Ikuo Azuma

Experimental Optic Cup Enlargement Caused by Endothelin-1–Induced Chronic Optic Nerve Head Ischemia

PURPOSE Vascular insufficiency of the optic nerve head may contribute to glaucomatous optic neuropathy, especially in normal-tension glaucoma. We investigated the effect of chronic optic nerve head ischemia, created by repeated intravitreal injection of endothelin-1 (ET-1), on the morphology and function of the optic nerve. METHODS In pigmented rabbits, we injected ET-1 (10(-6) M, 10 microL) into the posterior vitreous of one eye twice a week for 4 weeks (N = 7). The vehicle for ET-1 was injected into the contralateral eye as a control (N = 7). The subsequent observation period was set at 8 weeks. The microcirculation of the optic nerve head was noninvasively monitored with a laser speckle circulation analyzer. To evaluate the changes of visual function, visual-evoked potentials were recorded. Morphologic changes of the optic nerve head were analyzed with stereography, and the ratio of cup area (CA) to disk area (DA) was measured by calculating the number of pixels in each area with a microcomputer. RESULTS Capillary blood flow in the optic nerve head was continuously below 80% of the baseline throughout the study. The visual-evoked potential latency was significantly delayed in ET-1-treated eyes. The CA/DA ratio was significantly increased relative to baseline in the ET-1 treated eyes. Histologic examination showed axonal loss and demyelination affecting the prelaminar portion of the optic nerve. The intraocular pressure was not significantly different from the control value. CONCLUSION Optic nerve head ischemia could contribute to the enlargement and excavation of the disk cup independent of the intraocular pressure level.

Effects of prostaglandin D2 and its analogue, BW245C, on intraocular pressure in humans.

The effects of topically applied prostaglandin (PG) D2 and BW245C, a potent PGD2 agonist, on intraocular pressure (IOP) were studied in normotensive human volunteers. Doses of 5 and 10 μg PGD2 induced a mean reduction in IOP of 0.8 and 1 mmHg, respectively. At a dose of 50 μg, hypotension was preceded by initial hypertension (4 mmHg at 0.5 h) and the magnitude of the mean 101? reduction during the hypotensive phase was 1.1 mmHg. The application of BW245C (2.5 μg) induced an IOP change similar to that observed following treatment with 50 μg PGD2. Side effects caused by these compounds included conjunctival hyperemia, itching, and foreign-body and mild burning sensations. However, miosis and signs of intraocular inflammation were not observed. These results indicate that although PGD2 and BW245C are effective in reducing human IOP, their clinical usefulness as anti-glaucoma drugs may be limited by the extraocular side effects.

Clinical evaluation of UF-021 (Rescula; isopropyl unoprostone).

We have reviewed two Phase III clinical studies of isopropyl unoprostone conducted in Japan: a 12-week comparative study of 0.12% isopropyl unoprostone and 0.5% timolol, and a 52-week administration of two concentrations of isopropyl unoprostone in ocular hypertensive and primary open-angle glaucoma patients. These studies showed a similar ocular hypotensive effect of 0.12% isopropyl unoprostone to 0.5% timolol and a sustained ocular hypotensive effect of the drug for up to one year. Adverse reactions of isopropyl unoprostone were minor and similar to those of timolol. No pigmentary changes of the irides were noticed. In view of these results, isopropyl unoprostone seems to be a useful antiglaucoma medication.

Dorzolamide, a topical carbonic anhydrase inhibitor: a two-week dose-response study in patients with glaucoma or ocular hypertension.

We investigated the dose-response relationship of the intraocular pressure-lowering activity of dorzolamide, a novel topical carbonic anhydrase inhibitor previously known as MK-507. A double-masked, randomized, multicenter study of 113 patients with either primary open-angle glaucoma or ocular hypertension was conducted; dorzolamide (0.2, 0.5, 1, or 2%) was administered three times daily for 14 days. All of the dorzolamide concentrations substantially lowered intraocular pressure from baseline measurements. The percentage change in baseline intraocular pressure with 0.5, 1, and 2% dorzolamide 2, 4, and 6 h after dosing on day 14 ranged from 12.0 to 17.0% on average, which was greater than after treatment with 0.2% dorzolamide. No dose response was seen for 0.5, 1, or 2% dorzolamide. The most frequently reported ocular symptom was transient smarting, which occurred in 35.6-74.1% of every treatment group. Smarting and mild hyperemia were most frequent with 2% dorzolamide (74.1 and 18.5%, respectively). The present results indicate that the 0.5, 1, and 2% concentrations of dorzolamide are almost equally effective and that 2% concentrations may be less well-tolerated than 0.5 or 1% concentrations.

Evaluation of the Circulation in the Retina, Peripapillary Choroid and Optic Disk in Normal-Tension Glaucoma

Computerized image analysis, including fluorescein angiography, was used to evaluate the retinal, choroidal and optic disk blood flow in 16 patients with normal-tension glaucoma (NTG) and to correlate this measurement with visual fields, retinal vessel width, optic disk pallor and blood pressure (BP). The angle of the ascending slope of the fluorescein dye curve was measured as an index of blood flow from the densitometric and time curves of the fluorescein angiograms in the optic disk, peripapillary choroid, retinal artery and vein for each quadrant. While the ascending slope as well as the retinal vessel width were most reduced in the inferior and nasal regions, the mean threshold was lowest in the superior and nasal quadrants. There were positive significant correlations between artery width and threshold value, between angles of slopes and pallor. In addition, systolic BP had a negative correlation with pallor, and diastolic BP had a positive one with slope in the choroid. These results indicated the probable association of a decrease in retinal, choroidal and optic disk blood flow in the inferior and nasal quadrants as well as vessel width in the inferior nasal quadrant with visual field loss in the superior quadrant, and also demonstrated an increasing blood flow for enlargement of pallor. A decrease in BP was found to be related to reduced blood flow in choroid and optic disk impairment.

Effect of topical prostaglandin D2 on the aqueous humor dynamics in rabbits.

Effects of topically applied prostaglandin (PG) D2 on the aqueous outflow facility, uveoscleral flow, and aqueous flow rate were studied in rabbits to reveal its intraocular pressure (IOP)-reducing mechanism. The outflow facility after PGD2 application (50 μg) as measured by 2-min tonography was 0.19 μl/min/mm Hg and did not differ from that before the application (0.22) or from that of the control contralateral eye (0.21). Direct measurement of the uveoscleral flow by perfusion of the anterior chamber for 30 min with fluorescein isothiocyanate-labeled dextran solution showed the flow rate to be about 0.15 μl/min in indomethacin-treated (10 mg/kg, i.p.) rabbits. In these animals, PGD2 (50 μg) was ineffective in changing the flow rate, while PGF2α (50 μg) significantly increased the flow by about 35%. Indirect assessment of the effects of PGs on this flow system was made using the uveoscleral flow-antagonizing ability of topical pilocarpine (1.5 mg). IOP reduction by PGD2 (50 μg) was only slightly inhibited by pilocarpine, while that by PGF2α (10 μg) was markedly reduced. Aqueous flow rate measured fluorophotometrically was about 3.5 μl/min in normal eyes. After PGD2 (50 μg) the flow rate was significantly reduced to 3.0 μl/min. The magnitude of this reduction was estimated to be enough to account for the IOP reduction after application of 50 μg of PGD2. These results indicate that IOP reduction caused by topical PGD2 application is due mostly to the inhibition of aqueous flow rate.

Efficacy and Safety of Latanoprost Eye Drops for Glaucoma Treatment : A 1-Year Study in Japan

PURPOSE To evaluate the intraocular pressure (IOP)-lowering effect and safety of latanoprost, a prostaglandin analogue, in patients with primary open-angle glaucoma or ocular hypertension. METHOD One hundred and twenty-four Japanese patients with primary open-angle glaucoma or ocular hypertension were enrolled in this open-labeled study and were treated with 0.005% latanoprost once daily for 1 year. RESULTS At all follow-up visits there was a significant (P < .001) reduction in IOP compared with the baseline value. After 1 year, the IOP was reduced by 5.4 +/- 2.9 (mean +/- SD) mm Hg from a baseline value of 23.5 +/- 2.2 mm Hg. No evidence of an upward drift in the IOP was observed during the treatment period. The most frequently reported adverse ocular events were mild conjunctival hyperemia and iris pigmentation. Very few adverse systemic events were observed. CONCLUSIONS Latanoprost eye drops showed a marked and stable IOP-lowering effect during the 1-year treatment period. Furthermore, latanoprost was well-tolerated and should be a valuable contribution to the management of glaucoma.

Novel Mutations in the Myocilin Gene in Japanese Glaucoma Patients

Myocilin is a gene responsible for juvenile onset primary open angle glaucoma (POAG) mapped as the GLC1A locus and, many mutations have been reported worldwide. Some mutations were found not only in patients with juvenile onset POAG, but also in patients with late onset POAG and in patients with normal tension glaucoma. To investigate the mutation prevalence in Japan, we performed a mutation analysis in 140 unrelated Japanese patients. We have identified the 10 sequence variants, of which four were highly probable for disease‐causing mutations (Arg46ter, Arg158Gln, Ile360Asn, and Ala363Thr), and six polymorphisms (Gln19His, Arg76Lys, Asp208Glu, Val439Val, Arg470His, and Ala488Ala). Thus, myocilin mutations were found at the rate of 4/140 (2.9%) probands, similar to previous reports with other ethnic populations. Hum Mutat 16:270, 2000.

Long-term effect of topically applied isopropyl unoprostone on microcirculation in the human ocular fundus.

PURPOSE To investigate the long-term effect of 0.12% isopropyl unoprostone (Rescula) on microcirculation in the human ocular fundus. METHODS A laser speckle tissue circulation analyzer was used to measure normalized blur (NB), a quantitative index of blood flow velocity, in the optic nerve head (ONH) and choroid-retina before and 4.5 hours after the instillation of a placebo into both eyes of 11 healthy volunteers. The intraocular pressure (IOP), blood pressure, and pulse rate were also recorded in this control experiment. Thereafter, a drop of unoprostone or a placebo was instilled into each eye in a double-blind manner twice a day for 21 days to form treated and untreated groups. RESULTS After 21 days, the NB values in the ONH and choroid-retina had increased significantly and the IOP had decreased significantly in the unoprostone-treated eyes. Ocular perfusion pressure showed no significant change. CONCLUSIONS These results suggest that long-term application of unoprostone can increase microcirculatory blood flow in the human ocular fundus, probably due to a reduction in vascular resistance.

Effect of Topically Applied Iganidipine Dihydrochloride, a Novel Calcium Antagonist, on Optic Nerve Head Circulation in Rabbits

PURPOSE We studied the effect of topically applied iganidipine dihydrochloride, a novel water-soluble calcium channel blocker on the blood flow of optic nerve head (ONH), intraocular pressure, and blood pressure in rabbits. METHODS 1. 0.1% iganidipine (20 microliters) was instilled into a normal eye. The change in blood flow in the ONH was measured using a hydrogen gas clearance flowmeter. 2. Iganidipine (0.0001%-0.1%) was instilled into a circulation-disordered eye before or after the intravitreal injection of endothelin-1, and change in the blood flow in the ONH was measured. 3. Changes in intraocular pressure and blood pressure after instillation of 0.1% iganidipine were measured. In all experiments, physiological saline was instilled in each contralateral eye as a control. RESULTS 1. Instillation of iganidipine significantly increased the blood flow in the ONH by 40% at 45 minutes after instillation. 2. Pre-instillation of 0.01 and 0.1% iganidipine almost completely inhibited the decrease of blood flow in the ONH in the circulation-disordered model. The decrease of blood flow in the ONH was corrected with post-instillation of 0.1% iganidipine. These effects were continuous. 3. Instillation of 0.1% iganidipine did not change either intraocular pressure or blood pressure. CONCLUSION It was shown that instillation of iganidipine continuously increased and maintained the blood flow in the ONH in normal and circulation-disordered rabbit eye models.