Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

Pastor, J.C., De La Rua, E.R., Martin, F. (2002). Proliferative vitreoretinopathy: risk factors and pathobiology. Prog. Retin. Eye Res. 21(1), 127–144.

Perkins, T.W., Faha, B., Ni, M., Kiland, J.A., Poulsen, G.L., Antelman, D., Atencio, I., Shinoda, J., Sinha, D., Brumback, L., Maneval, D., Kaufman, P.L., Nickells, R.W. (2002). Adenovirus-mediated gene therapy using human p21WAF-1/Cip-1 to prevent wound healing in a rabbit model of glaucoma filtration surgery. Arch. Ophthalmol. 120(7), 941–949.

Poonyathalang, A., Preechawat, P., Charoenkul, W., Tangtrakul, P. (2005). Retrobulbar injection of triamcinolone in thyroid associated orbitopathy. J. Med. Assoc. Thai. 88(3), 345–349.

Rabowsky, J.H., Dukes, A.J., Lee, D.A., Leong, K.W. (1996). The use of bioerodible polymers and daunorubicin in glaucoma filtration surgery. Ophthalmology 103, 800–807.

Razzaque, M.S., Foster, C.S., Ahmed, A.R. (2003). Role of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid. Invest. Ophthalmol. Vis. Sci. 44(5), 1998–2003.

Reich, S.J., Fosnot, J., Kuroki, A., Tang, W., Yang, X., Maguire, A.M., Bennett, J., Tolentino, M.J. (2003). Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vis. 9, 210–216.

Rich, R.M., Rosenfeld, P.J., Puliafito, C.A., Dubovy, S.R., Davis, J.L., Flynn, H.W. Jr, Gonzalez, S., Feuer, W.J., Lin, R.C., Lalwani, G.A., Nguyen, J.K., Kumar, G. (2006). Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 26(5), 495–511.

Roberts, A.B., Tian, F., Byfield, S.D., Stuelten, C., Ooshima, A., Saika, S., Flanders, K.C. (2006). Smad3 is key to TGF-beta-mediated epithelial-to-mesen- chymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev. 17(1–2), 19–27.

Rosenfeld, P.J., Brown, D.M., Heier, J.S., Boyer, D.S., Kaiser, P.K., Chung, C.Y., Kim, R.Y. (2006). Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355(14), 1419–1431.

Rosenfeld, P.J., Moshfeghi, A.A., Puliafito, C.A. (2005). Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration.

Ophthalmic Surg. Lasers Imaging 36(4), 331–335. Rubinfeld, R.S., Pfister, R.R., Stein, R.M., Foster, C.S.,

Martin, N.F., Stoleru, S., Talley, A.R., Speaker, M.G. (1992). Serious complications of topical mitomycin C after pterygium surgery. Ophthalmology 99, 1647–1654.

Saika, S., Ikeda, K., Yamanaka, O., Flanders, K.C., Ohnishi, Y., Nakajima, Y., Muragaki, Y., Ooshima, A. (2006). Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mes- enchymal transition of lens epithelium in mice. Am. J. Physiol. Cell Physiol. 290(1), C282–C289.

Saika, S., Ikeda, K., Yamanaka, O., Sato, M., Muragaki, Y., Ohnishi, Y., Ooshima, A., Nakajima, Y., Namikawa, K.,

Kiyama, H., Flanders, K.C., Roberts, A.B. (2004a). Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab. Invest. 84(10), 1259–1270.

Saika, S., Kono-Saika, S., Tanaka, T., Yamanaka, O., Ohnishi, Y., Sato, M., Muragaki, Y., Ooshima, A., Yoo, J., Flanders, K.C., Roberts, A.B. (2004b). Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice. Lab. Invest. 84(10), 1245–1258.

Saika, S., Ooshima, A., Yamanaka, O., Okada, Y., Tanaka, S., Ohnishi, Y. (1996). Effect of fibrostatin C, an inhibitor of prolyl 4-hydroxylase, on collagen secretion by human Tenon’s capsule fibroblasts in vitro. Graefe’s Arch. Clin. Exp. Ophthalmol. 234(Suppl. 1), S214–S222.

Saika, S., Yamanaka, O., Ikeda, K., Kim-Mitsuyama, S., Flanders, K.C., Yoo, J., Roberts, A.B., NishikawaIshida, I., Ohnishi, Y., Muragaki, Y., Ooshima, A. (2005). Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells.

Lab. Invest. 85(7), 838–850.

Sakaguchi, H., Takai, S., Sakaguchi, M., Sugiyama, T., Ishihara, T., Yao, Y., Miyazaki, M., Ikeda, T. (2002). Chymase and angiotensin converting enzyme activities in a hamster model of glaucoma filtering surgery. Curr. Eye Res. 24(5), 325–331.

Schiller, M., Javelaud, D., Mauviel, A. (2004). TGF- beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J. Dermatol. Sci. 35(2), 83–92.

Secchi, A.G., Tognon, M.S. (1996). Intraoperative mitomycin C in the treatment of cicatricial obliterations of conjunctival fornices. Am. J. Ophthalmol. 122(5), 728–730.

Shaunak, S., Thomas, S., Gianasi, E., Godwin, A., Jones, E., Teo, I., Mireskandari, K., Luthert, P., Duncan, R., Patterson, S., Khaw, P., Brocchini, S. (2004). Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat. Biotechnol. 22(8), 977–984.

Sheridan, C.M., Occleston, N.L., Hiscott, P., Kon, C.H., Khaw, P.T., Grierson, I. (2001). Matrix metalloproteinases: a role in the contraction of vitreo-retinal scar tissue. Am. J. Pathol. 159(4), 1555–1566.

Shigeeda, T., Tomidokoro, A., Chen, Y.N., Shirato, S., Araie, M. (2006). Long-term follow-up of initial trabeculectomy with mitomycin C for primary open-angle glaucoma in Japanese patients. J. Glaucoma 15(3), 195–199.

Shin, D.H., Kim, Y.Y., Ren, J., Weatherwax, A.L., Pearlman, R.B., Kim, C., Glover, K.B., Muenk, S.B. (1998). Decrease of capsular opacification with adjunctive mitomycin C in combined glaucoma and cataract surgery. Ophthalmology 105(7), 1222–1226.

Shinohara, K., Tanaka, M., Sakuma, T., Kobayashi, Y. (2003). Efficacy of daunorubicin encapsulated in liposome for the treatment of proliferative vitreoretinopathy. Ophthalmic Surg. Lasers Imaging 34(4), 299–305.

Singh, K., Mehta, K., Shaikh, N.M., Tsai, J.C., Moster, M.R., Budenz, D.L., Greenfield, D.S., Chen, P.P.C.J.S., Baerveldt, G.S., Shaikh, S. (2000). Trabeculectomy with intraoperative mitomycin C versus 5-fluoro- uracil. Prospective randomized clinical trial.

Ophthalmlogy 107, 2305–2309.

Siriwardena, D., Khaw, P.T., King, A.J., Donaldson, M.L., Overton, B.M., Migdal, C., Cordeiro, M.F. (2002). Human antitransforming growth factor beta(2) monoclonal antibody – a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study. Ophthalmology 109(3), 427–431.

Spaide, R.F., Sorenson, J., Maranan, L. (2003). Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 110(8), 1517–1525.

Spinks, R.L., Baker, S.N., Jackson, A., Khaw, P.T., Lemon, R.N. (2003). Problem of dural scarring in recording from awake, behaving monkeys: a solution using 5-fluorouracil. J. Neurophysiol. 90(2), 1324–1332.

Sponer, U., Pieh, S., Soleiman, A., Skorpik, C. (2005). Upregulation of alphavbeta6 integrin, a potent TGFbeta1 activator, and posterior capsule opacification.

J. Cataract Refract. Surg. 31(3), 595–606.

Spoor, T.C., McHenry, J.G., Shin, D.H. (1995). Longterm results using adjunctive mitomycin C in optic nerve sheath decompression for pseudotumor cerebri. Ophthalmology. 102, 2024–2028.

Stramer, B.M., Zieske, J.D., Jung, J.C., Austin, J.S., Fini, M.E. (2003). Molecular mechanisms controlling the fibrotic repair phenotype in cornea: implications for surgical outcomes. Invest. Ophthalmol. Vis. Sci.

44(10), 4237–4246.

Symonds, J.G., Lovicu, F.J., Chamberlain, C.G. (2006). Differing effects of dexamethasone and diclofenac on posterior capsule opacification-like changes in a rat lens explant model. Exp. Eye Res. In press.

Tseng, S.C., Di Pascuale, M.A., Liu, D.T., Gao, Y.Y., Baradaran-Rafii, A. (2005). Intraoperative mitomycin C and amniotic membrane transplantation for fornix reconstruction in severe cicatricial ocular surface diseases. Ophthalmology 112(5), 896–903.

Tsuchiya, T., Ayaki, M., Onishi, T., Kageyama, T., Yaguchi, S. (2003). Three-year prospective randomized study of incidence of posterior capsule opacification in eyes treated with topical diclofenac and betamethasone. Ophthalmic Res. 35(2), 67–70.

Turacli, E., Gunduz, K., Aktan, G., Tamer, C. (1996). A comparative clinical trial of mitomycin C and cyclosporin A in trabeculectomy. Eur. J. Ophthalmol. 6(4), 398–401.

Usui, T., Ishida, S., Yamashiro, K., Kaji, Y., Poulaki, V., Moore, J., Moore, T., Amano, S., Horikawa, Y., Dartt, D., Golding, M., Shima, D.T., Adamis, A.P. (2004). VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest. Ophthalmol. Vis. Sci.

45(2), 368–374.

Watts, K.L., Sampson, E.M., Schultz, G.S. (2005). Simvastatin inhibits growth factor expression and modulates profibrogeneic markers in lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 32, 290–300.

Wells, A.P., Bunce, C., Khaw, P.T. (2004). Flap and suture manipulation after trabeculectomy with adjustable sutures: titration of flow intraocular pressure in guarded filtration surgery. J. Glaucoma. In press.

Wells, A.P., Cordeiro, M.F., Bunce, C., Khaw, P.T. (2003). Cystic bleb formation and related complications in limbus versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C. Ophthalmology 110(11), 2192–2197.

Weng, D.E., Usman, N. (2001). Angiozyme: a novel angiogenesis inhibitor. Curr. Oncol. Rep. 3(2), 141–146.

Wiedemann, P., Hilgers, R.D., Bauer, P., Heimann, K. (1998). Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Daunomycin Study Group. Am. J. Ophthalmol. 126(4), 550–559.

Wiersinga, W.M., Prummel, M.F. (2001). Pathogenesis of Graves’ ophthalmopathy – current understanding. J. Clin. Endocrinol. Metab. 86(2), 501–503.

Wilson, S.E., Liu, J.J., Mohan, R.R. (1999). Stromal-epi- thelial interactions in the cornea. Progress in Retinal and Eye Research 18(3), 293–309.

Wong, H.T., Seah, S.K., Tym, W.H. (1999). Augmentation of filtering blebs with perfluoropropane gas bubble: an experimental and pilot clinical study. Ophthalmology 106(3), 545–549.

Wong, T.T., Daniels, J.T., Crowston, J.G., Khaw, P.T. (2004). MMP inhibition prevents human lens epithelial cell migration and contraction of the lens capsule. Br. J. Ophthalmol. 88(7), 868–872.

Wong, T.T., Mead, A.L., Khaw, P.T. (2003). Matrix metalloproteinase inhibition modulates postoperative scarring after experimental glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci. 44(3), 1097–1103.

Wong, T.T., Mead, A.L., Khaw, P.T. (2005). Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci. 46(6), 2018–2022.

Wormstone, I.M., Tamiya, S., Anderson, I., Duncan, G. (2002). TGF beta2 induced matrix modification and cell transdifferentiation in the human lens capsular bag. Invest. Ophthalmol. Vis. Sci. 43(7), 2301–2308.

Wu, X.Y., Yang, Y.M., Guo, H., Chang, Y. (2006). The role of connective tissue growth factor, transforming growth factor beta1 and Smad signaling pathway in cornea wound healing. Chin. Med. J. (Engl.) 119(1), 57–62.

WuDunn, D. (1997). Intracameral urokinase for dissolution of fibrin or blood clots after glaucoma surgery. Am. J. Ophthalmol. 124(5), 693–695.

Yasukawa, T., Kimura, H., Tabata, Y., Ogura, Y. (2001). Biodegradable scleral plugs for vitreoretinal drug delivery. Adv. Drug Deliv. Rev. 52(1), 25–36.

You, Y.A., Fang, C.T. (2001). Intraoperative mitomycin C in dacryocystorhinostomy. Ophthal. Plast. Reconstr. Surg. 17(2), 115–119.

Young, A.L., Leung, G.Y., Wong, A.K., Cheng, L.L., Lam, D.S. (2004). A randomised trial comparing 0.02% mitomycin C and limbal conjunctival autograft after excision of primary pterygium. Br. J. Ophthalmol. 88(8), 995–997.

Zaczek, A., Laurell, C.G., Zetterstrom, C. (2004). Posterior capsule opacification after phacoemulsification in patients with postoperative steroidal

and nonsteroidal treatment. J. Cataract Refract. Surg. 30(2), 316–320.

Zhang, X., Barile, G., Chang, S., Hays, A., Pachydaki, S., Schiff, W., Sparrow, J. (2005). Apoptosis and cell proliferation in proliferative retinal disorders: PCNA, Ki-67, caspase-3, and PARP expression. Curr. Eye Res. 30(5), 395–403.

Zimmermann, T.J. et al. (1997) Textbook of Ocular Pharmacology. Lippincott Raven, Philadelphia.

I. INTRODUCTION

Rapid advancements have been made in recent years in the field of anterior segment surgery. New instruments allow for more precise wound creation, while new sutures provide better tensile strength and result in less inflammation. In addition, phacoemulsification machines are more reliable and provide improved fluidics. In comparison, there has been relatively little major advancement in the field of ocular therapeutic medications for anterior segment surgery. Most advances in drug therapy

have represented minor changes in chemical structure or method of preservation of already existing medications.

Four classes of ophthalmic medications predominate for anterior segment surgery. These are (1) non-steroidal antiinflammatory drugs (NSAIDs); (2) steroids;

(3) antibiotics; and (4) topical ophthalmic anesthetics. Each class will be discussed separately, and recent advancements in novel preparations and next-generation medications will be detailed where they exist.

New discoveries have been made in the use of ocular adhesives for post-surgical

wound closure, as well as in the field of ophthalmic drug delivery systems. This chapter will discuss several topics in detail including newer adhesives and future trends for their use in anterior segment surgery, advancements in delivery of ophthalmic medications that improve penetration and sustainability of topical preparations, and finally, concepts for future medication and delivery system developments will be introduced.

II. NEW DEVELOPMENTS IN ANTERIOR SEGMENT ANTI-INFLAMMATORY

MEDICATIONS

A. Non-Steroidal Anti-Inflammatory

Drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs (NSAIDs) are generally used in the management of post-operative ocular inflammation and for prophylaxis against, or treatment of, cystoid macular edema (CME) after cataract surgery. They have also shown benefit in sustaining intra-operative mydriasis during cataract surgery and treating post-operative ocular pain (Flach, 1992, 1994). Topically applied medications achieve maximum concentration on the ocular surface, which gradually decreases as the drug moves past the corneal epithelium and into the eye. This results in decreased efficacy at target tissue and greater chance for ocular surface toxicity. Recently, prodrug formulations of NSAIDs have been investigated to improve penetration and decrease side effects compared to current topical NSAIDs.

1. NSAID prodrug preparations

Nepafenac (Nevanac™, Alcon, Fort Worth, TX) ocular suspension is the most recently introduced NSAID for ophthalmic use. Nepafenac is indicated for relief of eye pain and inflammation after cataract surgery. It is unique as a topical NSAID for two main reasons (Ke et al., 2000; Lindstrom

and Kim 2006; Kapin et al., 2003). First, it is delivered in the form of a prodrug, which penetrates the cornea and is converted to amfenac by tissue hydrolases. Amfenac is thought to inhibit prostaglandin H synthase (cyclooxygenase), an enzyme that plays a role in prostaglandin production.

Second, nepafenac is dosed 3 times per day whereas other NSAIDs used for ophthalmic indications are dosed 4 times per day. The cornea contains low levels of hydrolases capable of converting nepafenac to amfenac, thus leading to a high steady state concentration of this medication in the cornea and greater bioavailability over time. Superior ocular penetration of nepafenac has been demonstrated both in vitro and in vivo (Ke et al., 2000). This characteristic is attributable to improved corneal permeation of nepafenac across the corneal epithelium, the primary barrier to topical medication absorption. The action of nepafenac has been shown to be more efficacious compared to diclofenac despite the latter‘s intrinsic superiority in cyclooxygenase inhibitory activity.

B. Steroids

Topical steroid drops have long been used for post-operative inflammation control. Various formulations are available including loteprednol etabonate 0.5%, prednisolone acetate, and rimexolone, among others. Acetate formulations, such as prednisolone acetate, possess enhanced antiinflammatory activity compared to alcohol formulations, such as fluorometholone, due to enhanced bioavailability. While effective at controlling post-operative inflammation, corticosteroid drops can lead to increased intraocular pressure (IOP) making their use less attractive in patients with glaucoma or a history of steroid response ocular hypertension. The percentage of the population who experience increased IOP depends on the duration and dose of exposure and remains a serious concern for anterior segment surgeons. Newer steroid formulations

have been introduced, which appear to exhibit fewer effects on intraocular pressure while remaining effective at controlling inflammation.

1. Anecortave

Anecortave acetate (Retaane, Alcon, Fort Worth, TX) is an angiostatic medication that inhibits neovascularization. Anecortave belongs to a new class of steroid derived drugs know as “cortisenes” which are engineered to avoid the unwanted side effects of currently used steroid preparations. The engineering process removes chemical groups responsible for formation of cataracts and secondary open-angle glaucoma as seen with glucocorticoids. Anecortave blocks angiogenic signals downstream, thus effectively blocking the pathway of multiple pro-angiogenesis peptides, and potentially leading to better clinical outcomes (Bakri and Kaiser, 2006). This therapy is currently seeking FDA approval for AMD treatment as a juxtascleral depot.

Alternative uses for this medication would be very appealing for anterior segment surgeons. Post-cataract sub-Tenon‘s injections could offer the benefit of decreased inflammation independent of patient adherence to dosing regimens. Use of triamcinolone acetonide in trabeculectomy cases is also increasing, with ongoing prospective research evaluating the utility of this steroid verses mitomycin C (Tham et al., 2006; Jonas et al., 2004). Anecortave acetate may have similar utility, particularly in phakic patients, without some of the unwanted side effects seen with other glucocorticoids. More research is needed to investigate the possible role of Anecortave as an adjunct to anterior segment surgery.

III. NEW DEVELOPMENTS IN

ANTERIOR SEGMENT

ANTIBIOTIC MEDICATIONS

Fluoroquinolones have been the mainstay of topical ocular antibiotic therapy since the

early 1990s. The efficacy of these medications centers on rapid bactericidal activity, low toxicity, and excellent ocular penetration (Mah, 2004; Callegan et al., 2003; Donnenfeld et al., 2004). Successive generations of fluoroquinolones have been produced to counter emerging bacterial resistance, culminating in the introduction of the currently used fourth-generation which include Vigamox (moxifloxacin, Alcon, Fort Worth TX) and Zymar (gatifloxacin, Allergan, Irvine, CA). While viewed as powerful and effective against both gram-positive and gramnegative bacteria, the fourth generation fluoroquinolones may be less effective on gram-negative bacteria than previously thought. Additionally, there have been isolated reports of emerging resistance to this antibiotic class, making new discoveries and innovative approaches even more important for future infection control (Moshirfar et al., 2006; Hwang, 2004; Deramo et al., 2006).

Antimicrobial peptides (AMP) have been gaining interest as a possible new class of ophthalmic antibiotic (Mannis, 2002; Hancock, 1999). Anti-microbial peptides are single gene-encoded peptides that are generally synthesized and later activated as part of the innate host defense systems. They are very important in the initial response to infection as they are released from storage sites within or near affected tissue. AMPs have been divided into four different groups:

1.Cysteine-rich peptides such as defensins, tachyplesins, and protegrins.

2.Linear molecules without cysteine such as cecropins and magainins.

3.Molecules with one disulfide bond or cysteine-disulfide ring peptides such as brevinins and ranalexin.

4.Peptides with an over-representation of one or two amino acids such as Pro, Arg, Trp, and Gly.

This group of innate antimicrobial proteins acts through a mechanism of pore formation and subsequent increased permeability which disrupts biological

membranes of target cells (Ojcius et al., 1998). Research on these peptides has shown effective bactericidal activity, as well as efficacy against fungi and some enveloped viruses (Martin et al., 1995; Boman, 1994; Ganz et al., 1985, 1986; Ganz and Lehrer, 1997; Gallo and Huttner, 1998). One attractive feature of AMPs is their rapid kill rate for bacteria, acting within 5 minutes of contact with target organisms. Additionally, AMPs act by directly altering permeability of cell walls rather than influencing intracellular activity or cell wall synthesis, making the development of resistance to these peptides much more difficult than resistance to other traditional antibiotics. Previous publications have shown that AMPs are synergistic with other commonly used antibiotics (Darveau et al., 1991). While an attractive candidate for future ophthalmic use, AMPs remain unproven and largely untested in the clinical realm. Further studies are needed to investigate their utility in human infections and potential utility in the peri-operative period in anterior segment surgery.

IV. NEW DEVELOPMENTS

IN TREATING DRY

EYE SYNDROME

The advent of refractive surgery and popularization of laser ablation of the cornea have led to more intense research in understanding and treating dry eye syndrome. Neural-based mechanisms are believed to be the cause of dry eye postrefractive surgery (Chuck et al., 2000; Kannellopoulos et al., 1997). Prospective studies have shown that the incidence of dry eye symptoms and Schirmer testing abnormalities increases post-LASIK and photorefractive keratotomy surgery (Yu et al., 2000; Benitez-del Castillo et al., 2001; Aras et al., 2000; Ozdamar et al., 1999). While treatment of dry eye has long revolved around use of artificial tears and mild steroid preparations, pharmaceutical companies are now focusing on new thera-

peutic targets to improve tear production and ocular surface health.

The recent introduction of topical cyclosporin (Restasis, Allergan, Irvine, CA) led to a change of practice in treating dry eyes. Restasis acts by inhibiting T-cell activation, which then decreases inflammation in the lacrimal gland and leads to increased tear production. Use of this medication has proven to be beneficial in dry eye patients undergoing refractive surgery (Salib et al., 2006). New agents that also seek to treat the underlying cause of dry eye syndrome, rather than treat symptoms, are now being investigated and are showing early promise.

Targeting hormone imbalances as a cause of dry eye has shown some promise in early studies. Androgen Tear (Allergan, Irvine, CA) has been studied as a topical preparation targeting dysfunctional meibomian glands in the eyelid. Androgen hormone levels are known to be low in post-meno- pausal women and in Sjogren‘s syndrome and it has been postulated this imbalance may lead to drying of mucosal surfaces throughout the body (Baudouin, 2001; Krenzer et al., 2000). While early results were reported to be promising, this medication has not yet made it to the market.

Secretagogues, such as INS365 (Inspire, Durham, NC) a P2Y2 nucleotide receptor agonist, stimulate conjunctival epithelial secretion of the three major components of tear film including aqueous, mucin, and lipids. INS365 has been shown to provide normal tear volumes in animals even after lacrimal glands have been removed (Fujihara et al., 2001). This class of medication remains unproven in human studies and requires further research prior to clinical application.

V. NEW DEVELOPMENTS IN

TOPICAL OCULAR MEDICATION

DELIVERY SYSTEMS

Inherent corneal properties act as major barriers to effective delivery of medications

into the anterior chamber after anterior segment surgery. The corneal tissue itself consists of hydrophilic stroma surrounded by hydrophobic epithelium and endothelium. This trilaminar barrier does not allow for simple diffusion across the corneal tissue. The ideal topical ophthalmic medication would exist in an equilibrium of ionized and non-ionized molecules.

Many ophthalmic preparations are weak bases so that they exist in both their charged and uncharged form when mixing with the tear film, which has a pH of 7.4. Other methods to increase permeability of topical medications include adding a surfactant preservative such as benzalkonium chloride to disrupt epithelial cells and allow for increased flux across this hydrophobic barrier. Gel formations, which increase medication contact time with the cornea and increased concentrations per unit volume, also allow for increased penetration of topically applied medications. Unfortunately, in the process of increasing the bioavailability of some medications, they are made less stable and thus impractical as a topically applied medication. A great deal of research time has been devoted to applying new methods of topical medication delivery and the following text discusses three of the most promising methods being studied.

A. Nanosuspensions

Nanoparticles are polymeric colloidal particles varying in size between 10 and 1000 nm. Use of nanosystems as a “vehicle” for transport of medications across biologic membranes has been an area of intensive research. Medications are dissolved, entrapped or encapsulated in these macromolecules for delivery across an inhospitable environment or biologic barrier. Recorded success in implementation has only increased interest in the wide use of this technology. In the past, insulin has been successfully incorporated into a poly (alkylcyanoacrylate) nanocapsule, which was then delivered orally and absorbed

across the intestinal epithelium (Damge et al., 1988).

In the 1980s, Wood and colleagues (1985) investigated the utility of polyalkylcyanoacrylate nanoparticles to cross intact corneal epithelium. While success was achieved in crossing this hydrophobic barrier, damage was noted to the individual cells. Chitosincoated nanosystems have also been studied, and appear to have less deleterious effects on the corneal epithelium while still allowing for transcellular transport and penetration into hydrophilic corneal stroma (Calvo et al., 1997). More research is needed to fully understand the role of nanosystems in delivering ophthalmic medications and which polymers will be best suited for assisting in topical drug delivery.

B. Liposomes

Liposomes, like nanoparticles, are classified as colloidal systems and are composed of a lipid bilayer surrounding an inner compartment. A unique property of liposomes is their ability to incorporate both hydrophilic drugs in the inner compartment, and hydrophobic drugs in their outer shell, while remaining biodegradable and compatible with non-toxic topical delivery. It is also possible to coat liposomes with adhesive polymers to increase corneal retention (Davies et al., 1992; Durrani et al., 1992). Finally, subconjunctival and intravitreal injections of liposomes may allow for long-lasting depots, thus decreasing the need for frequent reinjection of medications. Research in this area continues and could provide an option for anterior segment delivery of post-operative medications.

C. Collagen Shields

Cataract extraction is the most common elective procedure performed in the United States. This surgical procedure, however, still carries the risk of post-operative complications, the most devastating of which

is endophthalmitis. Endophthalmitis rates post-cataract extraction have been estimated to be approximately 1 in 1000 and may be increasing with the popularization of clear cornea incisions (Busbee, 2006; West et al., 2005; Olson, 2004). Collagen shields have been investigated as an alternative method of delivering medications to the anterior segment after surgery (Marmer, 1988; Haaskjold et al., 1994; Wallin et al., 2005; Hariprasad et al., 2004; Kleinmann et al., 2006). Studies have shown that this method led to increased and sustained delivery of medications through the cornea and into the aqueous and vitreous humors. This delivery system may also benefit the patient by overcoming problems with short-term adherence to postoperative drop regimen.

In a study by Wallin and colleagues (2005), factors found to be statistically associated with endophthalmitis post-cataract extraction included wound leak on the first post-operative day, capsular or zonular surgical complication, topical antibiotic started the day after surgery rather than the day of surgery, and not using a collagen shield soaked in antibiotic. Use of a collagen shield appears to have decreased the rate of endophthalmitis in this retrospective cohort study. Hariprasad and colleagues (2004) compared the penetration of moxifloxacin 0.5% into human aqueous and vitreous by topical and collagen shield. They noted that vitreous levels at 4 hours, as well as aqueous and vitreous levels at 24 hours, were insignificant. Still, this method of drug delivery resulted in significant aqueous humor antibiotic concentrations (0.30 0.17 mcg/mL 4 hours after placement). They concluded that further study was needed to define the role of antibiotic soaked collagen shields for infection prophylaxis in ocular surgery.

Kleinmann and colleagues (2006) compared the penetration of gatifloxacin and moxifloxacin into the anterior chamber using collagen shields in rabbits. Initial concentrations of gatifloxacin and

moxifloxacin were 5.43 0.16 mg/mL and 3.14 0.22 mg/mL, respectively. Concentrations of both antibiotics remained high at the 6-hour sample (1.39 1.13 mcg/ mL versus 0.816 0.6 mcg/mL at 6 hours, respectively, P 0.22). They concluded that the measured concentrations exceeded the minimal inhibitory concentration (MIC 90) of most organisms known to cause postoperative endophthalmitis.

VI. NEW DEVELOPMENTS IN

ANTERIOR SEGMENT

SURGICAL ADHESIVES

Ophthalmic tissue adhesives belong to two groups: (1) synthetic adhesives such as cyanoacrylate; and (2) biologic adhesives such as fibrin-based adhesives. Cyanoacrylate preparations, while offering high tensile strength, often cause an inflammatory foreign body reaction and must be used on the external surface of the eye. Alternatively, fibrin-based adhesives such as Tisseel (Baxter AG, Vienna, Austria) are more biocompatible and can be used in much the same way as suture material. Biologic adhesives cause less inflammation, but offer less tensile strength than synthetic adhesives. Biologic adhesives also carry the theoretical risk of transmitting blood-borne diseases if the donor pool is contaminated; however, none have been reported. Both synthetic and biologic adhesives have been used for anterior segment surgery and their role appears to be expanding as experience evolves (Sharma et al., 2003; Lagoutte et al., 1989; Duchesne et al., 2001; Sumich et al., 2003; Watts and Collin, 1992; Grewing and Mester, 1997; Kaufman et al., 2003).

Kaufman and colleagues (2003) investigated the efficacy of using fibrin adhesives in performing sutureless lamellar keratoplasty and attachment of amnion to bare sclera. They noted that while fibrin adhesives provided satisfactory surgical outcomes, an adhesive designed specifically for ophthalmic applications would

increase the desirability of using this technique. Szurman and colleagues (2006) compared the use of fibrin glue versus sutures for transplantation of amniotic membranes onto the de-epithelialized cornea of 12 rabbits. They noted that membranes of both groups stayed in place throughout followup. Histologic evaluation of the tissues revealed a continuous stratified layer of epithelium in the fibrin group, whereas the suture group exhibited prominent membrane edges with epithelial ingrowth into the submembrane interface. They concluded that fibrin glue offered improved biocompatibility, better epithelialization pattern, and less membrane shrinkage. Similar fibrin glue efficacy has been reported for conjunctival autografts with pterygium surgery and trabeculectomy surgery (Marticorena et al., 2006; Bahar et al., 2006).

More recently, Kahook and Noecker (2006a) described the use of fibrin glue as a suture substitute for portions of glaucoma drainage device surgery. This retrospective case series noted no statistically significant differences in post-operative IOP levels in Baerveldt drainage devices with use of fibrin glue versus traditional suture material. Conjunctival inflammation was more pronounced in the suture group (p 0.0013) versus the Tisseel group. Notably, the time of surgery was significantly less for the Tisseel group, 15.0 ( 3.11) minutes, compared to the suture group, 25.93 ( 4.04) minutes (p 0.0001). They concluded that Tisseel glue appears to have no impact on post-operative outcomes while significantly reducing time and cost of surgery.

Other ophthalmic adhesives are currently under investigation but remain unproven (Miki et al., 2002; Kalayci et al., 2003; Bloom et al., 2003). Miki and colleagues (2002) reported the use of a novel polymer made from hyaluronic acid and methacrylate groups that is laser activated. Kalayci and colleagues (2003) studied the use of a hydrogel compound to seal corneal incisions in rabbit eyes. Bloom and colleagues (2003) studied the tensile strength of a light

activated biologic adhesive in attaching extraocular muscles to sclera. Production of fibrin glue in ready-to-use syringes and quantities appropriate for ophthalmic use would facilitate wider use, and perhaps decrease the cost of this option even further. More studies are needed to tease out the role of fibrin glue in anterior segment surgery.

VII. NEW ADVANCEMENTS IN

ANTI-ANGIOGENIC

MEDICATIONS

Ocular angiogenesis plays a part in many ophthalmic diseases, including retinopathy of prematurity, diabetic retinopathy, neovascular glaucoma, and agerelated macular degeneration. Recent advances in understanding the angiogenic cascade has led to the introduction of several compounds intended for the treatment of wet age-related macular degeneration (Gragoudas et al., 2004; Rosenfeld et al., 2006). Both pegaptanib (Macugen, Eyetech Pharmaceuticals/Pfizer) and ranibizumab (Lucentis; Genentech, S. San Francisco, CA) are FDA approved anti-vascular endothelial growth factor drugs which appear effective in reversing choroidal neovascular membranes and improving vision. Avastin (Bevacizumab, Genentech, S. San Francisco, CA) is related to Lucentis, and has found a role in treating both anterior and posterior ocular neovascular disease. Avastin is not FDA approved for ophthalmic use.

Neovascular glaucoma (NVG) is a devastating disease usually related to ischemic disease of the retina. Treatment of NVG often involves use of panretinal photocoagulation and/or glaucoma drainage device implantation to control pressure. Visual outcomes are usually dismal despite intensive treatment. Recent publications have outlined the utility of bevacizumab in treating iris, angle neovascularization and, in some cases, decreasing intraocular pressure (Kahook et al., 2006b,c; Grisanti et al., 2006). Kahook and colleagues (2006b) reported