of the drug on aqueous humor formation.     

Relationship of patient age and tolerance to carbonic anhydrase inhibitors

A retrospective review of the records of 222 patients indicated a significantly higher incidence of long-term tolerance to carbonic anhydrase inhibitors among patients 40 years of age or less than in older patients. This finding indicated that since argon laser trabeculoplasty and conventional glaucoma surgery have low rates of success in young individuals, it seems prudent to consider carbonic anhydrase inhibitors as part of long-term maximum medical therapy particularly in younger individuals unless specific contraindications exist.     

Ocular hypotensive effects of topically administered agmatine in a chronic ocular hypertensive rat model

Agmatine, a primary polyamine and potential neuromodulator, exhibits a high affinity to the α₂-adrenergic receptor as well as imidazoline receptors. As α₂-adrenergic receptor agonists display positive ocular hypotensive effects, we assessed whether agmatine effectively lowers intraocular pressure (IOP) using a chronic ocular hypertensive rat model. We raised IOP in unilateral eyes of Sprague-Dawley rats by cauterizing three episcleral veins per eye. Four weeks later, we topically administered 10⁻³ M agmatine solution 4 times a day for 6 consecutive weeks. After confirming the recovery of IOP to pretreatment level at 13 weeks after cauterization, the retinal ganglion cells (RGCs) were retrogradely labeled and counted. Eyes subjected to episcleral vein cauterization (EVC) demonstrated significant increases in IOP (48.39% increase over baseline IOP), and the elevated IOP was well maintained until 12 weeks. Topically administered agmatine powerfully lowered IOP to 30.29% of its pretreatment level, and the associated washout period was about two weeks. EVC was associated with a 55.44% loss of RGCs in the control group, but agmatine appeared to attenuate this RGC loss to 18.65%. Overall, topically administered agmatine appeared to effectively lower IOP and rescue RGCs in a chronic ocular hypertensive rat model. Although the mechanism underlying these effects is not yet established, it is possible that agmatine offers a powerful new ocular hypotensive agent for eyes with chronic ocular hypertension and/or glaucoma.     

三种前列腺素类药物降眼压效果比较

目的比较拉坦前列素、曲伏前列素和贝美前列素三种前列腺素类药物的降眼压效果。方法选取原发性开角型青光眼和高眼压症患者,拉坦前列素组51例(51眼),曲伏前列素组24例(24眼),贝美前列素组27例(27眼),分别使用相应滴眼液,均为每日1次,共观察4周,测量用药前后的眼压值。结果三组患者用药4周后眼压均有明显下降,拉坦前列素组在8:30测得平均眼压从(24.57±3.68)mmHg(1 mmHg=0.133 kPa)降至(15.29±2.67)mmHg,下降幅度(用药前后眼压差值/用药前眼压值)为37.8%;曲伏前列素组从(24.54±2.95)mmHg降至(16.29±3.11)mmHg,下降幅度为33.6%;贝美前列素组从(25.41±3.63)mmHg降至(16.00±4.45)mmHg,下降幅度为37.0%。用药前及用药后三组间眼压值比较,差异均无显著性(分别为F=0.579、P=0.562;F=0.868、P=0.423)。结论拉坦前列素、曲伏前列素、贝美前列素滴眼液对于原发性开角型青光眼和高眼压症患者都有明显、持久的降眼压作用,且降眼压作用相互间没有明显差异。     

Intraocular pressure effects of carbonic anhydrase inhibitors in primary open-angle glaucoma

We tested the effect on intraocular pressure of three commonly used oral carbonic anhydrase inhibitor preparations in a controlled, randomized, comparative study on patients with primary open-angle glaucoma. Preparations tested included acetazolamide tablets, acetazolamide Sequels, and methazolamide tablets. The effect of the three carbonic anhydrase inhibitors was assessed by using a statistical modeling approach as well as by evaluating the average maximum reduction in intraocular pressure for each preparation. Dosage and time effects were also determined. As expected, each drug preparation was more effective in reducing intraocular pressure when administered to a patient who had already been treated with the carbonic anhydrase inhibitor preparation. The amount of intraocular pressure lowering was directly related to dose for both acetazolamide preparations. Of particular interest was the finding that maximal rapid reduction of intraocular pressure was obtained with a 500-mg dosage of acetazolamide tablets.     

A comparison of the ocular hypotensive efficacy of once-daily and twice-daily levobunolol treatment

The authors compared the ocular hypotensive efficacy of two different treatment regimens of levobunolol 0.5% in a double-masked, randomized, controlled clinical trial. Seventy-one patients with open-angle glaucoma or ocular hypertension received levobunolol 0.5% as their sole glaucoma medication either on a once-daily or twice-daily treatment regimen for 3 months. Approximately 81% of the patients in the once-daily treatment group and 88% of subjects in the twice-daily treatment group successfully completed the 3-month study period. The overall mean decrease in intraocular pressure (IOP) was 4.5 mmHg in the once-daily group and 5.6 mmHg in the twice-daily group. These differences were not statistically different. For both treatment groups, effects on mean heart rate and blood pressure were minimal. The authors' data from this population suggest that once-daily treatment with levobunolol is an effective glaucoma regimen.     

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)     

The role of carbonic anhydrase inhibitors in the management of macular edema

Medical treatment of cystoid macular edema (CME) with carbonic anhydrase inhibitors has been known for over a decade. Initial observations were based on experimental data which suggested that acetazolamide can increase fluid absorption across the retinal pigment epithelium. Carbonic anhydrase inhibitors (CAI) have also been shown to have other direct effects both on retinal and retinal pigment epithelial cell function by inducing an acidification of the subretinal space, a decrease of the standing potential as well as an increase in retinal adhesiveness. It is thought that acidification of the subretinal space is finally responsible for the increase in fluid resorption from the retina through the RPE into the choroid. Several clinical studies have suggested that patients with cystoid macular edema due to retinitis pigmentosa and uveitis may react more favorably to CAI treatment than other etiologies such as diabetic maculopathy or macular edema after retinal vein occlusion. The present working hypothesis is that diffuse leakage from the RPE responds more readily to CAI treatment than leakage from retinal vessels. This may be due to the modulation of membrane- bound CA IV in the RPE which may have lost its polarised distribution in the presence of macular edema. A normal clinical starting dose of CAI is 500 mg/day which should be continued for at least one month to see an effect. This dose may be reduced by the patients over the course of therapy. Metaphylaxis to the drug may occur with a rebound of the edema despite continuation of treatment. This revised version was published online in July 2006 with corrections to the Cover Date.     

Two topical carbonic anhydrase inhibitors sezolamide and dorzolamide in Gelrite vehicle: A multiple-dose efficacy study

The ocular hypotensive activities of the two potent topical carbonic anhydrase inhibitors sezolamide (previously known as MK-417) and dorzolamide (previously known as MK-507 and L-671,152) were compared formulated in Gelrite vehicle, a novel ophthalmic drug delivery system. This was a four-center, double-blind, randomized, placebo-controlled, parallel study in 73 patients with a diagnosis of bilateral primary open-angle glaucoma or ocular hypertension and a morning intraocular pressure (IOP) of greater than 23 mmHg in both eyes following washout of ocular hypotensive medications. Parallel 12-h modified diurnal curves were performed prestudy and on day 6, with a 4-h IOP curve on day 1. On day 6 the peak mean percentage decrease in IOP from baseline occurred 4 h after the dose of dorzolamide (22.1%) and 6 h after the dose of sezolamide (21.3%). There were no significant differences between 2% dorzolamide and 1.8% sezolamide at any time point, although the decrease in IOP for sezolamide tended to be slightly greater than that for dorzolamide. Duration of action of both compounds was, at most, slightly prolonged by the use of Gelrite vehicle when compared with former studies on sezolamide and dorzolamide.     

Optic nerve oxygen tension in pigs and the effect of carbonic anhydrase inhibitors.

PURPOSE: To evaluate how the oxygen tension of the optic nerve (ONP(O)2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture. METHODS: Polarographic oxygen electrodes were placed in the vitreous humor immediately over the optic disc in 20 anesthetized pigs. Blood gasses and cardiovascular physiology were monitored. ONP(O)2 was recorded continuously with breathing gasses of 21% O2-79% N2, 100% O2, 20% O2-80% N2, and 5.19% CO2-19.9%, O2-74.9% N2. Acetazolamide (15-1000 mg) and dorzolamide (6-1000 mg) were administered intravenously. RESULTS: The mean (+/- SD) ONP(O)2 was found to be 24.1+/-11.6 mm Hg when the pigs were breathing room air and 50.7+/-29.3 mm Hg when they were breathing 100% O2 (n = 15; P < 0.001). In response to breathing 5.19% CO2, ONP(O)2 changed from 20.8+/-5.6 mm Hg (with 20.0% O2) to 28.9+/-3.6 mm Hg (n = 4; P < 0.001). Intravenous injections of 500 mg dorzolamide increased ONP(O)2 from 16.4+/-6.1 mm Hg to 26.9+/-12.2 mm Hg, or 52.5%+/-21.2% (n = 5; P = 0.017). A dose-dependent effect on ONP(O)2 was seen with intravenous dorzolamide doses of 1000, 500, 250, 125, 63, 27, 15, and 6 mg. Intravenous injections of 500 mg acetazolamide increased ONP(O)2 from 23.6+/-9.5 mm Hg to 30.9+/-10.0 mm Hg (n = 6; P < 0.001), and a dose-dependent effect was seen with doses of 1000, 500, 250, 125, 31, and 15 mg. CONCLUSIONS: ONP(O)2 is significantly increased by the carbonic anhydrase inhibition of dorzolamide and acetazolamide, and the effect is dose dependent. These data demonstrate for the first time a direct effect of carbonic anhydrase inhibitors on ONP(O)2.     

Some factors affecting the ocular hypotensive and mydriatic responses of the rabbit to topically applied l-adrenaline bitartrate

Single topical treatment with l-adrenaline bitartrate in eyes of albino rabbits gave a prompt concentration-related increase in pupil diameter, peak values occurring at 1–2 hr. Ocular tension decrease commenced 2–3 hr after treatment, at the same time that the mydriatic effect started to decline. The decrease was concentration-related over approximately the same range as the pupil effect. Where a second topical treatment with a submaximal (0·5%) concentration of l-adrenaline bitartrate, equal to the first, was applied 3 or 4 hr later, a secondary delay in ocular hypotensive effect occurred and the tension returned to values not significantly different from controls for at least 1 hr. A second peak mydriasis occurred after the second treatment, equal in extent to the first. Onset of hypotension again coincided with offset of mydriasis. 0·25% l-Adrenaline bitartrate applied 3 hr after 0·5% caused a shorter secondary delay in tension fall and the mydriasis, although prolonged, did not give a further peak. 1% l-Adrenaline bitartrate applied 3 hr after 0·5% had similar effect on tension to the second treatment with 0·5%, but a significantly higher peak mydriasis occurred with 1%.No significant correlation was found between maximum observed pupil increases and tension decreases in a group of rabbits after a single treatment with a submaximal concentration of l-adrenaline bitartrate.0·5% l-Adrenaline bitartrate applied topically at 0 and 3 hr in the absence of tonometric procedures gave two equal peaks of mydriasis, but these were significantly lower than those found with similar treatment in the presence of tonometric procedures. Local anaesthetic applied for tonometry is implicated.