Echothiophate-Induced Structural Alterations in the Anterior Chamber Angle of the Cynomolgus Monkey

Echothiophate-induced structural alterations in the anterior chamber angle of the cynomolgus monkey

Elke Liitjen-Drecoll and Paul L. Kaufman

Four cynomolgus monkeys were treated topically twice daily in one eye with echothiophate iodide (PI) doses of 63, 75, or 250 fjig per treatment for 7.7 weeks to 7 months. The opposite eyes of two monkeys received a control solution (diluent). The anterior ocular segments of all six eyes were studied by light and transmission electron microscopy during treatment. In the Pl-treated eyes, the cribriform and outer corneoscleral meshwork were unusually dense. The trabecular meshwork was collapsed and the lamellae showed thickened basement membranes and thickened sheaths of elastic-like material. Most endothelial cells were enlarged and activated. Some contained many glycogen particles; others showed evidence of degeneration. The cribriform meshwork contained much more extracellular fine fibrillar material than normal, and the endothelium of the inner wall of Schlemm's canal was damaged. The Pi-contracted ciliary muscle had a more rectangular shape than normally contracted muscles, and the inner edge extended so far anteriorly that in some areas it overlapped and occluded the trabecular meshwork. The muscle cells appeared damaged, and their basement membranes were thickened. The nonpigmented epithelial cells of the ciliary processes showed signs of degeneration, and within the pars plana some contained large, weakly osmiophilic inclusions. The basement membrane of the ciliary epithelium was thickened everywhere. The stromal vessels of the pars plana were dilated, and signs of inflammation were present. The sphincter iridis was damaged and there were iridocorneal adhesions. The 5 month diluent-treated eye demonstrated mild structural abnormalities in the meshwork.

Key words: angle-closure glaucoma, anterior chamber angle, canal of Schlemm, cholinesterase inhibitors, ciliary muscle, ciliary processes, echothiophate, iris, monkey eye, trabecular meshwork

Long-acting cholinesterase (ChE) inhibitors From the Department of Anatomy, University of are applied topically to the human eye for the Erlangen-Niirnberg, Erlangen, West Germany; the treatment of some cases of glaucoma. These Department of Medical Pharmacology, University of drugs lower intraocular pressure (IOP) at Uppsala, Uppsala, Sweden; and the Department of least initially by increasing the facility of Ophthalmology, University of Wisconsin Medical aqueous humor outflow. Although ChE in- School, Madison, Wise. Supported by grants from the Deutsche Forschungsge- hibitors may provide long-term lowering of meinschaft, Bad Godesberg (Ro 81/14, to Prof. J. W. IOP in many cases, some eyes eventually be- Rohen) and the National Institutes of Health (EY00231, come refractory to these drugs.1 A possible IF03 EY55678, 5 SOI RR05435). reason for this is decreased sensitivity of Submitted for publication Aug. 15, 1978. outflow facility to cholinomimetic com- Reprint requests: Dr. Elke Liitjen-Drecoll, Anatom- 2 isches Institut der Universitat Erlangen-Niirnberg, pounds, presumably due to acetylcholine- 8520 Erlangen, Krankenhausstrasse 9, West Germany. induced cholinergic subsensitivity of the

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70 105 140 210 DAYS Fig. 1. Treatment protocols. Control eyes (110 R and 225 L) received same volume of diluent, containing NaCl in place of PI, as fellow experimental eyes. Cynomolgi (CYNO) 110 and 225 received virtually all treatments while fully conscious; cynomolgus 280 received alternate treatments under CI-744 anesthesia for the first 3 months. Aniridic, Iris totally removed8 previously; R, right eye; L, left eye; j, slit-lamp examination; P, posterior subcapsular lens opacities; A, anterior subcapsular opacities; V, lens vacuoles; ±, questionable lens opacities; C, clear lens; f, procedure or event other than slit-lamp examination (refraction not indicated); Eu enucleation following death by intracardiac pentobarbital; E2, enucleation in vivo under pentobarbital anesthesia.

ciliary muscle.2 4 We report here another sodium phosphate, mannitol, and potassium ace- possible reason for loss of the IOP-lowering tate necessary to give concentrations equal to effect of ChE inhibitor treatment: ChE those in the corresponding PI solution. The os- inhibitor-induced structural alterations in the molality of the diluent was adjusted to approxi- anterior chamber angle. mate that of the corresponding PI solution by adding sodium chloride (1.8 or 9.0 mg/ml). The 0.5% Materials and methods PI solution had pH = 6.39 and osmolality = 435 Animals. Four adolescent or young adult cyno- mOsm; the corresponding diluent had pH = 6.30 molgus monkeys (Macaca fascicularis), weighing and osmolality = 425 mOsm. The 2.5% PI so- 1.8 to 2.4 kg, were studied. lution had pH = 6.97 and osmolality = 1900 Drugs. Ophthalmic PI was purchased com- mOsm; the corresponding diluent had pH = 6.91 mercially. To the drug powder was added the ac- and osmolality = 1820 mOsm. companying diluent to yield either a 0.5% or a Topical drug treatment. The eyes were treated 2.5% solution of echothiophate iodide (PI). Dilu- topically twice daily on weekdays (7:15 to 7:45 ent was made by adding to distilled water the A.M. and 4:15 to 4:45 P.M.) and once daily on quantities of boric acid, chlorobutanol, dibasic weekends (9:00 to 9:30 A.M.) with either PI or

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Fig, 2. For legend see facing page.

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diluent. The conscious animal was removed from treated with 1% periodic acid for 5 min to demon- its cage and restrained supine by a gloved assis- strate glycogen particles.10 tant. The upper lid was retracted digitally, and Results with a specially prepared microdropper, a 2.5 /xl drop of drug solution was applied to the central The morphological appearances of the PI cornea every 20 to 30 sec until the desired drug and diluent-treated eyes were compared with dose had been administered. Blinking was pre- each other and with the appearances of a large vented between drops and for 20 to 30 sec after number of non-PI-, non-fZi/«en£-treated the last drop. The lids were then wiped dry and cynomolgus eyes.11"15 Total iridectomy8 itself the animal returned to its cage. Treatments under caused no abnormalities visible by LM or general anesthesia were given in a similar manner, TEM in the ciliary muscle, trabecular but without assistance. Separate droppers were meshwork, or Schlemm's canal.8' 15 used for each of the four drug solutions. PI-treated eyes Slit-lamp examination. This was performed pe- Trabecular meshwork and Schlemm's canal riodically on the anesthetized monkey.5'6 Anesthesia. General anesthesia for topical 54 DAYS PI. The cribriform meshwork adja- treatments and slit-lamp examination was by in- cent to Schlemm's canal was thicker and tramuscular CI-744 (Tilazol; Parke-Davis), 5 to 10 more dense than normal (Fig. 2, B). The mg/kg.7 cribriform endothelial cells were enlarged Fig. 1 gives additional details of treatment and and exhibited enlarged nuclei, prominent enucleation. Treatment was started with smaller nucleoli, and large amounts of rough surfaced doses (same solutions, fewer drops), and the dos- endoplasmic reticulum. Beneath the inner age was gradually increased over several weeks to wall endothelium and within the cribriform 2 minimize the risk of systemic toxicity. meshwork there was more fine fibrillar ma- Tissue processing terial than normal (Fig. 3, B). In the Cynomolgus 275. Immediately following enu- corneoscleral and uveal meshwork, the tra- cleation, postequatorial scleral windows were cut, and the eye was immersed in phosphate-buflfered becular endothelial cells were also activated. (pH 7.2) 2.5% glutaraldehyde for 1 hr. The eye 138 AND 155 DAYS PI. The changes were in was then opened equatorially, the posterior half general similar to those seen after 54 days but discarded, and the anterior half cut into small were much more pronounced. In some re- sagittal wedges. The wedges were processed for gions there was so much fine fibrillar material light microscopy (LM) and transmission electron that the inner canal wall was separated from 9 microscopy (TEM). the first subendothelial cell layer (Figs. 2, C, Cynomolgi 110, 225, and 280. Immediately fol- and 3, C). In the inner portion of the lowing enucleation, the eye was opened equato- corneoscleral meshwork and in the uveal rially, and the posterior half discarded. Under an meshwork, some of the trabecular endothe- operating microscope, the zonule was cut all lial cells were degenerating (evidenced by around with a fine Vannas scissors, with care being taken not to touch the lens or ciliary processes. swollen mitochondria and vacuolization The lens was lifted free by a stainless steel ring and within the cytoplasm), and in some places a glass rod and processed for other studies. Small they were separated from the trabecular sagittal wedges of the anterior ocular segment beams. However, in the subopercular12 re- were then cut and processed for LM and TEM.9 gion of the anterior part of the meshwork Some ultrathin sections from each eye were there were clusters of activated cells, perhaps

Fig. 2. Trabecular meshwork and Schlemm's canal. A, Monkey 225 R, 54 days diluent. Meshwork and inner canal wall appear normal. SC, Schlemm's canal; SCL, sclera. B, Monkey 225 L, 54 days PI. Arrows indicate thickened cribriform meshwork. C, Monkey 110 L, 155 days PI. Arrows indicate separation of inner wall endothelium from first subendothelial cell layer, d, Degenerating trabecular and corneal endothelial cells; O, operculum; cc, subopercular endothelial cell clusters. D, Monkey 280 L, 215 days PI. Cribriform and corneoscleral meshwork are dense and collapsed. (LM, semithin sagittal sections, Richardson's stain; x 160.)

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Fig. 3. Inner wall region. A, Monkey 225 R, 54 days diluent. Inner wall region appears normal. SC, Schlemm's canal. B, Monkey 225 L, 54 days PI. Inner wall and cribriform endothelial cells are activated. C, Monkey 110 L, 155 days PI. Arrows indicate fine fibrillar material separating inner wall endothelium from first subendothelial cell layer. D, Monkey 280 L, 215 days PI. Q, Glycogen, (TEM; x5200.)

representing an attempt at regeneration of ment membrane of the trabecular lamellae endothelium. These cell clusters were most and the sheath of elastic-like material within prominent in areas where the trabecular the lamellae were extremely thickened (Fig. meshwork was collapsed and the trabecular 4, A, B). In general, this eye exhibited the endothelial cells were degenerating (Fig. most pronounced changes. 2, C). Ciliary body 215 DAYS PI. Most spaces in the cribriform 54 DAYS PI. The ciliary muscle was strongly region were filled with a fine fibrillar material contracted. However, in contrast to the tri- (Fig. 3, D). In some places, the inner wall angular shape of an acutely contracted mus- endothelium was damaged, as evidenced by cle,11 the muscle here had a more rectangular clusters of degranulated platelets adhering to shape because the anterior edge extended the endothelium. Most cribriform endothe- primarily forward, rather than inward (Fig. lial cells showed signs of degeneration. Some 5). The portion of the muscle occupied by contained large amounts of glycogen particles circular fibers extended farther posteriorly (Fig. 3, D). Over most of the circumference, than normal (Fig. 5). The muscle fibers con- the corneoscleral meshwork was collapsed, tained swollen mitochondria, and the base- and the endothelial cells were in various ment membrane was thickened. These stages of degeneration; in places, the base- changes were most prominent along the

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Fig. 4. Collapsed corneoscleral mesh work. A, Monkey 280 L, 215 days PI. T, Trabecular endothelial cells with enlarged cisteniae of rough surfaced endoplasmic reticulum; arrows indicate thickened basement membrane. B, Higher magnification. Arrowheads indicate thickened sheath of elastic-like material within trabecular lamella. (TEM; A X4500; B x 18,000.)

inner edge of the muscle. The blood vessels cle were in general more pronounced than in in this region and also in the stroma of the the 54 day Pi-treated eye. pars plana were dilated. The ciliary processes The blood vessels in the ciliary muscle and appeared normal over most of the cir- in the stroma of the pars plana were dilated. cumference, but in some parts of the pars In the posterior portion of the ciliary body plana there were small, homogeneous, weak- the stroma adjacent to the dilated blood ves- ly osmiophilic inclusions in the nonpig- sels was filled with neutrophils, lymphocytes, mented epithelium (NPE) and between the plasma cells, and protein-evidence of in- two epithelial layers and slight thickening of flammation (Fig. 7). The stroma of the cho- the basement membrane of the epithelium. roid just posterior to the ora serrata was filled 138 AND 155 DAYS PI. The ciliary muscle with protein. (We did not examine the more extended so far anteriorly that the inner por- posterior portions of the globe.) The inclu- tion was at the level of the anterior part of sions in the NPE and between the epithelial Schlemm's canal, producing a narrow cham- layers of the pars plana were larger and more ber angle (Fig. 5). In some places the muscle numerous than in the 54 day PI-treated eye and the iris root were actually in contact with (Fig. 8). the trabecular meshwork, occluding the an- In the pars plicata, the basement mem- gle. Where the angle was thus closed, all the brane was thickened, and some NPE cells previously described changes in the mesh- contained swollen mitochondria and myelin work were especially striking. There was evi- figures. In some places, the basal portions of dence of severe damage to muscle fibers— both PE and NPE cells contained numerous large vacuoles and markedly thickened small vesicles (Fig. 9). basement membranes—throughout the en- 215 DAYS PI. In this surgically aniridic eye, tire muscle (Fig. 6). The changes in the mus- the inner edge of the ciliary muscle also ex-

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Fig. 5. For legend see facing page.

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tended forward, rather than inward, but not as far forward as in the 138 and 155 day PI- treated eyes, and the muscle was never in contact with the trabecular meshwork. The changes within the muscle fibers, stroma, and epithelium were similar to those in the 138 and 155 day PI-treated eyes. Iris 54, 138, AND 155 DAYS PI. Some of the muscle fibers of the sphincter iridis showed vacuolization and swollen mitochondria. In some areas there was iridocorneal contact anterior to and sparing the trabecular meshwork. In such areas, the corneal endothelium was absent. Lens. All four eyes demonstrated charac- teristic lens opacities.5' 6 Cornea. The corneas remained biomicroscopically normal and the peripheral 1 to 2 mm (the only region studied) appeared light and electron microscopically normal in all four eyes. Diluent-treated eyes Trabecular meshtoork and Schlemm's canal 54 DAYS DILUENT. The trabecular meshwork and Schlemm's canal appeared entirely normal. 155 DAYS DILUENT. The cribriform and trabecular endothelial cells were enlarged and activated, and there was more fine fibrillar material present within the cribriform meshwork than normally. The changes were much less pronounced than in the opposite Pi-treated eye; rather, the meshwork re- sembled that in the 54 day Pi-treated eye. Ciliary body and iris 54 AND 155 DAYS DILUENT. The ciliary body

Fig. 6. Extensively damaged ciliary muscle fiber, Fig. 5. Ciliary muscle. A, Monkey 225 R, 54 days Monkey 110 L, 155 days PI. Asterisks indicate diluent. Contracted (by fixative) ciliary muscle ap- swollen mitochondria; arrows indicate thickened pears normal. T, Trabecular meshwork; SC, basement membrane. (TEM; X 18,600.) Schlemm's canal. Vertical line indicates level of scleral spur; curved line is the demarcation of circular muscle fibers. B, Monkey 225 L, 54 days PI. and iris appeared entirely normal, and there C, Monkey 110 L, 155 days PI. D, Monkey 280 L, was no iridocorneal contact. 215 days PI. Note progressive thinning and an- Lens. The lens remained crystal clear in 5 terior extension of muscle and increase in pro- both eyes. portional area occupied by circular fibers. (LM, Cornea. Both corneas remained biomi- semithin sagittal sections, Richardson's stain; croscopically and light and electron micro- X16.) scopically normal.

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Fig. 7. Posterior pars plana, Monkey 110 L: 155 days PI. PE, Pigmented epithelium; NPE, nonpigmented epithelium; PL, plasma cells; arrowheads indicate inclusions within NPE: arrow indicates collection of inflammatory cells. (LM, semithin sagittal section, Richardson's stain; x 160.)

Fig. 8. Ciliary epithelium, pars plana, Monkey 110 L, 155 days PI. PE, Pigmented epithelium; NPE, nonpigmented epithelium; asterisks indicate inclusions within NPE and between PE and NPE. (TEM; X5000.)

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Fig. 9. Ciliary epithelium, pars plicata, Monkey 110 L, 155 days PI. PE, Pigmented epithelium; NPE, nonpigmented epithelium; V, basal vesicles; M, damaged mitochondria containing myelin figures. (TEM; X5000.)

Discussion muscle might also cause chronic obstruction Chronic topical application of echothio- of uveoscleral drainage17 perhaps preventing phate to the cynomolgus monkey eye causes removal of protein and toxic metabolites from structural alterations in the ciliary muscle, the ciliary body. ciliary processes, iris, and trabecular mesh- Areas of angle closure were seen, as has work. The changes increase in severity with been described in chronically Pi-treated increasing treatment duration, at least up to 7 human eyes.1 Underperfusion of the mesh- months. The pathophysiology of the changes work14 may have contributed to the espe- is unknown. They might be due to cellular cially striking changes in meshwork anatomy effects of acetylcholine or echothiophate it- seen in these areas. self, to inhibition of enzymes other than The eye treated with diluent for 54 days ChEs within the tissues, or to altered aque- appeared entirely normal, but the eye treat- 10 ous humor composition. An altered me- ed with diluent for 155 days showed some of chanical state of the meshwork or ciliary the meshwork changes seen in the Pi-treated muscle, perhaps due to sustained intense eyes. This could represent the effect of PI contraction of the muscle, might also play a absorbed systemically or transferred to the role. Continuous contraction of the ciliary control eye by the monkey rubbing its eyes

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or, far less likely, the effect of a component modation4 and the lens.5' 6' 19 The material of the diluent. We have never observed thus became available in a rather random, ad lens opacities biomicroscopically,5' 18 his- hoc manner. The striking and surprising tologically,19 or microradiographically19 nor findings led us to present these preliminary changes in cholinergic sensitivity of the ac- results. A more rigid and comprehensive ex- commodative3' 4 or aqueous outflow mecha- perimental approach, involving drug dose, nisms2 in chronically diluent-treated monkey treatment duration, surgical and pharma- eyes. cological manipulation, tissue processing, We have insufficient data at present to and morphometric analysis of tissue changes, make definite statements as to reversibility of will be undertaken in future studies. the structural changes after stopping PI We are grateful to Angelika Hauser, Gertrud Link, treatment, but preliminary observations sug- Ka'the Pantel, Waltrant Schlicher, Ingrid Hjelm, Lena gest that the alterations are at least partly Carlsson, Ella-Cari Enqvist, Ann-Marie Wenker, Hans reversible. Eklund, Arne Brostrom, Ake Fondelius, and Jan Melan- The maximum PI dosage employed clini- der for expert technical assistance. cally in glaucoma treatment is one drop of REFERENCES 0.25% PI twice daily. Assuming a drop vol- 1. Kolker, A.E., and Hetherington, J., Jr.: Becker- ume of 50 fx\, this amounts to 125 fxg of PI Shaffer's Diagnosis and Therapy of the Glaucomas, twice daily. Our dosages ranged from 63 to ed. 4, St. Louis, 1976, The C. V. Mosby Co. 250 fig twice daily—that is, from one-half to 2. Kaufman, P. L., and Barany, E.H.: Subsensitivity to twice the maximum clinical dose. However, pilocarpine of the aqueous outflow system in mon- intraocular bioavailability of drug may not be key eyes after topical anticholinesterase treatment, Am. J. Ophthalmol. 82:883, 1976. comparable because of differences in mode of 5 6 3. Kaufman, P. L., and Barany, E.H.: Subsensitivity to application ' and ocular penetration. pilocarpine in primate ciliary muscle following topi- Although other factors may be involved, cal anticholinesterase treatment, INVEST. OPHTHAL- the structural changes in the ciliary muscle MOL. 14:302, 1976. and trabecular meshwork might partly ex- 4. Kaufman, P.L.: Anticholinesterase-induced cholinergic subsensitivity in primate accommodative plain some of the physiological and clinical mechanism, Am. J. Ophthalmol. 85:622, 1978. findings in animal and human eyes chron- 5. Kaufman, P.L., Axelsson, U., and Barany, E.H.: ically treated with long-acting ChE inhib- Induction of subcapsular cataracts in cynomolgus itors: (1) the subsensitivity of the accom- monkeys by echothiophate, Arch. Ophthalmol. modative3' 4 and outflow facility2 response to 95:499, 1977. 6. Kaufman, P.L., Axelsson, U., and Barany, E.H.: pilocarpine in Pi-treated monkeys; (2) the Atropine inhibition of echothiophate cataractogene- tendency for resting outflow facility following sis in monkeys, Arch. Ophthalmol. 95:1262, 1977. ganglionic blockade to be lower in the PI- 7. Kaufman, P. L., and Hahnenberger, R.: CI-744 an- treated eyes of unilaterally Pi-treated mon- esthesia for ophthalmological examination and sur- keys2; (3) the decreased outflow facility of liv- gery in monkeys, INVEST. OPHTHALMOL. 14:788, 1975. ing and enucleated rabbit eyes treated in vivo 8. Kaufman, P. L., and Liitjen-Drecoll, E.: Total with diisopropyl fluorophosphate as com- iridectomy in the primate in vivo: surgical technique 20 21 pared to their untreated opposite eyes ' ; and postoperative anatomy, INVEST. OPHTHALMOL. (4) the gradual loss of the facility-increasing, 14:766, 1975. IOP-lowering effect of ChE inhibitors in 9. Liitjen-Drecoll, E.: Structural factors influencing outflow facility and its changeability under drugs. A some glaucomatous human eyes. The ability study in Macaca arctoides, INVEST. OPHTHALMOL. of pilocarpine to increase facility and lower 12:280, 1973. IOP in such eyes after PI is discontinued1 10. Perry, M.M.: Identification of glycogen in thin sec- might be due to reversibility of the Pi- tions of amphibian embryos, J. Cell Sci. 2:257, 1967. induced changes. 11. Liitjen, E.: Histometrische Untersuchungen uber den Ciliarmuskel der Primaten, Albrecht von The animals presented here were all in- Graefes Arch. Klin. Exp. Ophthalmol. 171:121, volved in various protocols studying the ef- 1966. fects of chronic PI treatment on accom- 12. Rohen, J.W., Liitjen, E., and Barany, E.H.: The

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relation between the ciliary muscle and the trabecu- traocular pressure and some drugs on aqueous flow lar meshwork and its importance for the effect of and entry of cycloleucine into the aqueous humor of miotics on aqueous outflow resistance. A study in vervet monkeys (Cercopithecus ethiops), INVEST. two contrasting monkey species, Macaca irus and OPHTHALMOL. 8:446, 1969. Cercopithecus aethiops, Albrecht von Graefes Arch. 17. Bill, A.: Effects of atropine and pilocarpine on aque- Klin. Exp. Ophthalmol. 172:23, 1967. ous humor dynamics in cynomolgus monkeys 13. Barany, E.H., Linner, E., Lutjen-Drecoll, E., and (Macaca irus), Exp. Eye Res. 6:120, 1967. Rohen, J.W.: Structural and functional effects of 18. Kaufman, P. L., and Axelsson, U.: Induction of sub- trabeculectomy in cynomolgus monkeys, Albrecht capsular cataracts in aniridic vervet monkeys by von Graefes Arch. Klin. Exp. Ophthalmol. 184:1, echothiophate, INVEST. OPHTHALMOL. 14:863, 1975. 1972. 19. Philipson, B., Kaufman, P.L., Fagerholm, P., 14. Lutjen-Drecoll, E., and Barany, E.H.: Functional Axelsson, U., and Barany, E.H.: Echothiophate and electron microscopic changes in the trabecular cataracts in monkeys: electron microscopy and mi- meshwork remaining after trabeculectomy in cyno- croradiography, Arch. Ophthalmol. 97:340, 1979. molgus monkeys, INVEST. OPHTHALMOL. 13:511, 20. Auricchio, G., and Diotallevi, M.: La resistenza al 1974. deflusso in occhi di coniglio dopo prolungato trat- 15. Lutjen-Drecoll, E., Kaufman, P.L., and Barany, tamento con diisopropilfluorofosfato, Ann. Ottal- E.H.: Light and electron microscopy of the anterior mol. Clin. Ocul. 85:493, 1959. chamber angle structures following surgical disin- 21. Auricchio, G., and Diotallevi, M.: Ulteriori ricerche sertion of the ciliary muscle in the cynomolgus mon- sull' influenza esercitata dal DFP sulla resistenza al key, INVEST. OPHTHALMOL. VISUAL SCI. 16:218, deflusso in occhi di coniglio, Ann. Ottalmol. Clin. 1977. Ocul. 85:567, 1959. 16. Walinder, P-E., and Bill, A.: Influence of in-

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