Skip to main content

Advertisement

SpringerLink
Log in

Effect of Diabetes on Transscleral Delivery of Celecoxib

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To investigate the effects of diabetes on transscleral retinal delivery of celecoxib in albino and pigmented rats.

Methods

Albino (Sprague Dawley—SD) and pigmented (Brown Norway—BN) rats were made diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg) following 24 h of fasting and diabetes was confirmed (blood glucose >250 mg/dL). Two months after diabetes induction, the integrity of blood-retinal-barrier in control versus diabetic rats from both strains was compared by using FITC-dextran leakage assay. Fifty microliter suspension of celecoxib (3 mg/rat) was injected periocularly in both the strains in one eye, 2 months following diabetes induction. The animals were euthanized at the end of 0.25, 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing and celecoxib levels in ocular tissues and plasma were estimated using a HPLC assay.

Results

Diabetes (2-month duration) resulted in 2.4 and 3.5 fold higher blood-retinal barrier leakage in diabetic SD and BN rats, respectively, compared to controls. The area under tissue celecoxib concentration versus time curves (AUC) for sclera, cornea, and lens were not significantly different between control and diabetic animals. However, retinal and vitreal AUCs of celecoxib in treated eyes were approximately 1.5-fold and 2-fold higher in diabetic SD and BN rats, respectively, as compared to the controls.

Conclusions

Transscleral retinal and vitreal delivery of celecoxib is significantly higher in diabetic animals of both strains. The increase in retinal delivery of celecoxib due to diabetes is higher in pigmented rats compared to albino rats. Higher delivery of celecoxib in diabetic animals compared to control animals can be attributed to the disruption of blood-retinal barrier due to diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. S. In. Causes and prevalence of visual impairment among adults in the United States. Am. Med. Assoc. 122:477–485 (2004).

    Google Scholar 

  2. M. V. Emerson, and A. K. Lauer. Emerging therapies for the treatment of neovascular age-related macular degeneration and diabetic macular edema. BioDrugs. 21:245–257 (2007).

    Article  PubMed  CAS  Google Scholar 

  3. D. J. D’Amico, M. F. Goldberg, H. Hudson, J. A. Jerdan, D. S. Krueger, S. P. Luna, S. M. Robertson, S. Russell, L. Singerman, J. S. Slakter, L. Yannuzzi, and P. Zilliox. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology. 110:2372–2383 (2003)discussion 2384–2385.

    Article  PubMed  Google Scholar 

  4. U. B. Kompella, N. Bandi, and S. P. Ayalasomayajula. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest. Ophthalmol. Vis. Sci. 44:1192–1201 (2003).

    Article  PubMed  Google Scholar 

  5. S. P. Ayalasomayajula, and U. B. Kompella. Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur. J Pharmacol. 458:283–289 (2003).

    Article  PubMed  CAS  Google Scholar 

  6. S. P. Ayalasomayajula, and U. B. Kompella. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model. Eur. J. Pharmacol. 511:191–198 (2005).

    Article  PubMed  CAS  Google Scholar 

  7. J. Y. Tsui, C. Dalgard, K. R. Van Quill, L. Lee, H. E. Grossniklaus, H. F. Edelhauser, and J. M. O'Brien. Subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma. Invest. Ophthalmol. Vis. Sci. 49:490–496 (2008).

    Article  PubMed  Google Scholar 

  8. J. Ambati, E. S. Gragoudas, J. W. Miller, T. T. You, K. Miyamoto, F. C. Delori, and A. P. Adamis. Transscleral delivery of bioactive protein to the choroid and retina. Invest. Ophthalmol. Vis. Sci. 41:1186–1191 (2000).

    PubMed  CAS  Google Scholar 

  9. J. Ambati, and A. P. Adamis. Transscleral drug delivery to the retina and choroid. Prog. Retin. Eye Res. 21:145–151 (2002).

    Article  PubMed  CAS  Google Scholar 

  10. I. Ahmed, and T. F. Patton. Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest. Ophthalmol. Vis. Sci. 26:584–587 (1985).

    PubMed  CAS  Google Scholar 

  11. J. Ambati, C. S. Canakis, J. W. Miller, E. S. Gragoudas, A. Edwards, D. J. Weissgold, I. Kim, F. C. Delori, and A. P. Adamis. Diffusion of high molecular weight compounds through sclera. Invest. Ophthalmol. Vis. Sci. 41:1181–1185 (2000).

    PubMed  CAS  Google Scholar 

  12. T. W. Olsen, H. F. Edelhauser, J. I. Lim, and D. H. Geroski. Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest. Ophthalmol. Vis. Sci. 36:1893–1903 (1995).

    PubMed  CAS  Google Scholar 

  13. D. E. Rudnick, J. S. Noonan, D. H. Geroski, M. R. Prausnitz, and H. F. Edelhauser. The effect of intraocular pressure on human and rabbit scleral permeability. Invest. Ophthalmol. Vis. Sci. 40:3054–3058 (1999).

    PubMed  CAS  Google Scholar 

  14. T. W. Olsen, S. Y. Aaberg, D. H. Geroski, and H. F. Edelhauser. Human sclera: thickness and surface area. Am. J. Ophthalmol. 125:237–241 (1998).

    Article  PubMed  CAS  Google Scholar 

  15. S. B. Lee, D. H. Geroski, M. R. Prausnitz, and H. F. Edelhauser. Drug delivery through the sclera: effects of thickness, hydration, and sustained release systems. Exp. Eye Res. 78:599–607 (2004).

    Article  PubMed  CAS  Google Scholar 

  16. M. R. Robinson, S. S. Lee, H. Kim, S. Kim, R. J. Lutz, C. Galban, P. M. Bungay, P. Yuan, N. S. Wang, J. Kim, and K. G. Csaky. A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp. Eye Res. 82:479–487 (2006).

    Article  PubMed  CAS  Google Scholar 

  17. L. Pitkanen, V. P. Ranta, H. Moilanen, and A. Urtti. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest. Ophthalmol. Vis. Sci. 46:641–646 (2005).

    Article  PubMed  Google Scholar 

  18. N. P. Cheruvu, and U. B. Kompella. Bovine and porcine transscleral solute transport: influence of lipophilicity and the Choroid–Bruch’s layer. Invest. Ophthalmol. Vis. Sci. 47:4513–4522 (2006).

    Article  PubMed  Google Scholar 

  19. N. P. Cheruvu, A. C. Amrite, and U. B. Kompella. Effect of eye pigmentation on transscleral drug delivery. Invest. Ophthalmol. Vis. Sci. 49:333–341 (2008).

    Article  PubMed  Google Scholar 

  20. A. C. Amrite, H. F. Edelhauser, and U. B. Kompella. Modeling of corneal and retinal pharmacokinetics after periocular drug administration. Invest. Ophthalmol. Vis. Sci. 49:320–332 (2008).

    Article  PubMed  Google Scholar 

  21. F. Ozturk, S. Kortunay, E. Kurt, S. S. Ilker, N. E. Basci, and A. Bozkurt. Penetration of topical and oral ciprofloxacin into the aqueous and vitreous humor in inflamed eyes. Retina. 19:218–222 (1999).

    Article  PubMed  CAS  Google Scholar 

  22. F. Ozturk, S. Kortunay, E. Kurt, S. S. Ilker, U. U. Inan, N. E. Basci, A. Bozkurt, and O. Kayaalp. Effects of trauma and infection on ciprofloxacin levels in the vitreous cavity. Retina. 19:127–130 (1999).

    Article  PubMed  CAS  Google Scholar 

  23. F. Ozturk, S. Kortunay, E. Kurt, U. U. Inan, S. S. Ilker, N. Basci, and A. Bozkurt. The effect of long-term use and inflammation on the ocular penetration of topical ofloxacin. Curr. Eye Res. 19:461–464 (1999).

    Article  PubMed  CAS  Google Scholar 

  24. F. Ozturk, S. Kortunay, E. Kurt, U. Ubeyt Inan, S. Sami Ilker, N. E. Basci, A. Bozkurt, and S. Oguz Kayaalp. Ofloxacin levels after intravitreal injection. Effects of trauma and inflammation. Ophthalmic. Res. 31:446–451 (1999).

    Article  PubMed  CAS  Google Scholar 

  25. F. Ozturk, E. Kurt, U. U. Inan, M. C. Kortunay, S. S. Ilker, N. E. Basci, and A. Bozkurt. Penetration of topical and oral ofloxacin into the aqueous and vitreous humor of inflamed rabbit eyes. Int. J. Pharm. 204:91–95 (2000).

    Article  PubMed  CAS  Google Scholar 

  26. F. Ozturk, E. Kurt, U. U. Inan, S. Kortunay, S. S. Ilker, N. E. Basci, and A. Bozkurt. The effects of prolonged acute use and inflammation on the ocular penetration of topical ciprofloxacin. Int. J. Pharm. 204:97–100 (2000).

    Article  PubMed  CAS  Google Scholar 

  27. R. Yagci, Y. Oflu, A. Dincel, E. Kaya, S. Yagci, B. Bayar, S. Duman, and A. Bozkurt. Penetration of second-, third-, and fourth-generation topical fluoroquinolone into aqueous and vitreous humour in a rabbit endophthalmitis model. Eye. 21:990–994 (2007).

    Article  PubMed  CAS  Google Scholar 

  28. N. P. Blair, M. O. Tso, and J. T. Dodge. Pathologic studies of the blood-retinal barrier in the spontaneously diabetic BB rat. Invest. Ophthalmol. Vis. Sci. 25:302–311 (1984).

    PubMed  CAS  Google Scholar 

  29. S. X. Zhang, J. X. Ma, J. Sima, Y. Chen, M. S. Hu, A. Ottlecz, and G. N. Lambrou. Genetic difference in susceptibility to the blood-retina barrier breakdown in diabetes and oxygen-induced retinopathy. Am. J. Pathol. 166:313–321 (2005).

    PubMed  Google Scholar 

  30. A. C. Amrite, and U. B. Kompella. Celecoxib inhibits proliferation of retinal pigment epithelial and choroid-retinal endothelial cells by a cyclooxygenase-2-independent mechanism. J. Pharmacol. Exp. Ther. 324:749–758 (2008).

    Article  PubMed  CAS  Google Scholar 

  31. L. De Schaepdrijver, P. Simoens, H. Lauwers, and J. P. De Geest. Retinal vascular patterns in domestic animals. Res. Vet. Sci. 47:34–42 (1989).

    PubMed  Google Scholar 

  32. Z. Dagher, Y. S. Park, V. Asnaghi, T. Hoehn, C. Gerhardinger, and M. Lorenzi. Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes. 53:2404–2411 (2004).

    Article  PubMed  CAS  Google Scholar 

  33. J. A. De Juan, F. J. Moya, A. Ripodas, R. Bernal, A. Fernandez-Cruz, and R. Fernandez-Durango. Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment. Diabetologia. 43:773–785 (2000).

    Article  PubMed  Google Scholar 

  34. A. De Roetth Jr., and F. P. Yen. Experimental diabetic retinopathy. Retinal metabolism in the alloxan diabetic rat. Arch. Ophthalmol. 63:226–231 (1960).

    Google Scholar 

  35. E. A. Ellis, D. L. Guberski, B. Hutson, and M. B. Grant. Time course of NADH oxidase, inducible nitric oxide synthase and peroxynitrite in diabetic retinopathy in the BBZ/WOR rat. Nitric Oxide. 6:295–304 (2002).

    Article  PubMed  CAS  Google Scholar 

  36. G. G. Quin, A. C. Len, F. A. Billson, and M. C. Gillies. Proteome map of normal rat retina and comparison with the proteome of diabetic rat retina: new insight in the pathogenesis of diabetic retinopathy. Proteomics. 7:2636–2650 (2007).

    Article  PubMed  CAS  Google Scholar 

  37. W. G. Robison Jr. Diabetic retinopathy: galactose-fed rat model. Invest. Ophthalmol. Vis. Sci. 36:(4A), 1743–1744 (1995).

    Google Scholar 

  38. R. Rollin, A. Mediero, A. Fernandez-Cruz, and R. Fernandez-Durango. Downregulation of the atrial natriuretic peptide/natriuretic peptide receptor-C system in the early stages of diabetic retinopathy in the rat. Mol. Vis. 11:216–224 (2005).

    PubMed  CAS  Google Scholar 

  39. E. Rungger-Brandle, and A. A. Dosso. Streptozotocin-induced diabetes—a rat model to study involvement of retinal cell types in the onset of diabetic retinopathy. Adv. Exp. Med. Biol. 533:197–203 (2003).

    PubMed  Google Scholar 

  40. Z. Zheng, H. Chen, X. Xu, C. Li, and Q. Gu. Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy. Exp. Eye Res. 84:745–752 (2007).

    Article  PubMed  CAS  Google Scholar 

  41. A. C. Amrite, S. P. Ayalasomayajula, N. P. Cheruvu, and U. B. Kompella. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest. Ophthalmol. Vis. Sci. 47:1149–1160 (2006).

    Article  PubMed  Google Scholar 

  42. S. P. Ayalasomayajula, A. C. Amrite, and U. B. Kompella. Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur. J. Pharmacol. 498:275–278 (2004).

    Article  PubMed  CAS  Google Scholar 

  43. S. P. Ayalasomayajula, and U. B. Kompella. Induction of vascular endothelial growth factor by 4-hydroxynonenal and its prevention by glutathione precursors in retinal pigment epithelial cells. Eur. J. Pharmacol. 449:213–220 (2002).

    Article  PubMed  CAS  Google Scholar 

  44. S. Ishida, T. Usui, K. Yamashiro, Y. Kaji, E. Ahmed, K. G. Carrasquillo, S. Amano, T. Hida, Y. Oguchi, and A. P. Adamis. VEGF164 is proinflammatory in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 44:2155–2162 (2003).

    Article  PubMed  Google Scholar 

  45. S. P. Ayalasomayajula, and U. B. Kompella. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration. Pharm. Res. 21:1797–1804 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. O. Weijtens, E. J. Feron, R. C. Schoemaker, A. F. Cohen, E. G. Lentjes, F. P. Romijn, and J. C. van Meurs. High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am. J. Ophthalmol. 128:192–197 (1999).

    Article  PubMed  CAS  Google Scholar 

  47. D. Ghate, W. Brooks, B. E. McCarey, and H. F. Edelhauser. Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry. Invest. Ophthalmol. Vis. Sci. 48:2230–2237 (2007).

    Article  PubMed  Google Scholar 

  48. T. Ishibashi, K. Tanaka, and Y. Taniguchi. Disruption of blood-retinal barrier in experimental diabetic rats: an electron microscopic study. Exp. Eye Res. 30:401–410 (1980).

    Article  PubMed  CAS  Google Scholar 

  49. M. O. Tso, J. G. Cunha-Vaz, C. Y. Shih, and C. W. Jones. Clinicopathologic study of blood-retinal barrier in experimental diabetes mellitus. Arch. Ophthalmol. 98:2032–2040 (1980).

    PubMed  CAS  Google Scholar 

  50. I. H. Wallow. Posterior and anterior permeability defects? Morphologic observations on streptozotocin-treated rats. Invest. Ophthalmol. Vis. Sci. 24:1259–1268 (1983).

    PubMed  CAS  Google Scholar 

  51. A. Do carmo, P. Ramos, A. Reis, R. Proenca, and J. G. Cunha-vaz. Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp. Eye Res. 67:569–575 (1998).

    Article  PubMed  CAS  Google Scholar 

  52. W. M. Kirber, C. W. Nichols, P. A. Grimes, A. I. Winegrad, and A. M. Laties. A permeability defect of the retinal pigment epithelium. Occurrence in early streptozocin diabetes. Arch. Ophthalmol. 98:725–728 (1980).

    PubMed  CAS  Google Scholar 

  53. S. A. Vinores, P. A. Campochiaro, and B. P. Conway. Ultrastructural and electron-immunocytochemical characterization of cells in epiretinal membranes. Invest. Ophthalmol. Vis. Sci. 31:14–28 (1990).

    PubMed  CAS  Google Scholar 

  54. S. A. Vinores, P. A. Campochiaro, A. Lee, R. McGehee, C. Gadegbeku, and W. R. Green. Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin. Lab. Invest. 62:742–750 (1990).

    PubMed  CAS  Google Scholar 

  55. S. A. Vinores, P. A. Campochiaro, R. McGehee, W. Orman, S. F. Hackett, and L. M. Hjelmeland. Ultrastructural and immunocytochemical changes in retinal pigment epithelium, retinal glia, and fibroblasts in vitreous culture. Invest. Ophthalmol. Vis. Sci. 31:2529–2545 (1990).

    PubMed  CAS  Google Scholar 

  56. S. A. Vinores, R. McGehee, A. Lee, C. Gadegbeku, and P. A. Campochiaro. Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats. J. Histochem. Cytochem. 38:1341–1352 (1990).

    PubMed  CAS  Google Scholar 

  57. R. B. Caldwell, and B. J. McLaughlin. Freeze-fracture study of filipin binding in photoreceptor outer segments and pigment epithelium of dystrophic and normal retinas. J. Comp. Neurol. 236:523–537 (1985).

    Article  PubMed  CAS  Google Scholar 

  58. R. B. Caldwell, S. M. Slapnick, and B. J. McLaughlin. Lanthanum and freeze-fracture studies of retinal pigment epithelial cell junctions in the streptozotocin diabetic rat. Curr. Eye Res. 4:215–227 (1985).

    Article  PubMed  CAS  Google Scholar 

  59. A. W. Stitt, T. Bhaduri, C. B. T. McMullen, T. A. Gardiner, and D. B. Archer. Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats. Molec. Cell Biol. Res. Commun. 3:380–388 (2000).

    Article  CAS  Google Scholar 

  60. J. I. Gallin, I. M. Goldstein, and R. Snyderman. Inflammation: basic principles and clinical correlates. Raven Press, New York, N. Y, 1992.

    Google Scholar 

  61. A. Garner. Histopathology of diabetic retinopathy in man. Eye. 7(Pt 2):250–253 (1993).

    PubMed  Google Scholar 

  62. K. Miyamoto, and Y. Ogura. Pathogenetic potential of leukocytes in diabetic retinopathy. Semin. Ophthalmol. 14:233–239 (1999).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants DK064172, EY013842, and EY017045 (through Emory University). We are very thankful to Leena Patel for her assistance in the preparation of this manuscript.

Author information

Author notes

  1. Narayan P. S. Cheruvu

    Present address: Covidien Ltd., Hazelwood, Missouri, USA

  2. Aniruddha C. Amrite

    Present address: Quintiles Inc., Overland Park, Kansas, USA

Authors and Affiliations

  1. University of Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA

    Narayan P. S. Cheruvu, Aniruddha C. Amrite & Uday B. Kompella

  2. Departments of Pharmaceutical Sciences and Ophthalmology, University of Colorado Denver, Aurora, Colorado, 80045, USA

    Uday B. Kompella

Authors
  1. Narayan P. S. Cheruvu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aniruddha C. Amrite
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Uday B. Kompella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uday B. Kompella.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheruvu, N.P.S., Amrite, A.C. & Kompella, U.B. Effect of Diabetes on Transscleral Delivery of Celecoxib. Pharm Res 26, 404–414 (2009). https://doi.org/10.1007/s11095-008-9757-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9757-2

KEY WORDS

Search

Navigation