sign in sign up
<<
Home , Betamethasone phosphate, Clobetasone butyrate, Fluorometholone acetate, Prednisolone, Prednisolone acetate

British Journal ofOphthalmology 1992; 76: 681-684 681

MINI REVIEW Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from

Pharmacokinetics of ophthalmic

Corticosteroids have been used by ophthalmologists with an identical vehicle, the aqueous humour concentrations of increasing frequency over the past 30 years, with the these are almost identical.'9 None the less it is concomitant development of a diverse range of drop, essential when considering such empirical data, to recall that ointment, subconjunctival, and oral preparations. Though the systemic anti-inflammatory effect of both the clinical benefits and side effects of such and is five to seven times that of predniso- preparations have been well documented, their basic lone.39"' The local anti-inflammatory potency of ocular in the human eye have yet to be fully steroids has yet to be fully investigated and whilst early work established. Indeed most of our pharmacokinetic knowledge suggested that 1% had the greatest anti- of these drugs has been elucidated by extrapolation of data inflammatory effect in experimental keratitis,'7 later studies obtained from rabbit experiments.1-26 These results can be demonstrated that acetate in a 1% formu- significantly disparate from human data because of the lation was equally efficacious in the same model.26 However, thinner rabbit cornea, lower rabbit blink rate, effect of 1 -0% drops have been shown to signific- general anaesthetic, upright or recumbent position, antly inhibit the tear film polymorphonuclear leucocyte vascularity ofthe rabbit orbital plexus, and small rabbit body response to partial denudation of the corneal epithelium, mass.'827-29 Thus, in general, measurements of con- whereas 0 1% concentrations of prednisolone acetate, dexa- centration in rabbit eyes27 13 19-212425 tend to be significantly , and fluorometholone are ineffective.3 As already higher than those recorded in humans.3135 noted, the absence of corneal epithelium can significantly affect the penetration of topical steroids, and it may also be relevant to the clinical situation that higher corneal concen- Topical ophthalmic drops/ointments trations of steroid may occur in the presence of intraocular These are still the most common methods of administering ,9 whereas the concomitant application of an steroids to the eye and following a single topical drop, drop within 60 seconds of steroid application can steroid is measurable in human aqueous humour within reduce the bioavailability of the applied steroid by almost 15-30 minutes.3132 Not surprisingly, increased steroid 70%.23 It has not been established which concentration of concentration in topical preparations generally results in steroid is desirable for minor ocular inflammatory conditions higher intraocular concentrations,'3 14 but for prednisolone such as postoperative , and whilst concentrations of acetate the optimum dose response effect in experimental 670 ng/ml of prednisolone have been recorded in human keratitis occurs at a 1% concentration, and is not improved aqueous humour,33 perhaps a peak of 25 ng/ml3' might

by further increases in concentration.20 Increasing ocular be sufficient to suppress inflammation and minimise side http://bjo.bmj.com/ contact time by preparing topical steroids in a microsus- effects.4' For comparison, peak timolol concentrations of pension,25 gel, or viscous formulation3536 can double the 2500 ng/ml have been recorded in rabbit aqueous humour corneal and aqueous humour concentrations of steroid following topical application, yet [ receptor blockade can be compared with the same drug applied as a solution.'33536 obtained by as little as 9 ng/ml.42 Other apparently minor changes in formulation, such as Preparation of prednisolone acetate as a gel provides a the addition of benzalkonium, can significantly alter the more prolonged release43 and higher peak aqueous concen-

pharmacokinetics of topical steroids.'3 For these reasons tration when compared with an equivalent topical solution.24 on September 25, 2021 by guest. Protected copyright. many workers chose to use commercially prepared 'off However, some viscous agents and ointments may actually the shelf' steroids in an attempt to unravel differences in produce lower peak ocular concentrations of steroid when pharmacokinetic behaviour, which may be associated with compared with drops.'243 Despite this, owing to prolonged clinical efficacy.'721261321 II37 In contradistinction, the prep- release, a single application of a steroid ointment such as aration of different derivatives in an identical dexamethasone phosphate results in only 25% less overall base vehicle has demonstrated that the greatest barrier to absorption of steroid than a single drop of the same steroid. 2 intraocular penetration is the lipid rich corneal epithelium, It is generally believed that most ofthe topical and, indeed, which retards the ingress of polar, hydrophilic derivatives subconjunctival steroid (see below), enters the eye via the such as prednisolone phosphate,9 126 but is much less of a cornea, thus radiolabelled produces only barrier to lipophilic derivatives such as the alcohol and 2 5% ofthe anticipated aqueous humour concentration when acetate forms of dexamethasone and prednisolone.'5 16202638 corneal penetration is prevented, compared with topical Interestingly, if this epithelial barrier is removed predni- application with free access to the cornea.44 However, for solone phosphate penetrates the cornea in much higher other drugs such as pilocarpine and timolol, penetration into quantities than the lipophilic, acetate derivative.'2 These the iris and ciliary body via the non-corneal route may additive effects of increased concentration, lipophilic deriv- account for drug concentrations which reach almost 10% of ation, and the increased contact time afforded by a micro- the combined corneal and non-corneal route," and such suspension have been demonstrated in humans, where a trans-scleral penetration may be even more important for single drop of prednisolone acetate 1-0% microsuspension larger molecules, such as inulin.4 has been shown to produce intraocular steroid concentrations which were 20-fold those of a single drop of prednisolone phosphate 0 5% solution,3133 and almost 100-fold those of a Periocular injections single drop of 0*l% solution.32 In Repeated subconjunctival injections of prednisolone (50 mg) contrast, when dexamethasone, prednisolone, and fluoro- have been shown to be inferior to hourly topical prednisolone metholone are all formulated at a concentration of 0-1% in acetate 1% drops (6-5 mg) in reducing the inflammatory 682 McGhee response in experimental keratitis.2' Early analytical tech- tact lenses could be presoaked in a drug solution and used as niques suggested that such subconjunctivally injected steroid a form ofdelayed release vehicle.52 A few years later Hull et al Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from entered the eye via the sclera.5 Indeed, the sclera is readily established that hydrophilic contact lenses, presoaked in 1% permeable to even relatively large molecules such as prednisolone phosphate, produced an aqueous humour peak albumin,* and therefore, not surprisingly, high levels of concentration that was three to fourfold that obtained by corticosteroid can be detected in the sclera underlying a application of topical drops and this advantage was main- subconjunctival injection site.5 However, the greater con- tained at 4 hours.53 The search for a topically applied, centration of such steroid appears to enter the eye by slow release drug system in other areas led to the successful diffusing through the puncture site in the conjunctiva into development of pilocarpine ocuserts, which though not the tear film, and thence via the cornea into the intraocular widely used, and despite some limitations, have been shown milieu.'I4 to be a viable alternative to topical drops in certain patients.54 In this context it is not unexpected that sub-Tenon's Similarly, early soluble inserts presoaked in injections of methyl prednisolone in monkeys produced produced higher tear film and corneal concentra- significant anterior segment steroid concentrations (approx tions of gentamicin than gentamicin administered in drop, 25 ng/ml) but could only produce peak vitreous concen- ointment, or subconjunctival form.55 The development of trations of 2 ng/ml.47 In contrast, retrobulbar methyl dissolving collagen shields has rekindled interest in this prednisolone in the same model produced much higher method of delivering ophthalmic drugs and such shields posterior uveal/retinal concentrations and significant presoaked in tobramycin have been well tolerated by vitreous levels which persisted for up to 9 days.48 These patients56 and have been shown to produce higher aqueous discrepancies might be partly explained by the lack of post- and corneal concentrations of tobramycin than subcon- equatorial diffusion of drug following subconjunctival and junctival injections.57 Collagen shields have also been sug- sub-Tenon's injections.29 It is notable that, in contrast to gested as the optimum vehicle for poorly soluble drugs such the enhanced corneal penetration of topical steroid drops as cyclosporin.58 Recently it has been demonstrated that previously noted in intraocular inflammation, when a peri- collagen shields presoaked in dexamethasone alcohol pro- bulbar injection is used, total ocular steroid levels may duce superior intraocular concentrations of dexamethasone actually be lower in eyes with intraocular inflammation than hourly drops over the first 4 hours, and that a compared with uninflamed eyes.29 combination of a presoaked shield and hourly topical drops The inherent risks of peribulbar injection of steroid (see doubles the cumulative delivery of steroid to the eye at below) and the availability ofalternative, superior methods of 6 hours when compared with hourly drops alone.59 For those application, suggest to the author, in the context of the looking for the ideal short term sustained release vehicle, and preceding data, that the role ofperibulbar injection is limited a safe yet superior alternative to subconjunctival injections, to the operating room and to a few other selected situations collagen shields would appear to provide increased compli- where frequent topical is not practicable. The ance, better 24 hour control, higher ocular drug concentra- short term local use of orbital floor steroids in non- tions than comparable methods of administration, and necrotising may be such an exception to this," good patient tolerance. However, like pilocarpine ocuserts whereas the role of retrobulbar steroid in the treatment of they have yet to gain wide acceptance by clinicians and persistent macular oedema remains unresolved.50 whether, like ocuserts, they will fail to gain a regular place in our pharmacological armamentarium, owing to limitations

yet to be identified, remains to be seen. In a note of caution, http://bjo.bmj.com/ Systemic administration it has already been highlighted that certain antibiotic and When one considers the bodywide distribution ofa systemic- steroid combinations in collagen shields may provoke ally administered steroid, it is easy to comprehend the adverse corneal reactions.? dramatically larger steroid doses required to equal the previously noted aqueous humour concentrations produced by topical drops; however, the extent of this disparity is Intravitreal injection, liposomes, and iontophoresis seldom fully appreciated. In the rabbit it has been shown that Whilst intravitreal injections of have become a on September 25, 2021 by guest. Protected copyright. an intravenous dose of 25 mg dexamethasone (equivalent to standard technique in the treatment of endophthalmitis the 500 mg in a 70 kg man!) was required to produce aqueous use of intravitreal steroids in ophthalmology is less well humour levels which were comparable with those achieved established. Ocular dialysis has demonstrated that after following topical dexamethasone alcohol drops, whereas a subconjunctival gentamicin, virtually no gentamicin is similar intravenous dose of prednisolone. only achieved 50% recorded in the vitreous, whereas intravitreal injection of of the peak aqueous concentration obtained by four drops of gentamicin may produce significant levels with a half life methyl prednisolone 0.5%.2 Similarly, intramuscular methyl of up to 22 hours.6' In contrast, intravitreally injected prednisolone in squirrel monkeys produced total ocular dexamethasone appears to have a halflife of3 hours with only tissue concentrations, and vitreous concentrations in par- 10% of the peak concentration remaining at 8 hours, ticular, which were less than 1% of those obtained by a although concentrations of 50 ng/ml may persist for up similar dose given as a periocular injection.' Indeed, to 4 days.62 maximal intraocular steroid concentration may actually The incorporation of drugs into liposomes has demon- represent as little as 0 5% of an intravenous dose.9 That strated an up to 10 times improvement in the intraocular systemic steroids have an important role in ophthalmic penetration of hydrophilic drugs following topical applica- practice, such as the treatment of corneal graft rejection,5' is tion.63 However, possibly because the commonly used not in question, but they must be used in the knowledge that ophthalmic steroids such as dexamethasone alcohol, they act by primarily affecting the systemic limb of ocular prednisolone acetate, and fluorometholone are already disease and that there are superior, local, alternative lipophilic, there has, as yet, been little utilisation ofliposome methods of producing significant intraocular concentrations delivery for steroids. Transcorneal and trans-scleral ionto- of steroid, if that is what is desired. phoresis of polar drugs, which normally penetrate these structures poorly, remain largely experimental, though the trans-scleral iontophoresis of dexamethasone phosphate can Coliagen shields and contact lenses produce higher vitreous concentrations than the retrobulbar, Waltman and Kaufmann demonstrated that hydrophilic con- subconjunctival, or topical routes.'9 Pharmacokinetics ofophthalmic corticosteroids 683

Side effects of ophthalmic steroids injected C14 hydrocortisone. Part 1. Time and major route of penetration in a normal eye. Am]fOphthalmol 1964; 58: 362-6. The adverse effects of systemic steroids are well known to 5 McCartney HJ, Drysdale IO, Gornall AG, Basu PK. An autoradiographic Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from ophthalmologists, therefore local administration is often seen study ofthe penetration ofsubconjunctivally injected hydrocortisone into the normal and inflamed rabbit eye. Invest Ophthalmol Vis Sci 1965; 4: 297-302. as a logical method of minimising such side effects.49 Some 6 Murdick PW, Keates RH, Donovan EF, Wyman M, Short C. Ocular local applications are not without obvious inherent risks such penetration studies. II. Topical administration of prednisolone. Arch Ophthalmol 1966; 76: 602-3. as bulbar perforation, choroidal injection, central retinal 7 Short C, Keates RH, Donovan EF, Wyman M, Murdick PW. Ocular artery occlusion, muscle imbalance and persistently raised penetration studies. I. Topical administration of dexamethasone. Arch Ophthalmol 1966; 75: 689-92. intraocular pressure following the periocular injection of 8 McDonald TO, Borgmann AR, Roberts MD, Fox LG. Corneal wound healing. steroids.65"7 Additionally, systemic absorption of periocular I. Inhibition of stromal healing by three dexamethasone derivatives. Invest Ophthalmol Vis Sci 1970; 9: 703-9. steroids in rabbits has been noted to decrease circulating 9 Cox WV, Kupferman AS, Leibowitz HM. Topically applied steroids in corneal lymphocytes and antibodies,27 and to reduce the total white disease. I. The role of inflammation in stromal absorption ofdexamethasone. Arch Ophthalmol 1972; 88: 308-13. blood cell count.22 Surprisingly, considering the small 10 McDonald TO, Kasten K, Hervey R, Gregg S, Smith D, Robb CA. volume of steroid administered, topical drop application of Comparative of dexamethasone and its tertiary butyl acetate ester after topical instillation in rabbits. Am]fOphthalmol 1973; 76: 117-25. steroid in rabbits produces significant liver, urine, and 11 Krupin T, Waltman SR, Becker B. Ocular penetration in rabbits of topically plasma concentrations36 and by 30 minutes almost a third of applied dexamethasone. Arch Ophthalmol 1974; 92: 312-4. 12 Kupferman A, Pratt MV, Suckewer K, Leibowitz HM. Topically applied the applied steroid is distributed systemically,3 with less than steroids in corneal disease. III. The role of drug derivative in stromal 5% of the administered steroid being recoverable from the absorption of dexamethasone. Arch Ophthalmol 1974; 91: 373-6. 13 Green K, Downs SJ. Prednisolone phosphate penetration into and through the eye.39 Owing to this significant systemic dissemination of cornea. Invest Ophthalmol 1974; 13: 316-8. steroid, topical application inhibits corneal wound healing 14 Kupferman A, Leibowitz HM. Topically applied steroids in corneal disease. IV. The role of drug concentration in stromal absorption of prednisolone in both the treated and the untreated, contralateral eye in acetate. Arch Ophthalmol 1974; 91: 377-80. rabbits.28 In larger experimental animals, following eight 15 Kupferman A, Leibowitz HM. Topically applied steroids in corneal disease. V. Dexamethasone alcohol. Arch Ophthalmol 1974; 92: 329-30. drops of prednisolone acetate 1-0% per day (4 mg of 16 Hull DS, Hine JE, Edelhauser HF, Hynduik RA. Permeability of the isolated prednisolone per day), both small dogs68 and large rabbit cornea to corticosteroids. Invest Ophthalmol 1974; 13: 457-9. 17 Leibowitz HM, Kupferman A. Anti-inflammatory effectiveness in the cornea (27-41 kg)69 have exhibited adrenal suppression, though the of topically administered prednisolone. Invest Ophthalmol 1974; 13: 757-61. adrenal axis is more readily suppressed in dogs than in 18 Sieg JW, Robinson JR. Corneal absorption of fluorometholone in rabbits. Arch Ophthalmol 1974; 92: 240-3. humans.6869 In humans, the systemic absorption of topically 19 Yamauchi H, Kito H. Studies on intraocular penetration and metabolism of applied drugs such as I blockers is well established,70 whereas fluorometholone in rabbits: a comparison between dexamethasone and prednisolone acetate.]7pn] Ophthalmol 1975; 19: 339-47. the systemic effects of topical ocular steroids is less clearly 20 Leibowitz HM, Kupferman A. Kinetics of topically administered prednisolone defined, and whilst Burch71 observed a 50% decrease in acetate. Arch Ophthalmol 1976; 94: 1387-9. 21 Kupferman A, Leibowitz HM. Biological equivalence of ophthalmic predni- endogenous steroid production in male volunteers given solone acetate suspensions. Am] Ophthalmol 1976; 82: 109-13. hourly dexamethasone 0-01% drops (0 75 mg dexamethasone 22 Leibowitz HM, Kupferman A. Periocular injection of corticosteroids. An experimental evaluation of its role in the treatment of corneal inflammation. per day) for 6 days. Krupin72 demonstrated a reduction in Arch Ophthalmol 1977; 95: 311-4. endogenous plasma but no adrenal axis suppression 23 Leibowitz HM, Kupferman A. Drug interaction in the eye. Concurrent corticosteroid-antibiotic therapy for inflammatory keratitis. Arch Ophthalmol following eight drops of dexamethasone 0-1% per day for 1977; 95: 682-5. 6 weeks. It seems reasonable, therefore, to suggest that the 24 Schoenwald RD, Boltralik JJ. A bioavailability comparison in rabbits of two steroids formulated as high-viscosity gels and reference aqueous prepara- possibility ofadrenal suppression should be considered when tions. Invest Ophthalmol Vis Sci 1979; 18: 61-6. ophthalmologists employ intensive topical steroids such as 25 Schoenwald RD, Stewart P. Effect ofparticle size on ophthalmic bioavailability of dexamethasone suspensions in rabbits.] Pharm Sci 1980; 69: 391-4. prednisolone acetate 1 0% and dexamethasone 0 1%. 26 Kupferman A, Berrospi AR, Leibowitz HM. . A new ophthalnic derivative of fluorometholone. Arch Ophthalmol 1982; 100:

640-1. http://bjo.bmj.com/ 27 Smolin G, Hall JM, Okumuto M, Ohno S. High doses of subconjunctival corticosteroid and antibody-forming cells in the eye and draining lymph Conclusion nodes. Arch Ophthalmol 1977; 95: 1631-3. Although more information on ophthalmic steroids in 28 Sugar J, Chandler JW. Experimental corneal wound strength. Arch Ophthalmol on data 1974; 92: 248-9. humans is becoming available, we still rely heavily 29 Levine ND, Aronson SA. Orbital infusion of steroids in the rabbit. Arch derived from animal models. Fortunately, while some of the Ophthalmol 1970; 83: 599-607. data are the trends appear to be 30 Watson D, Noble MJ, Dutton GN, Midgley JM, Healey TM. Penetration of animal conflicting, general topically applied dexamethasone alcohol into human aqueous humor. Arch similar in humans, though the magnitude of intraocular 106: 686-7. Ophthalmol 1988; on September 25, 2021 by guest. Protected copyright. 31 McGhee CNJ, Noble MJ, Watson DG, Dutton GN, Fern Al, Healey TM, et al. steroid penetration in humans appears less. The marked Penetration of topically applied prednisolone sodium phosphate into human differences in pharmacokinetic behaviour illustrated by aqueous humour. Eye 1989; 3: 463-7. concentrations of the same in different 32 Watson DG, McGhee CNJ, Midgley JM, Dutton GN, Noble MJ. Penetration identical steroid, of topically applied betamethasone sodium phosphate into human aqueous topical drop formulations, does mean that generic equival- humour. Eye 1990; 4: 603-6. ence cannot be assumed between merely on 33 McGhee CNJ, Watson DG, Midgley JM, Noble MJ, Dutton GN, Fern AI. preparations Penetration of synthetic corticosteroids into human aqueous humour. Eye the basis of equivalent steroid content. Topical and local 1990; 4:526-30. application of steroids appears preferable to systemic 34 McGhee CNJ, Watson DG, Midgley JM, Pyott AA, Fern AI. Penetration of fluorometholone into human aqueous humour. Eye 1992 (submitted for administration wherever possible; however, the limitations publication). of, and alternatives to, subconjunctival injection should be 35 Watson DG, Midgley JM, McGhee CNJ. The analysis ofcorticosteroid by GC-NIC-mass spectrometry. Rapid Communications in Mass Spectrometry carefully considered, as should the possibility of adrenal 1989; 1: 8-10. intensive 36 Rosenblum C, Dengler RE, Geoffroy RF. Ocular absorption of dexamethasone suppression following ophthalmic corticosteroid phosphate disodium by the rabbit. Arch Ophthalmol 1967; 77: 234-7. drops in children and small adults. 37 Srinivasan 0, Kulkarni PS. Polymorphonuclear leukocyte response. Inhibition CHARLES N J McGHEE following corneal epithelial denudation by steroidal and anti- inflammatory agents. Arch Ophthalmol 1981; 99: 1085-9. Tennent Institute of Ophthalmology, 38 Flint GR, Morton DJ. Effect of derivatization on the bioavailability of ophthalnic steroids. Development of an in vitro method of evaluation. Arch Western Infirmary, Glasgow and Ophthalmol 1984; 102: 1808-9. Division of Pharmaceutical Chemistry, 39 Havener WH. Corticosteroid therapy. In: WH Havener, ed. Ocular pharmaco- Department of Pharmacy, logy, 5th Ed. St Louis: Mosby, 1983: 433-500. University of Strathclyde, 40 Haynes RC, Murad F. In: Goodman LS, Gilman AG, eds. Goodman and Glasgow Gilman's: The pharmacological basis of therapeutics, 7th Ed. New York: Macmillan, 1985: 1475-7. 41 Eilon A, Walker SR. Clinical evaluation of butyrate eye drops in 1 Welmar VL, Irving LH. Intraocular penetration of local hydrocortisone and the treatment of anterior uveitis and its effect on intraocular pressure. Br] . AMA Arch Ophthalmol 1954; 52: 769-73. Ophthalmol 1981; 65: 644-7. 2 Irving LH, Kroman HS. Methyl and fluoro substituted prednisolones in the 42 Havener WH. Autonomic drugs. In: WH Havener, ed. Ocular pharmacology, blood and aqueous humor of the rabbit. Arch Ophthalmol 1960; 63: 943-7. 5th Ed. St Louis: Mosby, 1983: 302-7. 3 Janes RG, Stiles JF. The penetration of cortisol into normal and pathologic 43 Kupferman A, Ryan WJ, Leibowitz HM. Prolongation of anti-inflammatory rabbit eyes. Am] Ophthalmol 1965; 59: 84-90. effect of prednisolone acetate. Influence of formulation in high-viscosity gel. 4 Wine NA, Gornall AG, Basu PK. The ocular uptake of subconjunctivally Arch Ophthalmol 1981; 99: 2028-9. 684 McGhee

44 Doane MG, Jensen AD, Dohlman CH. Penetration routes of topically applied mental corneal allograft rejection in rabbits using cyclosporin-collagen

eye medication. AmJ Ophthalmol 1978; 85: 383-6. shields. Graefes Arch Clin Exp Ophthalmol 1991; 229: 69-74. Br J Ophthalmol: first published as 10.1136/bjo.76.11.681 on 1 November 1992. Downloaded from 45 Ahmed I, Patton TF. kmportance of the noncorneal absorption route in topical 59 Hwang DG, Stern WH, Hwang PH, MacGowan-Smith LA. Collagen shield ophthalmic drug delivery. Invest Ophthalmol Vis Sci 1985; 26: 584-7. enhancement of topical dexamethasone penetration. Arch Ophthalmol 1989; 46 Bill A. Movement ofalbumin and dextran through the sclera. Arch Ophthalmol 107: 1375-80. 1965; 74:248-52. 60 Friedberg ML, Plewer U, Mondino BJ. Device drug delivery to the eye: 47 Hynduik RA. Radioactive depot-corticosteroid penetration into monkey ocular collagen shields, iontophoresis, and pumps. Ophthalmology 1991; 98: tissue. Arch Ophthalmol 1969; 82: 259-62. 725-32. 48 Hyndiuk RA, Reagan MG. Radioactive depot-corticosteroid penetration into 61 Ben-Nun J, Cooper RL, Cringle SJ, Constable IJ. Ocular dialysis: a new monkey ocular tissue: retrobulbar and systemic administration. Arch technique for in vivo intraocular pharmacokinetic measurements. Arch Ophthalmol 1968; 80: 499-503. Ophthalmol 1988; 106: 254-9. 49 Hakin KN, Ham J, Lightman SL. Use of orbital floor steroids in the 62 Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment management of patients with uniocular non-necrotising scleritis. Br J of experimentally induced endophthalmitis. Arch Ophthalmol 1974; 92: Ophthalmol 1991; 75: 337-9. 149-54. 50 Jennings T, Rusin MM, Tessler HH, Cunha-vas JG. Posterior sub-Tenon's 63 Schaeffer HE, Krohn DL. Liposomes in topical drug delivery. Invest injections of corticosteroids in uveitis patients with cystoid macular edema. Ophthalmol VisSci 1982; 21: 220-7. JpnJ Ophthalmol 1988; 32: 385-91. 64 Lam TT, Edward DP, Zhu XA, Tso MO. Trans-scleral iontophoresis of 51 Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral dexamethasone. Arch Ophthalmol 1989; 107: 1368-71. versus single pulse therapy. Ophthalmology 1991; 98: 329-33. 65 Ellis PP. Occlusion of the central retinal artery after retrobulbar corticosteroid 52 Waltman SR, Kaufman HE. Use of hydrophilic contact lenses to increase injection. AmJ Ophthalmol 1978; 85: 352-6. ocular penetration oftopical drugs. Invest Ophthalmol Vis Sci 1970; 9: 250-5. 66 Raab EL. Limitation ofmotility after periocular corticosteroid injection. AmJ7 53 Hull DS, Edelhauser HF, Hyndiuk RA. Ocular penetration of prednisolone Ophthalmol 1974; 78: 996-8. and the hydrophilic contact lens. Arch Ophthalmol 1974; 92: 413-6. 67 Kalina RE. Increased intraocular pressure following subconjunctival cortico- 54 Quigley HA, Pollack IP, Harbin TS. Pilocarpine ocuserts. Long-term clinical steroid administration. Arch Ophthalmol 1969; 81: 788-90. trials-'and selected . Arch Ophthalmol 1975; 93: 68 Roberts SM, Lavach JD, Macy DW, Severin GA. Effect of ophthalmic 771-5. prednisolone acetate on the canine adrenal gland and hepatic function. AmJ7 55 Bloomfield SE, Miyata T, Dunn MW, Bueser N, Stenzel KH, Rubin AL. Vet Res 1984; 45: 1711-4. Soluble gentamicin ophthalmic inserts as a drug delivery system. Arch 69 Eichenbaum JD, Macy DW, Severin GA. Effect in large dogs of ophthalmic Ophthalmol 1978; 95: 885-7. prednisolone acetate on adrenal gland and hepatic function. JAm Anim Hosp 56 Poland DE, Kaufman HE. Clinical uses ofcollagen shields. J Cataract Refract Ass 1988; 24: 705-9. Surg 1988; 14: 489-91. 70 Salminen L. Systemic absorption of topically applied ocular drugs in humans. 57 Unterman SR, Rootman DS, Hill JM, Parelman JJ, Thompson HW, Kaufman J OcularPharmacol 1990; 6: 243-9. HE. Collagen shield drug delivery: therapeutic concentrations oftobramycin 71 Burch RG, Migeon CJ. Systemic absorption of topical steroids. Arch in the rabbit cornea and aqueous humour. J Cataract Refract Surg 1988; 14: Ophthalmol 1968; 79: 174-6. 500-3. 72 Krupin T, Mandell Al, Podos SM, Becker B. Topical corticosteroid therapy 58 Mahlberg K, Uusit.alo RJ, Gebhardt B, Kaufman HE. Prevention of experi- and pituitary-adrenal function. Arch Ophthalmol 1976; 94: 919-20. http://bjo.bmj.com/ on September 25, 2021 by guest. Protected copyright.