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.     

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.     

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.     

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。     

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.     

Effect of nutritional supplement based on melatonin on the intraocular pressure in normotensive subjects

International Ophthalmology - To evaluate the effect of a new nutritional supplement based on melatonin on the intraocular pressure (IOP) in normotensive subjects. A short-term prospective study...     

The effect of prostaglandin F2 alpha on intraocular pressure in normotensive human subjects

Hypotensive and other ocular effects were studied for 24 hr after topical application of prostaglandin F2 alpha as the tromethamine salt (PGF2 alpha) in 45 normotensive human subjects. After baseline intraocular pressure (IOP) measurements, 62.5 micrograms, 125 micrograms and 250 micrograms of PGF2 alpha dissolved in 50 microliter of saline was applied to one eye of 15 subjects for each dose tested. Contralateral control eyes received 50 microliter of saline. As compared with the IOP of the contralateral control eyes, topical application of 62.5 micrograms PGF2 alpha caused a significant IOP reduction at 1-12 hr, with a maximal IOP reduction of 2.2 mm Hg at 2 hr. Treatment with 125 micrograms of PGF2 alpha lowered IOP significantly at 1-21 hr, with a maximal reduction of 3.1 mm Hg at 9 hr. Administration of 250 micrograms PGF2 alpha produced a significant reduction of IOP, which lasted for at least 24 hr. A maximal IOP reduction of 2.9 mm Hg occurred at 7 hr. Pupillary diameter was not altered. Aqueous flare and anterior chamber cellular response were not seen in any of the eyes of the subjects at any time after topical application of 62.5-250 micrograms PGF2 alpha. The drug caused side effects consisting of reddened skin of lower lid, ocular irritation, conjunctival hyperemia and headache.     

Effect of topical indomethacin and timolol maleate on intraocular pressure in normal subjects

In a prospective randomized double-masked crossover study in ten healthy volunteers, conducted to determine if the intraocular hypotensive effect of timolol eyedrops was significantly affected by the concomitant use of the topically administered prostaglandin inhibitor, indomethacin, we found that significant ocular hypotension was achieved with timolol alone. This was not changed by the concurrent administration of indomethacin. The results provide further evidence that prostaglandins are not involved in the control of normal intraocular pressure.     

Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects

The effects of the type 1 angiotensin II receptor antagonist Losartan potassium on intraocular pressure (IOP) were studied. Four groups of subjects were analysed: group A, ten controls; group B, ten patients with essential arterial hypertension and with IOP within the normal range; group C, ten patients with primary open angle glaucoma (POAG), but without essential arterial hypertension; group D, ten patients with arterial hypertension and POAG. The study design was held in a randomized crossover double-blind fashion. Systolic and diastolic arterial pressure, heart rate, pupil diameter, IOP and total outflow facility were recorded at baseline and at 1 hr intervals up to 6 hr, following the oral administration of 50 mg of Losartan potassium and/or placebo. The alternative treatment was given a week later. Drug administration significantly reduced IOP in all subjects. No variation in heart rate and pupil diameter was observed during the follow-up period. Blood pressure dropped only in arterial hypertensive patients (groups B and D). Total outflow facility increased significantly in all groups. Placebo did not induce any variation in all groups. These findings demonstrate that the mechanism by which Losartan potassium reduces intraocular pressure is not mediated by a decrease in blood pressure, but rather it is more specific, confirming the role of the renin-angiotensin system also in the regulation of intraocular pressure in man.     

Effect of topical atenolol on intraocular pressure.

Placebo and topical atenolol (Tenormin), a selective beta1-adrenergic blocking substance with no intrinsic sympathomimetic or membrane-stabilising properties, were tested in 16 patients with ocular hypertension in a double-blind cross-over trial. Three different concentrations of atenolol (1, 2, and 4%) were investigated. After a single instillation there was a statistically significant fall in mean intraocular pressure (IOP) with all the concentrations after one hour, with a maximum after two to three hours. The effect had passed off after seven hours. In multiple-dose studies with applications three times a day for seven days there was a statistically significant fall in the mean IOP on the first day of treatment (all three concentrations), which persisted throughout the week. In the single-dose study only a slight dose-dependence was observed. This could not be confirmed in the multiple-dose trial. Pupil size, corneal sensitivity, systemic blood pressure, and heart rate were unaffected. No side effects were noted. Thus topically applied atenolol lowers IOP in patients with ocular hypertension and may be clinically useful.     

Failure of acetazolamide to decrease intraocular pressure in patients with carbonic anhydrase II deficiency

The effect of the carbonic anhydrase inhibitor acetazolamide on intraocular pressure was studied in two patients with carbonic anhydrase II deficiency and in six control subjects. The deficient patients had the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. A dose of 125 mg of intravenous acetazolamide caused a significant (P less than .01) decrease in intraocular pressure from baseline (15.0 +/- 1.5 mm Hg) in the control subjects one hour (11.3 +/- 1.5 mm Hg) and four hours (13.8 +/- 1.2 mm Hg) after drug administration. In contrast, the patients with carbonic anhydrase deficiency showed no such decrease in intraocular pressure; baseline intraocular pressure (19.2 +/- 0.2 mm Hg) was significantly unchanged (P greater than .5) at one hour (20.0 +/- 0.1 mm Hg) and four hours (19.2 +/- 0.2 mm Hg).     

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。     

Effect of topical ketanserin administration on intraocular pressure.

The effect of topical ketanserin on intraocular pressure (IOP) in normotensive and hypertensive eyes was evaluated. The study was performed on 10 healthy volunteers and 10 glaucomatous patients. Systolic arterial blood pressure (SBP), diastolic arterial blood pressure (DBP), heart rate (HR), IOP, tonographic outflow facility, pupil diameter, corneal thickness, and tear secretion were recorded at baseline and at 1 hour intervals for 12 hours after topical administration of 0.5% ketanserin or placebo, given in a randomised, double masked, crossover fashion. The alternative treatment was given 1 week later. In all subjects ketanserin significantly lowered IOP, while no variations in SBP, DBP, HR, pupil diameter, corneal thickness, and tear secretion were found. When subjects received placebo no significant variations of IOP occurred. Total outflow facility, measured by conventional tonography, increased significantly after drug administration in all subjects. Ketanserin is effective up to 6 hours in control subjects and 9 hours in glaucomatous patients. The placebo did not induce any change in this component of the aqueous humour dynamic in normal or in glaucomatous eyes. The findings indicate that topical ketanserin might be added to the list of antiglaucomatous agents.     

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.     

Effect of topical anesthetics on intraocular pressure and pachymetry

PURPOSE: The determination of intraocular pressure (IOP) by noncontact tonometry (NCT) has been reported to be affected by central corneal thickness (CCT) and by the instillation of topical anesthetics. METHODS: In order to determine the influence of topical anesthetics on CCT and IOP measured by NCT, 80 eyes from 49 patients were examined before and after the instillation of topical anesthetics. RESULTS: Average age was 55.3 years (SD 18.4, range 18 to 93). Twenty-eight patients were female and 21 were male. Average basal IOP was 16.1 mmHg (SD 5.2, range 8 to 35.3). IOP was 14.8 mmHg (SD 4.6, 7.4 to 32.4) (p=0.0005, Student t test for paired data) 5 minutes after topical anesthetics instillation. CCT averaged 541 micronm (SD 32, range 482 to 604) before topical anesthetic drops and 541 micronm (SD 32, 490 to 607, p=0.89, Student t test for paired data) 5 minutes after topical anesthetics instillation. CONCLUSIONS: The study confirms that the instillation of topical anesthetics causes a reduction in IOP. These changes do not seem to be associated with changes in CCT.     

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.     

Effect of oral donepezil on intraocular pressure in normotensive Alzheimer patients.

Donepezil, a selective acetylcholinesterase (AChE) inhibitor, has been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbit eyes. The aim of this investigation was to evaluate the effect of oral donepezil on IOP and pupil diameter after mid-term oral treatment in normotensive persons. Thirty-two newly diagnosed Alzheimer patients with normal IOP and no further antiglaucomatous treatment were included in the study. IOP and pupil diameter were evaluated before and 4 weeks after daily intake of 5 mg donepezil. IOP and pupil diameter were significantly lower/smaller after 4 weeks of treatment. The mean IOP of all 63 eyes was 14.1 mmHg before and 12.8 mmHg after treatment (8.8% reduction). Mean pupil diameter constricted from 3.9 to 3.6 mm (-7.4%). These findings show that donepezil, and, possibly, other selective AChE inhibitors, can potentially be used to treat glaucoma. They are also known to have neuroprotective effects in Alzheimer's, and, therefore, might have an additional therapeutic benefit.     

Effect of pilocarpine on intraocular pressure in ocular hypertensive subjects

In normal subjects, ocular administration of pilocarpine results in initial elevation of IOP succeeded by a fall. We have now examined the effect of pilocarpine on IOP in nontreated ocular hypertension. Our results demonstrate that the initial hypertensive phase is absent in these patients and that the subsequent hypotensive phase is more marked than in normotensive eyes. It is suggested that in normal eyes IOP is regulated by two opposing cholinergic effects, and imbalance the two may lead to ocular hypertension (or hypotension).