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A trial of topical therapy in one eye is advocated as part of the evaluation of the patient with elevated intraocular pressure. This will determine the effectiveness of pressure reduction and the side effects that can be expected. The results of such a trial are then used as one of the pieces of information to decide rationally when and on whom to reduce intraocular pressure medically.
Thymoxamine is an alpha-adrenergic blocking agent which works by competitive antagonism of norepinephrine. It is the only alpha-adrenergic blocker available which has tolerable side effects when used as an ophthalmic solution. When used as a 0.5% solution it consistently produces miosis without affecting the intraocular pressure or the ciliary muscle-controlled facility of outflow. The only regularly reported side-effects at this concentration are transient burning and conjunctival hyperemia. Potential applications of thymoxamine include reversal of phenylephrine mydriasis, treatment of angle-closure glaucoma, treatment of persistent mydriasis after penetrating keratoplasty for keratoconus, reversal of lid retraction in thyroid ophthalmopathy, testing to differentiate angle-closure glaucoma from open-angle glaucoma with narrow angles, aiding in repositioning and maintaining the position of intraocular lenses, treatment of pigmentary glaucoma. Thymoxamine may also contribute to a better understanding of the adrenergic nervous system on aqueous dynamics.
The mechanisms of the secondary glaucomas and the actions and side effects of antiglaucoma drugs are reviewed. Based on these observations, the advantages of timolol, as compared to other medications, in the management of secondary glaucomas are discussed. To illustrate some of these advantages, a study is reported in which timolol is evaluated for control of the early intraocular pressure elevation after routine cataract surgery.
Many of today's important ophthalmic pharmaceuticals have a rich ethnobotanical history. Solanaceous plants, the source of atropine, have contributed to medical therapy since the beginning of Western civilization. The botanical source of physostigmine played a pivotal role as an ordeal poison in the culture of Old Calabar, West Africa. Native peoples of Amazonia treasured plants containing pilocarpine as panaceas because of their impressive diaphoretic effect. Nineteenth century scientists examining these plants because of their folkloric reputations discovered their active compounds and documented their physiological effects. Ophthalmologists such as Argyll Robertson, Laqueur, and Weber built upon this research to bring these pharmaceuticals into therapeutic use. The ongoing loss of the world's tropical rain forests threatens to destroy a vast storehouse of untested biological compounds.
We studied the pupillary responses of various subjects to carbamylcholine chloride (CCC) in order to assess cholinergic responsiveness. Using the concentration of topical CCC required to induce greater than or equal to 1 mm miosis in the dark as the end point, we compared the responses of five groups of subjects: normal controls; patients with allergic asthma, allergic rhinitis, or intrinsic asthma; and a group who had reproducibly positive skin tests in the absence of symptoms. Subjects with allergic rhinitis or allergic asthma were significantly more sensitive than were normal controls. The patients with positive skin test and negative history were as sensitive as their symptomatic cohorts, suggesting that pupillary cholinergic hyperresponsiveness exists in atopic individuals regardless of symptoms. A small group with intrinsic asthma was examined and found to be even more sensitive than any of the atopic subjects. Thus abnormal hyperresponsiveness of the pupillary constrictor muscles to a topically instilled cholinomimetic has been found in all groups of atopic subjects plus nonallergic asthmatics. Analysis of pupillary responses may prove useful in assessment of autonomic responsiveness.
Pilocarpine nitrate, an alkaloid drug of plant origin induces spindle disfunction in bone marrow cells of mice. Further studies were carried out to investigate its mutagenic effects in somatic and germ cells of mice by assessing chromosome aberrations at mitotic metaphase and as micronuclei in bone marrow cells and sperm-shape abnormality in cauda epididymides. The dose and time yield effects of the drug were investigated. The statistically significant results that were obtained for both chromosomal aberrations and micronucleus test but not for the sperm-shape abnormality test, indicated the genotoxicity of this compound in somatic cells but not in germ cells.
The effect of calcitonin gene-related peptide (CGRP), a neuropeptide, on the apoptosis of murine thymocytes was investigated. CGRP enhanced apoptosis of thymocytes beyond the spontaneous level at concentrations of 10(-11) M or higher, and the effect attained a plateau at 10(-9) M, mainly by stimulating cAMP formation. Implication of cAMP-independent mechanism was also suggested in the CGRP-induced apoptosis. Flow cytometric analysis revealed that CGRP caused apoptosis preferentially in CD4+8+ thymocytes. In addition, RNA and protein synthesis was required for apoptosis induced by CGRP.
The Edinger-Westphal complex (EW) was explored as a possible site of action for the effects of morphine and clonidine to produce mydriasis in the cat and miosis in the dog. Morphine, normorphine and clonidine, dissolved in 0.5 microliter 0.9% NaCl, were injected via chronic indwelling cannulae into or near the EW of the restrained cat and dog. In the cat, all 3 drugs produced a dose-dependent mydriasis. Clonidine (3-30 nmol) was 1.7 times more potent than normorphine (3-30 nmol) and 9.6 times more potent than morphine (10-60 nmol). Normorphine was 5.5 times more potent than morphine. Significant miosis resulted from single doses of morphine (17.5 nmol), normorphine (15.5 nmol) and clonidine (19 nmol) injected in the EW of the dog. Injections sites closest to the EW yielded the greatest changes in pupillary diameter. Naloxone antagonized the pupillary effects of normorphine in the cat and dog but had no effect on clonidine mydriasis in one cat. It was concluded that the EW region is an important site of action for the effects of morphine and clonidine on pupil diameter in both species. However, the neurocircuitry and neurochemistry of the EW probably differ between the cat and dog.
Evidence from our previous work suggests that neurogenic mediators contribute to the inflammation following ultraviolet (UV) irradiation of the skin. We have investigated whether calcitonin gene-related peptide (CGRP), substance P and nitric oxide (NO) participate in the cutaneous inflammatory reaction of the rat hind paw and ear to UV irradiation. Skin blood flow was measured by laser Doppler technique. Oedema was quantified using a spring loaded micrometer to measure ear thickness. UV irradiation of the rat skin lead to a long lasting increase in skin blood flow. This increase was dose dependently attenuated by the CGRP receptor antagonist CGRP-(8-37) (0.15 nmol in 25 microliters to 6.0 nmol in 25 microliters, s.c.) up to 51% with a maximum of effectiveness at 24 h post irradiation. The inhibitor of NO synthase NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, 25 nmol in 25 microliters, s.c.) attenuated skin blood flow by 38%. Concurrent injections s.c. of CGRP-(8-37) (1.5 nmol in 12.5 microliters) and L-NAME (25 nmol in 12.5 microliters) demonstrated an augmentive effect in attenuating skin blood flow. The tachykinin NK1 receptor antagonist CP-96,345 (6.0 nmol in 25 microliters, s.c.) attenuated skin blood flow by 27%. NG-Nitro-D-arginine methyl ester hydrochloride (D-NAME) and CP-96.344 showed no effects on skin blood flow after UV irradiation. CGRP-(8-37) (0.6 nmol in 10 microliters) i.d. and L-NAME (10 nmol in 10 microliters) i.d. had no effect of oedema formation after UV irradiation. Furthermore, post UV irradiation enhanced CGRP- and NO synthase-immunoreactivity in nerve fibres in the exposed skin area were visible. Taken these findings together we suggest the involvement of the neuropeptides CGRP and substance P and of neuronal NO on the vasodilatory component of the UV-induced inflammatory reaction of the rat skin. CGRP contributing to UV-induced vasodilation acts in an endothelial NO-independent manner.
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The purpose of this research was to reassess the effects of topical pilocarpine on the integrity of the blood-aqueous barrier, using high resolution, magnetic resonance imaging, and the standard intravenous contrast agent gadolinium dimeglumine. It has long been known that topical pilocarpine gives rise to an increase in protein levels in the anterior chamber of the eye. This protein scatters light and is referred to clinically as 'flare'. Prior studies concluded that pilocarpine-induced flare resulted from disruption of the blood-aqueous barrier. These studies relied upon indirect methods that precluded direct visualization of the posterior chamber of the eye. Five normal, human volunteers (age 22-40) received a single drop of 3% pilocarpine in one eye, following baseline measurements of pupil size and anterior chamber 'flare'. These measurements were repeated every 15 min for 45 min. The subject was then positioned in the magnet and the eye that received pilocarpine was taped closed and covered with a 3 in.-diameter receive-only surface coil. The open contralateral eye focused on a target to maintain fixation of the imaged eye. A baseline image of the eye was obtained and the contrast agent was administered intravenously. A series of additional images was obtained during the following 60 min to track the movement of contrast material from the bloodstream into the tissues and compartments of the eye. Percent enhancement was calculated from selected regions of interest in the images, including the ciliary body, and the anterior and posterior chambers. Within the 45 min after administration of pilocarpine, pupil size in mm decreased from (mean+/-s.d.) 5.7+/-1.5 to 2.5+/-0.5 (p=0.0106). During this period, average flare/s.d. (photons msec-1) increased from 3.7+/-1.1 to 12.5+/-4.7 (p=0.0151). In all cases, MRI images showed rapid enhancement of the ciliary body, followed by a progressive increase in signal in the anterior chamber but not the posterior chamber. These studies confirm that topical pilocarpine gives rise to 'flare' in the anterior chamber. But the lack of enhancement in the posterior chamber strongly suggests that the presence of this added protein in the anterior chamber is not the result of increased permeability of the blood-aqueous barrier of the ciliary body. These studies also introduce the novel concept that not all clinically observed flare is the result of blood-aqueous barrier compromise.
PURPOSE: To determine the effect of intracameral injection of preservative-free lidocaine 1% and carbachol 0.01% on corneal endothelial cells of rabbits. SETTING: Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan. METHODS: Forty eyes of 20 New Zealand White rabbits were divided into 2 equal groups. In the first group, 1 eye was injected with 0.02 mL of preservative-free lidocaine 1% and the fellow eye was injected with 0.02 mL of normal saline as a control. In the second group, 1 eye was injected with 0.02 mL of carbachol 0.01% and the fellow eye was injected with 0.02 mL of normal saline. Specular microscopy was used to evaluate corneal endothelial cell loss and corneal thickness 1 week and 1 month postinjection. For morphologic studies, corneal buttons were excised and stained with alizarin red with trypan blue. Scanning electron microscopy (SEM) examination was performed. RESULTS: Specular microscopy revealed no significant endothelial cell loss and normal endothelial thickness with the intracameral injection of preservative-free lidocaine 1% and carbachol 0.01% compared with the control eye. Alizarin red with trypan blue stain and SEM examinations revealed smooth, distinct, and intact intercellular borders and normal viability of corneal endothelial cells in both groups. CONCLUSIONS: Intracameral injections of preservative-free lidocaine 1% and carbachol 0.01% do not produce morphologic and functional changes in the corneal endothelial cells of rabbits.
PURPOSE: To evaluate changes in the anterior and posterior corneal shape, corneal thickness, and anterior chamber depth (ACD) caused by mydriasis or miosis using scanning-slit corneal topography. SETTING: Department of Ophthalmology, Iwate Medical University School of Medicine, Iwate, Morioka, Japan. METHODS: Twenty-eight eyes of 28 healthy volunteers with refractive errors of -6.00 to +0.25 diopters were studied. One eye of each subject had instillation of tropicamide-phenylephrine hydrochloride (Mydrin P) to obtain mydriasis and of pilocarpine hydrochloride 2% (Sanpilo) to obtain miosis. To assess the corneal shape, the best-fit sphere (BFS), axial power, and tangential power were measured for the anterior and posterior corneal surfaces before and after mydriasis and before and after miosis using scanning-slit corneal topography (Orbscan version 3.0, Orbtek, Inc.). The pupil size, corneal thickness, and ACD were also examined before and after mydriasis and before and after miosis. RESULTS: The mean age of the patients was 31.1 years +/- 5.6 (SD) (range 20 to 46 years). The anterior BFS changed from a mean of 8.04 +/- 0.3 mm at the time of mydriasis to a mean of 8.00 +/- 0.3 mm at the time of miosis. The posterior BFS changed from 6.53 +/- 0.3 mm to 6.46 +/- 0.3 mm, respectively. Thus, the anterior and posterior cornea became significantly steeper after miosis (P<.01). The ACD was significantly more shallow after miosis than after mydriasis. However, there was no significant difference in corneal thickness after mydriasis or miosis. CONCLUSIONS: The anterior and posterior corneal shapes changed as a result of mydriasis and miosis, and the refractive power of the cornea significantly increased after miosis. To date, changes in refractive power from changes in pupil size have been attributed to a change in the refractive power of the crystalline lens; however, it is now thought that changes in corneal refractive power also occur.
PURPOSE: To study the efficacy of several subjective and objective methods of accommodation measurement in normal prepresbyopic and presbyopic populations to identify appropriate methods for measuring the outcome of accommodative restorative procedures. SETTING: University of Houston, College of Optometry, Houston, Texas, USA. METHODS: Thirty-one normal subjects with a mean age of 43.7 years (range 31 to 53 years) participated. Accommodation was measured monocularly using 3 subjective approaches--the push-up test, minus lenses to blur, and a focometer--and 2 approaches measured with a Hartinger coincidence refractometer, in which accommodation was stimulated with minus lenses to blur and topical pilocarpine 6%. RESULTS: The push-up method overestimated accommodative amplitude relative to objective measures in 28 subjects. Two subjective methods, minus lenses to blur and the focometer, produced comparable results, but with lower amplitudes in younger subjects and higher amplitudes in older subjects compared with objective methods. Comparable results were obtained when accommodation was stimulated in 1 of 2 ways and measured with the Hartinger. Pilocarpine elicited stronger accommodative responses than distance blur for subjects with low accommodative amplitudes. Pilocarpine 6% produced stronger responses in subjects with light irides than in those with dark irides. CONCLUSIONS: Hartinger-measured accommodation provides more realistic measurement of accommodative amplitude than the subjective methods tested, especially in the presbyopic population. In presbyopic subjects, the subjective tests resulted in accommodative amplitudes up to 4.0 diopters greater than those measured with objective tests. Measurements of accommodative amplitude are best achieved with objective methods to stimulate and measure accommodation.
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PURPOSE: To measure the changes of corneal curvature during contraction of the ciliary muscle. SETTING: Department of Ophthalmology, St. Luke's International Hospital, Tokyo, Japan. METHODS: Twenty-eight eyes of 14 healthy volunteers under 40 years old were enrolled in this prospective randomized controlled study and divided into pilocarpine and control groups. Intraocular pressure (IOP), pupil diameter, and corneal topography were measured before and 40 minutes after instillation of topical pilocarpine 4% or balanced salt solution. Corneal topography was analyzed for the mean ring-power of Placido rings 1 through 25, average corneal power (ACP), and for spherical equivalent, regular astigmatism, asymmetry, and high-order irregularity by Fourier analysis. RESULTS: Pilocarpine had no effect on IOP, but it did cause a significant decrease in mean pupil diameter. Simultaneously, pilocarpine increased the mean ring powers for Placido rings 1 through 4 and the ACP (+0.13 diopters (D) +/- 0.17 [SD]; P=.017). By Fourier analysis, the mean spherical component for the central 3.0 mm of the cornea increased in the pilocarpine group (+0.08 +/- 0.15 D; P=.020). There were no changes in components of regular astigmatism, asymmetry, and high-order irregularity. CONCLUSIONS: The central cornea steepened in curvature and increased in power owing to contraction of the ciliary muscle. The results suggest that changes in corneal curvature increase refractive power during accommodation.
PURPOSE: To evaluate the factors influencing AcrySof intraocular lens (IOL) (Alcon Laboratories) movement and near visual acuity after cyclopentolate 1% and pilocarpine 2%. SETTING: Department of Ophthalmology, University of Ankara, Ankara, Turkey. METHODS: Thirty eyes of 22 patients with AcrySof IOL implantation were included in this prospective study. Near visual acuity (Jaeger) at 35 cm through best distance correction without an add and pupil diameter were measured and correlated with anterior chamber depth (ACD) measured with ultrasound biomicroscopy (UBM) after application of cyclopentolate 1% and pilocarpine 2%, respectively. The magnitude of the change in the ACD was correlated with the accommodation amplitude, patient age, time interval between surgery and imaging, preoperative axial length, capsulorhexis diameter, ACD during cycloplegia, IOL diameter, and presence of posterior capsule opacification (PCO). RESULTS: Near visual acuity significantly decreased after application of cyclopentolate 1% and increased after application of pilocarpine 2% (P < .001) in all eyes. The IOL moved anteriorly in 8 (26%) eyes and posteriorly in 22 (74%) eyes after pilocarpine 2%. There was no correlation between the ACD and near visual acuity under cyclopentolate 1% (r = 0.06, P > .05) or pilocarpine 2% (r = 0.04, P > .05). There was a moderate correlation between the anterior IOL movement and accommodation amplitude (P < .05, r = 0.42). There was no correlation between the magnitude of the IOL movement and patient age, time interval between surgery and imaging, the preoperative axial length, capsulorhexis diameter, ACD during cycloplegia, IOL diameter, and the presence of PCO (P > .05). CONCLUSIONS: There was better near visual acuity in all eyes with the AcrySof MAIOL, although most IOLs move slightly backward after of pilocarpine 2%. This points out pseudoaccommodation rather than pseudophakic accommodation. Ultrasound biomicroscopy is useful in determining the ACD and the relation between the IOL and the surrounding tissues after cataract surgery.