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Drug Evaluation Riboflavin 0.1% (VibeX) for the treatment of keratoconus 1. Introduction 2. Keratoconus 3. Parasurgical crosslinking Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. therapy 4. Riboflavin 5. Expert opinion Cosimo Mazzotta†, Stefano Baiocchi, Tomaso Caporossi, Stefano Caragiuli, Anna Lucia Paradiso & Aldo Caporossi † Siena University, Policlinico Santa Maria alle Scotte, Department of Ophthalmology, Siena, Italy Introduction: Keratoconus is an ectatic disease of the cornea characterized by biomechanical instability of stromal collagen leading to reduction of corneal thickness, variation in posterior and anterior corneal curvatures with associated progressive deterioration of visual acuity mainly due to a secondary irregular astigmatism. Corneal collagen crosslinking (CXL) is a new approach to increase the mechanical strength and biochemical stability of the corneal stromal tissue affected from primary or secondary ectasia. A novel pharmacological series of riboflavin formulations from Avedro, Inc. (Waltham, Massachusetts, MA, USA), were recently granted orphan drug designation by the Food and Drug Administration for the treatment of keratoconus and secondary corneal ectasia. Areas covered: This report reviews the basic concepts concerning the role of riboflavin in crosslinking treatment in order to understand the potentiality of the new VibeX and VibeX Rapid solutions for riboflavin UVA-induced CXL. The treatment should be offered to those patients with documented progressive keratoconus and secondary corneal ectasia in order to halt or delay its progression preventing the necessity of donor corneal graft. Expert opinion: VibeX solution complies well with other standard riboflavin solutions currently available on the market for epithelium-off CXL therapy. Compared with VibeX riboflavin 0.1% -- dextran 20% formula, the VibeX Rapid has been proposed for a faster and homogeneous corneal soaking, avoiding the intraoperative corneal thinning often occurring with the standard riboflavin solutions containing high molecular weight dextran as excipient. Keywords: accelerated crosslinking, crosslinking, keratoconus, riboflavin, VibeX, VibeX Rapid Expert Opinion on Orphan Drugs (2013) 1(3):235-240 1. Introduction Keratoconus is an ectatic disease of the cornea characterized by biochemical and biomechanical instability of stromal collagen leading to reduction of corneal thickness, variation in posterior and anterior corneal curvatures and progressive deterioration of visual acuity due to irregular astigmatism [1,2]. The recent advent of corneal collagen crosslinking (CXL) in the ophthalmology panorama of the last decade [3,4] transformed the conventional therapy of keratoconus based at best, on a lifetime of rigid contact lens wearing or at worst on corneal transplant, improving its conservative treatment, thus reducing the necessity of lamellar or penetrating corneal graft. In 2011, the VibeX/KXL system promoted by Avedro, Inc. (Waltham, Massachusetts, MA, USA), was granted orphan designation by the Food and Drug Administration (FDA) for the treatment of keratoconus and corneal ectasia following refractive surgeries [5]. Orphan drug designation is granted by the FDA Office of Orphan Products Development to promote the development of new 10.1517/21678707.2013.765799 © 2013 Informa UK, Ltd. e-ISSN 2167-8707 All rights reserved: reproduction in whole or in part not permitted 235 C. Mazzotta et al. Box 1. Drug summary. Drug name Pharmaceutical company Indication Composition Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. Mechanism of action Route of administration VibeX Avedro, Inc. (Waltham, Massachusetts, MA, USA) Keratoconus and secondary corneal ectasia 100 mL of solution contains: riboflavin 0.1 g, dextran 500, disodium hydrogen phosphate, sodium phosphate monobasic dihydrate, sodium chloride, water for injectable solution Ophthalmic medical device used for corneal crosslinking treatment Topically Box 2. Drug summary. Drug name Pharmaceutical company Indication Composition Mechanism of action Route of administration VibeX Rapid Avedro, Inc. (Waltham, Massachusetts, MA, USA) Keratoconus and secondary corneal ectasia 100 mL of solution contains: riboflavin 0.1 g, HPMC, disodium hydrogen phosphate, sodium phosphate monobasic dihydrate, sodium chloride, water for injectable solution Ophthalmic medical device used for corneal crosslinking treatment Topically therapies for rare diseases and disorders. To date, Avedro, Inc., distributes four riboflavin solutions outside the United States: VibeX, VibeX Rapid (Box 1 and 2) (for epithelium-off crosslinking procedure), Paracel (for transepithelial or epithelium-on treatment) and VibeX Xtra specifically formulated for the use during a Lasik procedure (Lasik Xtra) and epithelium-on crosslinking. In this manuscript, we will refer to the Avedro, Inc. VibeX and VibeX Rapid solutions. 2. Keratoconus 3. Krachmer et al. in a 1984 article [1], defined the keratoconus as ‘an ectatic, asymmetric, non-inflammatory, progressive corneal degeneration characterized by thinning, increasing of corneal curvatures and loss of transparency of the central cornea’. The prevalence of keratoconus in the population reported in the literature [2] is 1/2,000 which is within the threshold used by the European Union to define a disease as rare disease (also referred to as an orphan disease) [6], and the incidence is 2 -- 3/100,000 [2], although many authors agree that in the coming years there will be an increase of these values due to a more widespread use of corneal topography. According to the experience of Ophthalmology School of Siena, the prevalence of keratoconus amounted to 1 in 1,000 or even 1 in 500 inhabitants [4]. Studies conducted in the precorneal tomography era reported a familiarity of 6 -- 8% meaning that about 6 -- 8% of patients with keratoconus also has one or more family members suffering from this disease. Still more striking epidemiological studies carried out in the post-corneal tomography era showed that 50% of patients with keratoconus have at least one close relative suffering from the same disease [7]. Keratoconus ectasia is characterized by corneal bulging with thinning typically occurring in the 236 inferior-temporal quadrant that represents the physiological weakest part of the cornea [8,9]. Keratoconus usually starts in the second decade of life (generally at puberty) progressing until the fourth decade of life [2] when it generally stabilizes due to a natural or physiological (age-related) process of crosslinking of stromal collagen [10]. Diabetes seems to be a protective factor against keratoconus onset and progression, due to increased crosslinking process related with the hyperglycemia in the so-called Maillard’s reaction [11,12]. Parasurgical crosslinking therapy Riboflavin ultraviolet type A (UVA) CXL is a relatively new approach for increasing the biomechanical and biochemical stability of the corneal stromal tissue against primary and secondary ectasia. The surgical technique consists in a photopolymerization of stromal collagen fibers by the combined action of a photosensitizing substance (riboflavin, also known as vitamin B2) and UVA. Photopolymerization increases the rigidity of corneal collagen contrasting ectasia progression. Different methods of enhancing the crosslinking of corneal collagen have been comparatively evaluated by Spoerl and Seiler [13] who discovered that the association of riboflavin and UV-A was effective (by significantly increasing corneal stiffening and Young modulus) and less toxic in vivo (by preserving corneal transparency, endothelium, lens and retina). The data reported in literature [14,15] at this time confirm that crosslinking has a main role in the management of early stage progressive keratoconus. In fact, if progression can be reliably documented by means of serial computerized topography, surface aberrometry and differential optical pachymetry, an early intervention is likely to be most beneficial in preventing a visual impairment or at least the development of advanced clinical signs. Sp€orl et al. [16] were the first to Expert Opinion on Orphan Drugs (2013) 1(3) Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. VibeX investigate the use of riboflavin and UVA irradiation in achieving crosslinking of corneal collagen. Using this method, Wollensak et al. [17] demonstrated a marked positive effect of crosslinking on the biomechanical properties of both porcine and human corneal tissue: crosslinking was shown to increase the rigidity of human corneal tissue (expressed by Young’s modulus at 6% strain) by a factor of 1.5 -- 1.7 x [18] (Young’s modulus, also known as the tensile modulus, is a measure of the stiffness of an elastic material). Below we cite the early clinical studies that have documented the effectiveness of the crosslinking treatment in slowing down or arresting the progression of keratoconus. The first report of a series of 23 eyes treated with crosslinking was published in 2003 by the eye school of Dresden [3]. Following Dresden studies, for the first time in Italy in 2006 the researchers of the Siena eye school in Italy [4] published the second international results of a case series of 10 patients affected from progressive keratoconus stabilized through riboflavin UVA-induced CXL. The in vivo safety and effective penetration of corneal crosslinking induced apoptotic effect correlating with its biomechanical and clinical efficacy; treatment was documented for the first time in humans by Mazzotta et al. [19-21] by using the confocal laser scanning microscopy following the previous Wollensak’s studies on animal model [22]. The presence of stromal edema, the reduction in keratocyte density via cells apoptosis and loss of nerve fibers were observed in the anterior stroma 1 month after crosslinking [20]. In the same studies, the progressive reduction of corneal edema associated with increased stromal density and time-depending cells repopulation of the anterior mid-stromal volume by activated keratocytes between 3 and 6 months after treatment were demonstrated; the deep stroma beyond 300 µm, endothelial cells morphology and count appeared unaffected [20]. Moreover, in a later publication, Mazzotta et al. [21] described numerous needle-shaped reflective striations or bands in the anterior mid-stroma until 2 years after crosslinking, interpreted as new structured collagen following treatment and explaining some morphological- and functional-related aspects of crosslinking itself [19]. 4. Riboflavin Riboflavin, also known as vitamin B2, belongs to the class of water-soluble vitamins. The etymology of the word riboflavin, composed of ribo(se) and flavin, refers to its chemical composition. Riboflavin is composed of a nucleus of dimethyl isoalloxazine (isoalloxazine is the basic structure of all flavin molecules) and ribitol (the reduced form of the sugar ribose): 7,8-dimethyl-10-(1¢-d-ribityl) isoalloxazine [23-25]. As suggested by its etymology (flavus in Latin means ‘yellow’), riboflavin crystals have a yellow-orange color, whereas neutral solutions of riboflavin have a typical yellowish-green color. This is why they are used as a food coloring, known as E101. Although riboflavin belongs to the group of watersoluble vitamins, it is in fact one of the least soluble in water TM and VibeX RapidTM (12 mg/100 mL at 25 C) and even less soluble in alcohol. It is more soluble in acidic solutions up to a temperature of 120 C, but unstable in alkaline media and when exposed to ultraviolet and visible light. The spectrum of riboflavin has four absorption peaks at wavelengths 223, 266, 373 and 445 nm. Riboflavin exhibits native fluorescence with an emission peak at 530 nm [23-25]. Vitamin B2 was first discovered in 1879 by the English chemist Alexander Wynter Blyth who called it ‘lactoflavin’ because he found it in cow’s milk. Similar substances were called ‘ovoflavin’, ‘hepatoflavin’ and so forth, because they were discovered in eggs, liver and other plant and animal tissues. It was not until 1934 that the Swiss chemist Paul Karrer and the Austrian-born German chemist Richard Kuhn, both Nobel laureates in chemistry, discovered that lacto-, ovo- and hepato-flavin were the same substance, which they called riboflavin [23,24]. Riboflavin plays a fundamental role acting as photosensitizer, favoring the production of free radicals mediating the crosslinking of stromal collagen [26]. The release of free radicals or reactive oxygen species induce (in the presence and/ or absence of oxygen) the type I and type II photochemical reactions (oxidative deamination of corneal collagen) leading to the formation of molecular bridges (crosslinks) between and within collagen fibrils. The second role of riboflavin is the UVA absorption, thus allowing the concentration of ultraviolet light A energy delivered by UV source in the anterior half of the corneal stroma. The so-called riboflavin shielding effect reduces the risk of UV-related damage of corneal endothelium, lens and retina [27]. Safety studies have shown that current UVA exposures associated with crosslinking are below the thresholds for endothelial cell damage. There is a risk of endothelial cell toxicity when riboflavin diffuses to the endothelium, and UVA exposures are high enough that they are not adequately attenuated by absorption on transit through a riboflavin-soaked cornea. 5. Expert opinion Standard riboflavin solution (VibeX) contains the same formulation of the original riboflavin formula used in the first crosslinking studies and protocols (Dresden and Siena); 0.1% riboflavin with 20% dextran T 500 solution has been already used and commonly applied today in the crosslinking therapy for progressive keratoconus. This solution has been CE marked and proven in several published clinical studies to be optimally tolerated in human eyes [20,27-30]. The drops contain 20% dextran 500.000 Da molecular mass in order to make the otherwise hyperosmolar 0.1% riboflavin solution iso-osmolar with the corneal stroma, thus preventing intraoperative corneal swelling [31]. The classic 0.1% riboflavin with 20% dextran T 500 solution was well tolerated and nontoxic, nonirritating and nonallergic for ocular surface during and after epitheliumoff crosslinking treatment. Syringe with large cannula provided in the sterile packaging facilitates an easy and Expert Opinion on Orphan Drugs (2013) 1(3) 237 Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. C. Mazzotta et al. Figure 1. Syringe and cannula, blunt metal spatula for epithelial scraping and forceps for contact lens in the epithelium-off accelerated crosslinking technique. Department of Ophthalmology, Siena University, Italy. Figure 2. Avedro, Inc. KXLTM : Epithelium-off accelerated crosslinking procedure. Department of Ophthalmology, Siena University, Italy. homogeneous distribution of the riboflavin on the corneal surface, Figure 1. Homogeneous distribution of the solution on the corneal surface is essential to avoid the presence of hot spots. Indeed, if hot spots are present, the damage thresholds may be locally exceeded leading to localized endothelial damage [27]. The so-called ‘rapid’ riboflavin solution consists in the presence of hydroxylpropyl methylcellulose (HPMC) instead of dextran as excipient. HPMC has long been established for ophthalmic safety and optimal tolerability [32-36]. Methylcellulose has a low surface tension and contact angle, which increases coating ability, having a lack of elasticity, which makes it more ‘viscoadherent’ than viscoelastic. It has been shown not to damage the endothelium [34]. Other advantages 238 are its availability, ability to be autoclaved, low cost and ability to be stored and shipped at room temperature. HPMC prevents the corneal thinning caused by corneal dehydration reported in literature with dextran solution as demonstrated by Kymionis et al. [37] and also experienced by us in the clinical practice (submitted unpublished data). As reported in literature by Spoerl et al. [27] and by Kamaev et al. [26], riboflavin and fluorescein have similar polarity and molecular mass (376 g/mol) with similar diffusion coefficients of 6 10-7 cm2/s at 35 C. Since the HPMC significantly increases the penetration of topical fluorescein as compared to other commonly used ophthalmic vehicles [38], it is theoretically reliable that HPMC could be a good vehicle for riboflavin molecules allowing its faster diffusion into the corneal stroma and decreasing the soaking time under 10 min as proposed in the new Avedro, Inc. ‘VibeX Rapid protocol’. The possibility to shorten the riboflavin soaking time is particularly favorable for patients and surgeons, being the entire crosslinking procedure less time-consuming with relative advantages. Both Avedro, Inc. riboflavin solutions (standard and rapid) were intraoperatively and postoperatively optimally tolerated, with no irritation and allergy and nontoxic for ocular surface having a good distribution and penetration of riboflavin into the corneal stroma and anterior chamber, Figure 2. In our experience, after epithelium-off crosslinking by using the standard 0.1% -- dextran 20% riboflavin solution and the rapid 0.1 % riboflavin with HPMC solution, the reepithelialization was complete after 3 days of soft contact lens bandage and subjectively patients reported a very small degree of discomfort. In conclusion the Avedro, Inc.’s standard riboflavin solution complies well with other solutions currently available on the market for epithelium-off crosslinking treatment. The ‘rapid’ solution containing 0.1 % riboflavin plus HPMC could become the future device for accelerated (epithelium-off) CXL. Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. Expert Opinion on Orphan Drugs (2013) 1(3) VibeX Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1. Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. 2. 3. .. 4. .. 5. 6. 7. 8. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984;28(4):293-322 Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol 1986;101(3):267-73 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620-7 CXL represents one of the most important novelties in Ophthalmology in the last decade, reducing the necessity of lamellar or penetrating corneal graft in keratoconus patients. Caporossi A, Baiocchi S, Mazzotta C, et al. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32(5):837-45 CXL represents one of the most important novelties in Ophthalmology in the last decade, reducing the necessity of lamellar or penetrating corneal graft in keratoconus patients. Avedro Announces FDA Orphan Drug Designation for Its Corneal Cross-linking. Available from: http:// avedro.com/WP/wp-content/uploads/ 2011/08/Avedro-FDA-Corneal-Crosslinking.pdf [Last accessed 21 November 2012] European Parliament and the Council of the European Union. Regulation (EC) No 141/2000 of the European Parliament and the Council of 16 December 1999 on orphan medicinal products. Off J Eur Commun 2000;L18:1-5 Gonzalez V, McDonnell PJ. Computer-assisted corneal topography in parents of patients with keratoconus. Arch Ophthalmol 1992;110(10):1413-14 Sherwin T, Nigel N. Morphological changes in keratoconus: pathology or pathogenesis. Clin Exper Ophthalmol 2004;32:211-17 9. Daxer A, Fratzl P. Collagen fibril orientation in the human corneal stroma and its implication in keratoconus. Invest Ophthalmol Vis Sci 1997;38(1):121-9 10. Malik NS, Moss SJ, Ahmed N, et al. Ageing of the human corneal stroma: structural and biochemical changes. Biochim Biophys Acta 1992;1138(3):222-8 11. Kuo IC, Broman A, Pirouzmanesh A, Melia M. Is there an association between diabetes and keratoconus? Ophthalmology 2006;113(2):184-90 12. Sady C, Khosrof S, Nagaraj R. Advanced maillard reaction and crosslinking of corneal collagen in diabetes. Biochem Biophys Res Commun 1995;214(3):793-7 13. Spoerl E, Seiler T. Techniques for stiffening the cornea. J Refract Surg 1999;15(6):711-13 14. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol 2010;149(4):585-93 15. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34(5):796-801 16. Sporl E, Huhle M, Kasper M, Seiler T. Increased rigidity of the cornea caused by intrastromal cross-linking. Ophthalmologe 1997;94(12):902-6 17. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavinultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003;29(9):1780-5 18. .. Schumacher S, Oeftiger L, Mrochen M. Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci 2011;52(12):9048-52 New riboflavin solutions dextran free or with HPMC combined with increased UVA power delivering same energy of standard procedure may represent a future development of crosslinking therapy reducing the time of the procedure and being equally Expert Opinion on Orphan Drugs (2013) 1(3) TM and VibeX RapidTM safe. The efficacy of the accelerated crosslinking is now under investigation. 19. Mazzotta C, Caporossi T, Denaro R, et al. Morphological and functional correlations in riboflavin UV A corneal collagen cross-linking for keratoconus. Acta Ophthalmol 2012;90(3):259-65 20. Mazzotta C, Balestrazzi A, Traversi C, et al. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 2007;26(4):390-7 Epithelium-off crosslinking technique by using the original ribflavin 0.1%, dextran 20% solution with 3 mW/cm2 UVA (5.4 J/cm2) represents today the gold standard of this therapeutic approach to keratoconus based on its penetration in corneal stroma as demonstrated by first in vivo confocal studies. .. 21. Mazzotta C, Traversi C, Baiocchi S, et al. Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 2008;146(4):527-33 22. Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23(1):43-9 23. Arienti G. Le basi molecolari della nutrizione. 2nd edition. Piccin, Padova; 2003 24. Cabras P, Martelli A. Chimica degli alimenti. Piccin, Padova; 2004 25. Ball G. Vitamins in foods: analysis, bioavailability, and stability. CRC Press; Boca Raton: 2006 26. Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 2012;53(4):2360-7 New riboflavin solutions dextran free or with HPMC combined with increased UVA power delivering same energy of standard procedure may represent a future development of crosslinking therapy reducing the time .. 239 C. Mazzotta et al. energy of standard procedure may represent a future development of crosslinking therapy reducing the time of the procedure and being equally safe. The efficacy of the accelerated crosslinking is now under investigation. of the procedure and being equally safe. The efficacy of the accelerated crosslinking is now under investigation. Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13 For personal use only. 27. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007;26(4):385-9 28. Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal cross-linking and safety issues. Open Ophthalmol J 2011;5:14-16 32. 29. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg 2003;29(9):1786-90 33. 30. 31. .. 240 Grewal DS, Brar GS, Jain R, et al. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg 2009;35(3):425-32 Vetter JM, Brueckner S, Tubic-Grozdanis M, et al. Modulation of central corneal thickness by various riboflavin eye-drop compositions in porcine corneas. J Cataract Refract Surg 2012;3):525-32 New riboflavin solutions dextran free or with HPMC combined with increased UVA power delivering same Fechner PU. Methylcellulose, a viscous cushioning material in ophthalmic surgery. Trans Ophthalmol Soc UK 1983;103:259-62 Steele AD. Visco-elastic material in keratoplasty. Trans Ophthalmol Soc UK 1983;103:268-9 34. MacRae SM, Edelhauser HF, Hyndiuk RA, et al. The effects of sodium hyaluronate, chondroitin sulfate, and methylcellulose on the corneal endothelium and intraocular pressure. Am J Ophthalmol 1983;95:332-41 35. Glaser DB, Matsuda M, Edelhauser HF. A comparison of the effi cacy and toxicity of and intraocular pressure response to viscous solutions in the anterior chamber. Arch Ophthalmol 1986;104:1819-24 36. Smith GS, Lindstrom RL. 2% hydroxypropyl methylcellulose as a viscous surgical adjunct. J Cataract Refract Surg 1991;17:839-42 Expert Opinion on Orphan Drugs (2013) 1(3) 37. Kymionis GD, Kounis GA, Portaliou DM, et al. Intraoperative pachymetric measurements during corneal collagen cross-linking with riboflavin and ultraviolet A irradiation. Ophthalmology 2009;116(12):2336-9 38. Waltman SR, Patrowicz TC. Effects of hydroxypropyl methylcellulose and polyvinyl alcohol on intraocular penetration of topical fluorescein in man. Invest Ophthalmol 1970;9(12):966-70 Affiliation Cosimo Mazzotta†1 MD PhD, Stefano Baiocchi1 MD PhD, Tomaso Caporossi2 MD, Stefano Caragiuli1 MD, Anna Lucia Paradiso1 MD & Aldo Caporossi1 MD FRCS † Author for correspondence 1 Siena University, Policlinico Santa Maria alle Scotte, Department of Ophthalmology, Viale Mario Bracci, 53100 Siena, Italy Tel: +0039 349 5550676; Fax: +0039 349 5550676; E-mail: [email protected] 2 Rome Catholic University, Policlinico Gemelli, Department of Ophthalmology, Rome, Italy