Ocular disposition of aminozolamide in the rabbit eye

We have previously determined that 6-amino-2-benzothiazolesulfonamide (aminozolamide) significantly lowers IOP in rabbits and, more importantly, in ocular hypertensive human subjects. Results from in vitro experiments established that both the inhibitory activity of aminozolamide against carbonic anhydrase B as well as the penetration rate across excised rabbit corneas were equivalent to ethoxzolamide. Consequently, we have investigated the ocular disposition of aminozolamide to explain its activity when instilled topically to the eye. A constant concentration of 67.4 micrograms/ml of drug was applied for 90 min to the left eye of anesthetized rabbits. Drug and metabolite were measured in both aqueous humor and iris/ciliary body over time. The metabolite was collected and purified. Identification using mass spectroscopy, high pressure liquid chromatography (HPLC) and fluorescence scans indicated that the metabolite was 6-acetamido-2-benzothiazolesulfonamide. Relatively high levels of metabolite were identified in the cornea and iris/ciliary body but were much lower in aqueous humor. Tissue concentrations over time for the metabolite in iris/ciliary body were approximately 2-fold higher than levels of metabolite measured in aqueous humor. When compared to drug levels measured in either aqueous humor or iris/ciliary body, metabolite levels in these respective tissues were much higher. It is hypothesized that topical activity is a consequence of both metabolite retention in the iris/ciliary body as well as inhibition of 99+% of carbonic anhydrase. Both of these events must occur over a sufficient time period to effect a significant lowering of IOP.     

Effect of a topical carbonic anhydrase inhibitor, 6-hydroxybenzo[b]thiophene-2-sulfonamide, on intraocular pressure in normotensive subjects

A prospective randomized clinical trial was carried out to determine the efficacy of 6-hydroxybenzo[b]thiophene-2-sulfonamide, a potent new carbonic anhydrase inhibitor, in lowering intraocular pressure (IOP) in normotensive volunteers. The drug was administered as a 2% suspension twice daily for 1 week to one eye in 10 subjects. Ten other subjects, serving as controls, received a placebo drop to one eye on the same schedule. Subjects and examiners were unaware of whether the drug or placebo was being used. IOP was measured before the study began and twice daily on days 1, 2, 4 and 8 of the study. The drug had no significant effect on IOP. The most likely explanation is failure of an adequate concentration of the drug to reach the ciliary body.     

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.     

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.     

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。     

Effects of dorzolamide hydrochloride on ocular tissues.

We studied the intraocular pharmacokinetics of dorzolamide hydrochloride eye drops and the effect of dorzolamide on carbonic anhydrase activity and localization in ocular tissues. Carbonic anhydrase activity was detected in normal ocular tissues. The activity was inhibited in corneal endothelial cells, the ciliary body, lens epithelial cells, or the retina 1 to 8 hours after instillation of dorzolamide eye drops. In lens epithelial cells and the retina, the enzyme activity had not recovered even 10 hours after instillation of the drug. Immunostaining did not reveal any differences between the group administered dorzolamide eye drops and the control group administered a physiologically balanced solution. Time-related changes in dorzolamide concentrations in ocular tissues were measured by high-performance liquid chromatography (HPLC). In the cornea, anterior aqueous, iris, ciliary body and retina, drug concentrations increased 15 minutes after the instillation and peaked within 1 hour. These results suggest that dorzolamide immediately suppresses carbonic anhydrase activity in ocular tissues, and is rapidly distributed among the tissues of the eye when administered as eye drops.     

Ophthalmic laser microendoscope ciliary process ablation in the management of neovascular glaucoma.

PURPOSE: To evaluate the potential efficacy of ophthalmic laser microendoscope photocoagulation of the ciliary processes in the management of intractable neovascular glaucoma. METHODS: Ten patients with intractable neovascular glaucoma underwent ophthalmic laser microendoscope ciliary process ablation via a pars plana incision. The device and surgical technique are discussed. RESULTS: Preoperative intraocular pressure (IOP) ranged from 36 mmHg to 62 mmHg (mean, 43.6 mmHg). Postoperative final IOP ranged from 3 mmHg to 27 mmHg (mean, 15.3 mmHg). This represents an absolute decrease of 28.3 mmHg (65%). Postoperatively, 9 eyes had an IOP of less than 21 mmHg, although 3 of these eyes required medication. One eye attained a final IOP of 27 mmHg. All eyes were treated once. Nine patients were treated with carbonic anhydrase inhibitors preoperatively, and six patients were able to discontinue this medication postoperatively. Phthisis was not observed, but hypotony evolved in two eyes with chronic retinal detachment. Follow-up ranged from 6 to 11 months (mean, 8.8 months). CONCLUSION: This new therapeutic modality, which combines endoscopic visualization of the ciliary processes with diode laser photocoagulation, can be effective in the management of intractable neovascular glaucoma.     

Preclinical overview of brinzolamide

The development of topically active carbonic anhydrase inhibitors (CAIs) is a significant recent achievement in glaucoma medical treatment. Brinzolamide, the newest topical CAI, exhibits selectivity, high affinity, and potent inhibitory activity for the carbonic anhydrase type II isozyme (CA-II), which is involved in aqueous humor secretion. These characteristics, along with good ocular bioavailability, make brinzolamide maximally effective in lowering intraocular pressure (IOP) by locally inhibiting CA-II in the ciliary processes and suppressing aqueous humor secretion. Notable among its attributes as a safe and efficacious glaucoma drug is brinzolamide's superior ocular comfort profile because of its optimized suspension formulation at physiologic pH. The degree of tolerability in the eye is considered an important determinant of a patient's willingness to comply with the dosing regimen for a long-term glaucoma medication. Results from the preclinical pharmacologic evaluation of brinzolamide indicated that it acts specifically to inhibit CA without significant other pharmacologic actions that could introduce undesired side effects. Moreover, the typical side effects associated with systemically administered CAIs are expected to occur at a lower incidence or not occur at all with brinzolamide, as its therapeutic dose and low systemic absorption do not produce a problematic level of systemic CA inhibition. Brinzolamide's long tissue half-life in the eye, particularly in the iris-ciliary body, favors a prolonged duration of IOP lowering. This was substantiated in clinical trials, which showed that twice-daily brinzolamide provides as significant an IOP reduction as three-times-daily brinzolamide or dorzolamide in a relatively high percentage of patients. Brinzolamide has been shown by the laser Doppler flowmetry technique to improve blood flow to the optic nerve head in pigmented rabbits after topical administration, without producing an increase of blood pCO2, indicating a potential for a local vasodilatory effect involving the optic nerve head circulation. The mean concentration of brinzolamide found in the retina of pigmented rabbits (0.338 microg equivalents/g) after a single dose of 14C-brinzolamide is sufficient to inhibit CA-II. These data suggest that topical brinzolamide could improve the blood flow in the optic nerve head in humans should it inhibit carbonic anhydrase in that vascular bed. Brinzolamide is a new topically active CAI that is safe and efficacious for reducing intraocular pressure. It offers the convenience of topical dose administration and greater freedom from side effects related to the inhibition of CA seen with the systemic administration of CAIs. Its formulation has been optimized to provide greater comfort upon instillation, and this can result in a higher compliance rate by the patient. Results of studies in animals show that brinzolamide has promise for increasing blood flow to the optic nerve head; however, this requires further assessment in the clinic. Brinzolamide represents a significant technical achievement and an important addition to the medical treatment of glaucoma as both a primary and an adjunctive drug.     

Endolaser treatment of the ciliary body for severe glaucoma

Endolaser photocoagulation of the ciliary body was used to treat 42 eyes with severe glaucoma that could not be managed successfully by medical therapy and conventional glaucoma surgery. Follow-up ranged from 6 to 36 months (mean, 13 months). The preoperative intraocular pressure (IOP) ranged from 13 to 76 mmHg (mean, 37 mmHg). The postoperative IOP ranged from 1 to 44 mmHg (mean, 17 mmHg), representing an absolute decrease of 20 mmHg, and a mean decrease of 48%. After one or two (7 eyes) treatment sessions, 11 eyes (26%) had an IOP less than 21 mmHg without medications; 21 eyes (50%) had an IOP less than 21 mmHg with medications; 5 eyes (12%) had an IOP of 21 to 25 mmHg with or without medications; and 5 eyes (12%) had an IOP greater than 25 mmHg. Postoperatively, the number of antiglaucoma medications required was reduced from a mean of 2.8 +/- 0.13 to a mean of 1.4 +/- 0.19. Twenty-three (72%) of 32 patients were able to discontinue carbonic anhydrase inhibitors.     

睫状环阻塞性青光眼的治疗方法的临床报道

目的探讨睫状环阻塞性青光眼的治疗方法及疗效。方法在本院行青光眼术后发生的睫状环阻塞性青光眼25例（27眼）,进行早期综合药物治疗,包括散瞳、皮质类固醇滴眼、碳酸酐酶抑制剂滴眼和口服,甘露醇静脉滴注等,疗程结束后所有患者均进行结果评定,并对其临床资料进行总结分析。结果术后早期均有轻度的角膜水肿,前房变浅或消失,眼压正常或升高。7眼青光眼联合白内障手术伴不同程度的前房渗出,2眼人工晶状体前膜形成,经皮质类固醇及散瞳局部治疗1周后角膜透明：渗出及膜均吸收,前房反应消失,前房深度恢复正常。此外,治疗后的平均眼压（17．3±2．3）mmHg,与治疗前平均眼压（25．0±2．0）mmHg比较,差异显著。结论早期综合药物治疗青光眼术后发生的睫状环阻塞性青光眼,眼压均得到有效的控制,治疗成功后部分患者继续长期滴用睫状肌麻痹剂的措施有一定效果。     

The transcorneal permeability of sulfonamide carbonic anhydrase inhibitors and their effect on aqueous humor secretion

Eleven sulfonamide carbonic anhydrase inhibitors of varied chemical and physical types were studied with respect to transcorneal permeability and reduction of intraocular flow and pressure. Using the isolated rabbit cornea, a constant drug concentration on the epithelial side and 6 ml solution in the endothelial chamber, first order rate constants (k_in) ranged from 0·1–40 × 10^?3/hr, roughly proportional to their lipid solubility. Drugs on the high side of this range were generally water insoluble and had pK_a's too high to yield sodium salts at useful pH; therefore, the actual amount of drug delivered was small. We sought compounds which combined low pK_a, good lipid solubility, and high activity against the enzyme. Trifluormethazolamide (TFM) has a pK_a of 6·6, ether partition coefficient of 6, and a K₁ of 2 × 10^?8m. k_in is 3 × 10^?3/hr. TFM and five other compounds were also studied in vivo for their ability to penetrate the eye into the anterior and posterior chambers. These rate constants were roughly proportional to those measured in vitro; however, significant differences in accession to the two chambers were observed, as a function of varying physico-chemical properties of the drugs. A 3% solution of TFM (100 mm) applied to the rabbit eye for 25 min generated 0·7 mm in the anterior chamber and 0·07 mm in the posterior. Tissue distribution of TFM (and its metabolite) showed a relatively high concentration in the ciliary body 6 hr after dose. Intraocular pressure was reduced by 4 mmHg. With 10 min exposure this concentration of TFM reduced pressure by about 1·7 mmHg. Although the use of this drug is limited by its chemical instability and the length of exposure needed, the principle of treating glaucoma by the topical use of carbonic anhydrase inhibitors appears feasible.     

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 5-HT(1A)Receptor agonist 8-OH-DPAT lowers intraocular pressure in normotensive NZW rabbits

The aims of this study were first to investigate the effect of topical instillation of the 5-HT(1A)receptor agonist 8-OH-DPAT on intraocular pressure (IOP) in normotensive rabbits and second to establish whether the drug reaches the aqueous humour of treated and contralateral eyes at concentrations sufficient to activate ciliary epithelial 5-HT(1A)receptors. Following topical unilateral instillation of (+/-), (+) or (-)8-OH-DPAT, the IOP of rabbits was measured using an applanation tonometer. For the penetration study, [(3)H]8-OH-DPAT was instilled into one eye of each rabbit. Animals were killed after 30 min and the radioactive content of treated and contralateral ocular tissues was assessed. Administration of (+/-)8-OH-DPAT caused dose-dependent decreases in IOP in treated eyes of rabbits during the light and dark. The full 5-HT(1A)agonist (+)8-OH-DPAT was shown to be a more effective hypotensive agent than the partial agonist (-)8-OH-DPAT. The effect of (+/-)8-OH-DPAT on IOP was blocked by pretreatment with pindolol, a mixed 5-HT(1A)antagonist/beta-blocker, but not by the specific beta-blocker betaxolol. After instillation of [(3)H]8-OH-DPAT, peak levels of radioactivity were found in the cornea, followed by similar amounts in the iris-ciliary body and aqueous. There was negligible radioactivity present in tissues of the contralateral eye. This study demonstrates that topical administration of the 5-HT(1A)agonist 8-OH-DPAT dose-dependently decreases IOP in normotensive rabbits during the light and dark. The action of 8-OH-DPAT is presumably local to the anterior uvea as IOP was reduced only in treated eyes and [(3)H]8-OH-DPAT failed to reach the contralateral eye after unilateral instillation. Moreover, since 5-HT(1A)receptors are located in the rabbit ciliary epithelium and the effect of 8-OH-DPAT is blocked by a recognized 5-HT(1A)antagonist, the mechanisms of action of 8-OH-DPAT may well involve a decreased secretion of aqueous humour.     

Topical ocular hypotensive activity and ocular penetration of dichlorphenamide sodium in rabbits

A single topical instillation (50 l) of the water soluble sodium salt of dichlorphenamide (10%) produced a pronounced and prolonged lowering of intraocular pressure (IOP), compared to suspensions of its free acid, in rabbits with alpha-chymotrypsin-induced ocular hypertension. In normal rabbits, instillation of dichlorphenamide sodium also produced a markedly elevated drug aqueous humor level relative to instillation of its free acid, indicating enhanced penetration into the eye. The IOP response after ocular instillation of dichlorphenamide sodium was equivalent to that produced by oral administration of 6 or 18 mg/kg dichlorphenamide sodium. Serum drug levels were lower and aqueous humor and iris-ciliary body levels were higher after instillation of dichlorphenamide sodium (10%) than after oral administration of 2 or 6 mg/kg. The data indicate that topically instilled dichlorphenamide sodium is capable of lowering IOP by a local action in the eye and provides a rationale for the potential utility of topical carbonic anhydrase inhibitors as a therapy for glaucoma in man.     

2-Substituted 1, 3, 4-thiadiazole-5-sulfonamides as carbonic anhydrase inhibitors: their effects on the transepithelial potential difference of the isolated rabbit ciliary body and on the intraocular pressure of the living rabbit eye

In order to understand the pharmacology of carbonic anhydrase inhibitors in reduction of aqueous secretion, three sorts of studies were conducted using five 2-substituted 1, 3, 4-thiadiazole-5-sulfonamides: an inhibition study of carbonic anhydrase II, electrical measurements of the isolated ciliary body, and pharmacological study on intraocular pressure of living animals. The inhibitors of carbonic anhydrase employed here were 2-amino-1, 3, 4-thiadiazole-5-sulfonamide; 2-methylamino-1, 3, 4-thiadiazole-5-sulfonamide; 2-formylamino-1, 3, 4-thiadiazole-5-sulfonamide; 2-acetylamino-1, 3, 4-thiadiazole-5-sulfonamide (acetazolamide); and 2-propionylamino-1, 3, 4-thiadiazole-5-sulfonamide. All of these compounds showed significant inhibitory activity to carbonic anhydrase II which exists in the ciliary epithelium, but their potencies of inhibition varied relative to one another (I50S were 1.91 X 10(-7) to 3.3 X 10(-8) M). The effects of the five compounds on electrical phenomena were observed using isolated rabbit ciliary body mounted on an Ussing's chamber. Each compound decreased the negative electrical potential of the tissue (-0.70 mV as the average of the initial values) by 10- to 33%, and this effect was proportional to its inhibitory activity to carbonic anhydrase II. The effects of the five compounds on intraocular pressure were determined, and each compound decreased the intraocular pressure (18 mmHg as the average of the initial values) by 7- to 32%. This effect was also proportional to the inhibitory activity to the enzyme. Correlation between the two effects was studied, and good correlation was observed. This implies that both effects have a common basis which relates to the physiological role of carbonic anhydrase. The present study, therefore, shows the importance of the bicarbonate ion in the aqueous humor formation since it is both substrate and product of carbonic anhydrase II.     

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 additive effect of topical dorzolamide and systemic acetazolamide in pediatric glaucoma.

BACKGROUND: The effect of adding oral to topical carbonic anhydrase inhibitors in the management of pediatric glaucoma is unknown. METHODS: We undertook a retrospective analysis of children with a diagnosis of glaucoma before the age of 16 years who initially were treated with topical dorzolamide or dorzolamide-timolol combination and then treated with oral acetazolamide. Children who had uveitic glaucoma or who had ocular surgery within 3 months before or during oral acetazolamide therapy were excluded. Various methods of intraocular pressure (IOP) measurement were used in the study. However, in each case, the IOP was measured using the same technique, once at the last visit before the addition of oral acetazolamide and once at the first examination after the addition of oral acetazolamide. RESULTS: Twenty-two patients were included in the study with an age range of 8 months to 15 years. Seventeen children were boys. Oral acetazolamide treatment was via a daily dose (13.3 to 30 mg/kg, mean 22.5 mg/kg), and duration (6 to 31 days, mean 18.1 days). The intraocular pressure (mean +/- SD) before acetazolamide (32.2 +/- 6.5 mm Hg) was significantly different than after acetazolamide (21.8 +/- 6.3 mm Hg) with a mean difference of 10.36 mm Hg (p < 0.0001) and a mean decrease in IOP of 29.6%. CONCLUSIONS: The addition of oral acetazolamide to topical dorzolamide may provide additional reduction in IOP in some children already being treated with topical carbonic anhydrase inhibitors. This possible additive effect has not been observed in adults treated with a combination of topical and systemic carbonic anhydrase inhibitors.     

The effect of epinephrine on ciliary process vasculature and IOP studied by intraocular microendoscopy in the albino rabbit.

The effect of epinephrine on intraocular pressure (IOP) and the hemodynamics of the ciliary process vasculature in albino rabbits was studied by intraocular microendoscopy. Intraarterial application of epinephrine (15, 50, 250 ng/kg bw) lead to an immediate vasoconstriction and a reduction in blood flow velocity (BFV) in the iridial and major ciliary processes lasting from 30 to 120 sec. This anemic phase was followed by a hyperemic phase of about 60 to 240 sec. showing a vasodilation up to 150% of the initial diameters and an increase in BFV. The hyperemic phase can be prevented by pretreatment with indomethacin. Simultaneously measured IOP decreases in the anemic and increases in the hyperemic phase parallel with the changes in vascular diameter. After topical administration of epinephrine (25-50 micrograms/kg bw) a marked vasoconstriction followed by a vasodilatory phase was similarly found. However, the reactive changes of the ciliary process vasculature lasted considerably longer. The anemic phase lasted 15 minutes, the hyperemic phase 40 to 60 min. Again, this hyperemia can be prevented by indomethacin-pretreatment. In the iridial processes the anemic phase persisted till 70 minutes. No hyperemia and no substantial influence of indomethacin-pretreatment was found in this territory. In the anemic phase the IOP decreased in average from 20 mmHg to 15 mmHg. However, in contrast to the reactive changes of the IOP after intraarterial epinephrine application, the IOP did not increase again in the hyperemic phase, but decreased further to about 12 mmHg. After pretreatment with indomethacin the IOP remained at the level of 15 mmHg. The short-term IOP-changes after i.a. application of epinephrine, mirror the vasoconstrictory and vasodilatory reactions in the ciliary processes and might be due to volume changes in the eye (plethysmographic effect). However, the long lasting IOP reduction after topical epinephrine in the hyperemic phase can not be due to vascular reactions in the ciliary processes. There must be other factors responsible for the long lasting pressure reducing effect of epinephrine.     

Patient tolerance to carbonic anhydrase inhibitors

We evaluated carbonic anhydrase inhibitors in a crossover study with a placebo and random allocation of treatment administration. Drugs evaluated included acetazolamide tablets and Sequels, dichlorphenamide, ethoxzolamide, methazolamide, and an ascorbic acid placebo. The best tolerated drug was acetazolamide Sequels. Methazolamide was next. The least tolerated drugs were ethoxzolamide, acetazolamide tablets, and dichlorphenamide.