How did Daisy Ridley treat her PCOS

The cataract or cataract is a disease of the eye in which The originally clear lens of the eye becomes cloudy due to various factors. It is estimated that about 18 million people have their eyesight have lost to cataracts and about 2 million diseases are added each year. The main symptom of cataract is slow and painless loss of vision. Visual acuity decreases, but glare sensitivity increases and the environment is increasingly perceived as blurred. In advanced The cataract stage is gray or brownish discoloration in the eye recognize and the patient goes blind. Although the exact triggers are still the subject of research and the Cataract can also occur in children, the majority of the disease is considered to be age-related Effect. The only treatment option is surgical removal the natural lens and its replacement with an artificial polymeric intraocular lens (IOL). A complication of this method that occurs in around 50% of cases is the cataract (secondary cataract) [1, 2]. Ephitel cells located in the eye migrate in the process on the IOL and the anterior and posterior capsular bags, which in turn reduces the view is severely affected. In addition to the possibility of cataracts through a laser capsulotomy, the not harmless thermal destruction of the rear wall of the Capsular bags, to treat, is currently a new approach based on photo-induced drug release examined from the lens implant itself. A therapeutic agent against the epithelial cells is applied to the polymer lens immobilized via a photochemical linker, which is then supported by a targeted photochemical cleavage is released. Since the link cleavage occurs on a Cycloreversion of a cyclobutane ring is based, for the cleavage of which via one-photon Absorption (SPA) light of wavelength <300 nm is required and the cornea is opaque to this wavelength, the required energy has to be via a two-photon process (TPA). This has the advantage that the active ingredient is released precisely controllable spatially by the two photons to be radiated is. The present work focuses on synthetic development and optimization of a new linker system for immobilizing 5FU, one already in Eye-tested cytostatic agent, as well as the effectiveness of the photochemical cleavage the synthesized linker-drug conjugates and the characterization of the release of the active ingredient from the finished polymer material. There were next to the already known coumarin synthesized six other monomers as linkers and tested. Coumarin is the already known system for the immobilization of active ingredients, however, brought various problems for the application with it. The lactone ring is in Dimer is very sensitive to hydrolysis, which is why it cannot be guaranteed that the coumarin in the hydrogel is stable in an aqueous environment. As an alternative linker 1,1-dimethylnaphtalenone, 1,2-dihydronaphthalene, stilbene, cinnamic acid, 1,4- Naphthoquinone and chalcone evaluated. It was found that in particular 1,1-dimethylnaphtalenone, but also coumarin, cinnamic acid and 1,2-dihydronaphthalene elevated temperatures were unstable. However, thermal stability is for sterilization by autoclaving, the only method of sterilization for hydrophilic ones Polymers, absolutely necessary. According to the Woodward-Hoffmann rules, this is the thermal [2 + 2] cycloreversion forbidden. Therefore, the reaction on the 1,1-dimethylnaphtalenone-H5FU dimer examined more closely and in this case not concerted, but radical Mechanism by means of radical scavenger reactions and ESR elucidated and for the first time proven. This discovery is for application as a linker system for the immobilization of 5FU quite unfavorable. For this reason, more polymers with the temperature stable Linkers 1,4-naphthoquinone and chalcone synthesized and analyzed. These polymer materials were found to be stable in the autoclaving test. Furthermore, in this work a general procedure for the synthesis of such active ingredient-loaded polymers developed, each with the monomers tailored small modifications successfully for coumarin, 1,1-dimethylnaphtalenone, 1,4-naphthoquinone and chalcone was carried out. The latter three monomers were more precise on their photochemical properties, the 5FU release investigated from the polymer and the diffusion behavior from the hydrogel. The release of 5FU was successfully demonstrated for all three polymers. Proven due to the requirement of autoclavability of the polymer materials 1,4-naphthoquinone and chalcone emerged as the appropriate linkers for 5FU. Additionally In comparison to previously investigated linker molecules, both have one high two-photon cross-section, which is advantageous for laser release, there here lower energies or shorter irradiation times are used in the eye can.

Cataract is a disease caused by a dysfunction of the metabolism in the eye which leads to an opacification of the natural ophthalmic lens. About 18 million people worldwide have already lost their vision by cataract and 2 millions new incidences are estimated per year. The course of the disease leads to a painless loss of sight, decreasing of the acuity and higher sensitivities towards glares. In the progression, a gray or brown discoloration of the lens develops and the patient may loose his vision completely. The reasons for the opacification vary and they are still under extensive research, but most cases of cataract are related to the aging process. The sole treatment of cataract is replacing the opacified natural lens with a polymer intraocular lens (IOL) via surgery. A typical complication of this treatment is secondary cataract or posterior capsule opacification (PCO), occurring in almost 50% of all cases within 5 years. Retained ephitelical cells migrate onto the IOL and the anterior and posterior capsule bag and cause a progressive deterioration of the visual acuity. The state-of-the-art treatment for PCO is Nd: YAG laser capsulotomy where the posterior capsule bag is destroyed to improve the transparency of the field of vision. However, this treatment has several drawbacks. The high energy beams may damage the IOL, the intraocular pressure is increased, which leads to glaucoma, and the retina can be damaged. Therefore another approach to treat PCO is investigated at present, which targets the epithelial cells via a photo-induced drug delivery system in the IOL. A cytotoxic drug is covalently bound to the polymer backbone of the IOL, which may be released via photochemical excitation when required. The linker cleavage occurs via a cyclobutane moiety which needs excitation at wavelengths below 300 nm, which are absorbed by the cornea. Therefore the required energy must be applied via a two-photon-processes (TPA) at wavelengths of 512 nm. This process guarantees a high selectivity for the linker and excellent spatial control of the drug release. This thesis describes the synthetical development of a new drug-linker-conjugate for the immobilization of 5-fluorouracile as cycotoxic drug and the effectivities of photochemical cleavage and drug releases from functionalized polymer materials. 5-Fluorouracile (5FU) has already been proven as a suitable drug for opthalmic applications. Coumarin and another six other potential linker molecules were examined for the application as linker for 5FU. Coumarin was the first molecule tested for this application, but showed several disadvantages. The lactone ring in the dimer is very vulnerable towards hydrolysis, which cannot be excluded in aqueous surroundings in the eye and leads to undesired reactions upon irradiation. Alternatively, several other molecules were examined which were 1,1-dimethylnaphtalenone, 1,2-dihydronaphtalene, stilbene, cinnamic acid, 1,4-naphtoquinone and chalcone. In the course of the synthesis coumarin, cinnamic acid-, 1,2-dihydronaphtalenes and especially 1,1-dimethylnaphtalenone-5FU dimers showed an unexpected [2 + 2] -cycloreversion reaction at higher temperatures. thesis temperatures are required for autoclaving the polymer material before insertion into the eye, the sole sterilization method for hydrogels. According to Woodward-Hoffmann a thermal [2 + 2] -cycloreversion of the 5FU-linker conjugate is not allowed under these conditions. This interesting finding was thoroughly investigated and the reaction successfully elucidated via radical scavenging reactions and ESR measurements. The reaction does not occur via a concerted mechanism, but via radicals, which may undergo several different following reaction pathways. Although these kind of reactions have already been noticed in the past, the radical mechanism was experimentally proven for the first time in this work. However, this thermal instability of the dimers is unfavorable for the application as a drug delivery device. Therefore, two molecules from the remaining three stable dimers were chosen for further examination. New polymers were synthesized with 1,4-naphtoquinone and chalcone as linkers for 5FU and proved the desired stability against higher temperatures and drug release via TPA processes. A general procedure for the synthesis of 5FU loaded polymers was developed in this thesis and successfully carried out with small modifications for coumarin, 1,1- dimethylnaphtalenone, 1,4-naphtoquinone and chalcone. The last three were further examined regarding photochemical properties, drug release and diffusion rates from the polymer material. Drug release was successfully carried out for all three of them, but only 1,4-naphtoquinone and chalcone have the desired thermal stability, which makes them suitable linkers for 5FU. Both have efficient TPA cross sections which are advantageous for the application due to the possibility of using lower energies and / or shorter irradiation times in the eye.

Bibliography / References

  1. S. Pedersen, J. L. Herek, A. H. Zewail, The Validity of the Diradical Hypothesis: Direct Femtosecond Studies of the Transition-State Structures, Science 1994, 266, 1359-1364.
  2. R. Wayne, Principles and Applications of Photochemistry, Oxford University Press, 1988.
  3. A. Lembaren, X.-H. Hu, G. W. Kalmus, Absorption Spectra of Corneas in the Far Ultraviolet Region, Investigative Ophthalmology & Visual Science 1997, 38, 1283-1287.
  4. R. Wormald, M. Wilkins, C. Bunce, Postoperative 5-Fluorouracil for glaucoma surgery., Cochrane Database of Systematic Reviews 2001, 3.
  5. H. Morrison, H. Curtis, T. McDowell, Solvent effects on the photodimerization of coumarin, J. Am. Chem. Soc. 1966, 88, 5415-5419.
  6. G. Montaudo, S. Caccamese, Structure and conformation of chalcone photodimers and related compounds, The Journal of Organic Chemistry 1973, 38 (4), 710-716.
  7. T. Wolff, H. Görner, Photodimerization of coumarin revisited: Effects of solvent polarity on the triplet reactivity and product pattern, Phys. Chem. Chem. Phys. 2004, 6, 368-376.
  8. N. Yonezawa, T. Yoshida, M. Hasegawa, Symmetric and Asymmetric Photo tocleavage of the Cyclobutane Rings in Head-to-head Coumarin Dimers and Their Lactone-opened Derivatives, J. Chem. Soc. Perkin Trans. 1 1983, 1083-1086.
  9. EJ Hollick, DJ Spalton, PG Ursell, MV Pande, SA Barman, JF Boyce, K. Tilling, The Effect of Polymethylmethacrylate, Silicone, and Polyacrylic Intraocular Lenses on Posterior Capsular Opacification 3 Years after Cataract Surgery, Ophthalmology 1999, 106, 49-55.
  10. A. Ruseckas, E. B. Namdas, J. Y. Lee, S. Mukamel, S. Wang, G. C. Bazan, V. Sundström, Conformations and Photophysics of a Stilbene Dimer, J. Phys. Chem. A 2003, 107 (40), 8029-8034.
  11. S. de Melo, R. Becker, A. Macanita, Photophysical behavior of coumarins as a function of substitution and solvent: experimental evidence for the existence of a lowest lying (n, phi *) - state, J. Phys. Chem. 1994, 98, 6054-6058.
  12. M. D. Auria, A. Vantaggi, Photochemical dimerization of methoxy substituted cinnamic acid methyl esters, Tetrahedron 1992, 48 (12), 2523-2528.
  13. N. Ibaraki, A brighter future for cataract surgery, Nature Medicine 1997, 3, 958-960.
  14. Ridley, N. H. L., Artificial intraocular lenses after cataract extraction, St. Thomas' Hospital Reports 1951, 7, 12-14.
  15. A. Trinavarat, L. Atchaneeyasakul, Neodynium: YAG laser damage threshold of foldable intraocular lenses, Journal of Cataract and Refractive Surgery 2001, 27, 775-780.
  16. S. Umezawa, K. Shimizu, Biocompatibility of surface-modified intraocular len- ses, Journal of Cataract and Refractive Surgery 19, 1993, 371-374.
  17. H. Gan, M. G. Horner, B. J. Hrnjez, T. A. McCormack, J. L. King, Z. Gasyna, G. Chen, R. Gleiter, N. C. Yang, Chemistry of syn-o, o-Dibenzene, J. Am. Chem.
  18. DG Amirsakis, AM Elizarov, MA Garcia-Garibay, PT Glink, JF Stoddart, AJP White, DJ Williams, Diastereospecific Photochemical Dimerization of a Stilbene-Containing Daisy Chain Monomer in Solution as well as in the Solid State, Angewandte Chemie 2003, 115 ( 10), 1158-1164.
  19. H.-P. Merkle, Diffusion, in: Fundamentals of drug form theory-galenics 2, (Ed .: C.-D. Herzfeldt, J. Kreuter), Springer Verlag, Berlin, 1999.
  20. R. G. Martin, D. R. Sanders, J. Souchek, M. G. Raanan, M. DeLuca, Effect of posterior chamber intraocular lens design and surgical placement on postoperative outcome, Journal of Cataract and Refractive Surgery 1992, 18 (4), 333-341.
  21. V. Fernandez, M. Fragoso, C. Billotte, P. Lamar, M. Orozco, S. Dubovy, M. Willcox, J. Parel, Efficacy of various drugs in the prevention of posterior capsule opacification: experimental study of rabbit eyes, J Cataract Refract Surg. 2004, 30 (12), 2598-2605.
  22. H. Zehner, W. Flossmann, E. Westhof, A. Müller, Electron spin resonance of irradiated single crystals of uracil., Molecular Physics 1976, 32, 869-878.
  23. M. Goeppert-Mayer, Elementary processes with two-quantum transitions, Ann.
  24. L. Werner, J. M. Legeais, M. D. Nagel, G. Renard, Evaluation of teflon-coated intraocular lenses in an organ culture method, Journal of Biomedical Materials Research 1999, 46 (3), 347-354.
  25. C. X. L. K. L. Z. Doering, W.v.E., Fate of the Intermediate Diradicals in the Caldera: Stereochemistry of Stereomutations, [2 + 2] Cycloreversions, and [2 + 4]
  26. No authors listed, Five-year follow-up of the Fluorouracil Filtering Surgery Study. The Fluorouracil Filtering Surgery Study Group., Am J Ophthalmol. 1996, 122, 751-752.
  27. A. Schaefer, H. Horn, R. Ahlrichs, Fully optimized contracted Gaussian basis sets for atoms Li to Kr., J. Chem. Phys. 1992, 97, 2571.
  28. Ridley, N. H. L., Further experiences of intraocular acrylic lens surgery, Br. J. Ophthalmol. 1954, 38, 156-162.
  29. N. H. L. Ridley, Further observations on intraocular acrylic lenses in cataract surgery, Trans. Am. Academy Ophthalmol. Otolaryngol. 1953, 57, 98-106.
  30. J. Liese, N. A. Hampp, 1,1-Dimethylnaphthalenon-dimers as photocleavable linkers with improved two-photon-absorption efficiency and hydrolytic stability, Journal of Photochemistry and Photobiology A: Chemistry 2010, 209, 128 - 134.
  31. T. Noh, H. Yu, Y. Jeong, K. Jeon, S. Kang, [2 + 2] Heterodimers of methyl phenanthrene-9-carboxylate and benzene, J. Chem. Soc., Perkin Trans. 1 2001, 21 , 1066-1071.
  32. S. Shizuya, M. Takeshi, Histology of anterior capsule opacification with a polyHEMA / HOHEXMA hydrophilic hydrogel intraocular lens compared to poly (methyl methacrylate), silicone, and acrylic lenses, Journal of Cataract and Refractive Surgery 2003, 29 (6), 1198.
  33. C. Latz, V. Migonney, G. Pavon-Djavid, Inhibition of lens epithelial cell proliferation by substituted PMMA intraocular lens, Graefes Archive for Clinical and Experimental Ophthalmology 2000, 238 (8), 696-700.
  34. S.L. X. Su, J. Zheng, Inhibition of rabbit lens epithelial cell proliferation, Zhonghua Yan Ke Za Zhi 1996, 32, 339.
  35. W.Y. S. Y. Nishimura, J., Intramolecular [2 + 2] Photocycloaddition. 14. Cyclo- reversion of Cyclophanes Possessing a Cyclobutane Ring at their Tether, Bull. Chem. Soc. Jpn. 1992, 65, 618-619.
  36. N. H. L. Ridley, Intraocular acrylic lenses, Transactions of the American Ophthalmic Society 1951, 71, 617.
  37. N. H. L. Ridley, Intraocular acrylic lenses -10 years development, Br. J. Ophthalmol. 1960, 44, 705-712.
  38. D. R. Absolom, C. Thomson, L. A. Hawthorn, W. Zingg, A. W. Neumann, Kinetics of cell adhesion to polymer surfaces, Journal of Biomedical Materials Research 1998, 22 (3), 215-229.
  39. J. Netto-Ferreira, V. Wintgens, J. Scaiano, Lifetimes of biradicals produced in the Norrish type I reaction of methyl-substituted 2-tetralones, Journal of Photochemistry and Photobiology A: Chemistry 1991, 57 (1-3) , 153-163, tetralone radicals.
  40. D. M. Albert, Men of Vision. Lives of Notable Figures in Ophthalmology, Saunders (W.B.) Co. Ltd., 1993.
  41. J. D. Bhawalkar, G. S. He, P. N. Prasad, Nonlinear multiphoton processes in organic and polymeric materials, Rep. Prog. Phys. 1996, 59, 1041-1070.
  42. T. Nagata, I. Watanabe, Optic sharp edge or convexity: comparison of effects on posterior capsular opacification, Japanese Journal of Ophthalmology 1996, 40 (3), 397-403.
  43. F. Neese, ORCA -an ab initio, Density Functional and Semiempirical program package version 2.6-35, University of Bonn, 2008.
  44. R. Hoffman, P. Wells, H. Morrison, Organic photochemistry XII further studies on the mechanism of coumarin photodimerization, J. Org. Chem. 1971, 36, 102-108.
  45. Segal, G.A., Organic transition states. III.Ab initio study of the pyrolysis of cyclobutane via the tetramethylene diradical, Journal of the American Chemical Society 1974, 96, 7892-7898.
  46. T. M. Rabsilber, G. U. Auffarth, Pharmacological approaches to the prevention of cataracta secundaria, Klin Monatsbl Augenheilkd 2006, 223, 559-567.
  47. C. H. Krauch, S. Farid, G. O. Schenck, Photo-C4-Cyclodimerisation von Cumarin, Chemischeberichte 1966, 99, 625-633.
  48. F. Lewis, S. Barancyk, Photodimerization and cross-cycloaddition of coumarin, J. Am. Chem. Soc. 1989, 111, 8653-8661.
  49. J. Rennnert, S. Japar, M. Guttman, Photo-Dimerization and Photo-Reduction of alpha-Naphtoquinone in Different Solvent Media, Photochemistry and Photobiology 1967, 6 (7), 485-490.
  50. J. Dekker, P. Janse van Vuuren, D. P. Venter, Photodimerization. I. The syn and anti photodimers of 1,4-naphthoquinone, J.Org.Chem. 1968, 33, 464-466.
  51. J. Dekker, T. G. Dekker, Photodimerization Part III. The Photodimerization of 1,2-Dihydronaphthalenes, Joernaal van die suid-afrikaanse chemiese Instituut 1973, 26, 25-29.
  52. S. Härtner, H.-C. Kim, N. A. Hampp, Photodimerized 7-hydroxycoumarin with improved solubility in PMMA: single-photon and two-photon-induced photocleavage in solution and PMMA films, J. Photochem. Photobiol. A 2007, 187, 242-246.
  53. J.V. Ellis, J.E. Jones, Photolysis of 2-alkoxy-1,4-naphthoquinones, The Journal of Organic Chemistry 1975, 40 (4), 485-488.
  54. G. O. Schenck, I. von Wilucki, C. H. Krauch, Photosensitized Cyclodimerization von Coumarin, Chemischeberichte 1962, 95 (6), 1409-1412.
  55. S. Härtner, H.-C. Kim, N. Hampp, Phototriggered release of photolabile drugs via two-photon absorption-induced cleavage of polymer-bound dicoumarin, Journal of Polymer Science Part A: Polymer Chemistry 2007, 45, 2443–2452.
  56. A. Shaikh1, F. Shaikh, JR Adwani, ZA Shaikh, Prevalence of different Nd: YAG Laser induced complication in patients with significant posterior cap- sule opacification and their correlation with time duration after standard cata- ract surgery, International Journal of Medicine and Medical Sciences 2010, 2, 12-17.
  57. I. M. Mohamed, J. Alió, M. J. Ruiz, Prevention of Secondary Cataract by Antimitotic Drugs: Experimental Study, Ophthalmic Res 1996, 28, 64-69.
  58. William J. Bailey, L.N., Carl H. Cunov, Pyrolysis of Esters. IV. Thermal Cleavage of the Cyclobutane Ring, Journal of the American Chemical Society 1955, 77, 2787-2790.
  59. Paquette, L.A., Kukla, M.J., Pyrolysis of stereotopically twisted Cyclobutane Rings, Tetrahedron Lett. 1973, 15, 1241-1244.
  60. X.-M. Zhang, Radical Substituent Effects of alpha-Fluorine and alpha-Trifluoromethyl Groups, The Journal of Organic Chemistry 1998, 63, 3590-3594.
  61. M. Hasegawa, H. Katsuki, N. Yonezawa, T. Yoshida, Y. Ikebe, Reaction of syn head-to-head Coumarin Dimer with Amines and Thermal Behavior of the Ad- ducts, Chemistry Letters 1982, 11, 1325-1328 .
  62. L. Hesse, L. Freisberg, H. Bienert, H. Richter, C. Kreiner, C. Mittermayer, Reduction of cataract by plasma etching of intraocular lenses. An animal experiment study, Ophthalmnung 1997, 94, 821-825.
  63. W. T. Wiesler, K. Nakanishi, Relative and Absolute Configurational Associations of Acyclic Polyols by Circular Dichroism. 1. Rationale for a Simple Procedure Based on the Exciton Chirality Method, J. Am. Chem. Soc. 1989, 111, 9205-9213.
  64. L. Rickman Barga, C. Florine, R. Larson, R. Lindstrom, Retinal detachement after neodymium: YAG laser posterior capsulotomy, Am J Ophthalmol 1989, 107, 531-536.
  65. Ring Enlargements of cis-and trans-1-Cyano-2- (E and Z) -propenyl-cis-3,4-di-deuteriocyclobutanes, J. Am. Chem. Soc. 2002, 124, 11642-11652.
  66. J.-S. Lee, C.-Y. Li, Y.-C. Lin, S.-Y. Chang, K.-K. Lin, Ripple-like intraocular lens damage from a neodymium: YAG laser, Journal of cataract and refractive surgery 2003, 29 (3), 621-623.
  67. X. Yu, D. Scheller, O. Rademacher, T. Wolff, Selectivity in the Photodimerization of 6-Alkylcoumarins, The Journal of Organic Chemistry 2003, 68, 73867399.
  68. S. Härtner, H.-C. Kim, N. Hampp, Single-and two-photon absorption induced photocleavage of dimeric coumarin linkers: therapeutic versus passive photocleavage in ophthalmologic applications, J. Photochem. Photobiol. A 2008, 197, [41] P. S. Giacomo Ciamician, Chemical light effects, Chem. Ber. 1902, 34, 1530-1543.
  69. AW, BM, T. Schoepf, E. Ambach, F. Katzengraber, F. Daxecker, A. Daxer, Spectral transmission of the optical media of the human eye with respect to keratitis and cataract formation, Documenta Ophthalmologica 1994, 88, 165– 173.
  70. R. B. Woodward, R. J. Hoffmann, Stereochemistry of Electrocyclic Reactions, J. Am. Chem. Soc. 1965, 87, 395-397.
  71. O. Wiest, Structure and [2 + 2] Cycloreversion of the Cyclobutane Radical Cation, The Journal of Physical Chemistry A 1999, 103, 7907- 7911.
  72. T. Reinhard, M. Klüppel, R. Sundmacher, 5-Fluorouracil Injection After Filtering Surgery, Klin Monatsbl Augenheilkd 1993, 203, 329-335.
  73. P. Yammine, G. Pavon-Djavid, G. Helary, V. Migonney, Surface modification of silicone intraocular implants to inhibit cell proliferation, Biomacromolecules 2005, 6 (5), 2630-2637.
  74. C. N. Cunanan, N. M. Tarbaux, P. M. Knight, Surface properties of intraocular lens materials and their influence on in vitro cell adhesion, Journal of Cataract and Refractive Surgery 1991, 17 (6), 767-773.
  75. D. T. Pham, U. Kraffel, J. Wollensak, Surgical Polishing of Cataracta Secundaria and Its Complications, Klin Monatsbl Augenheilkd 1993, 202 (6), 507-510.
  76. T. Noh, S. Kang, M. Joo, H. Yu, Syn- [2 + 2] Cyclodimers of 2-Cyanonaphthalenes and Benzene, Bull. Korean Chem. Soc. 2000, 21, 459-460.
  77. J. Liese, N.A. Hampp, Synthesis and Photocleavage of new [2 + 2] hetero di- Bibliography 173
  78. N. Yonezawa, M. Hasegawa, Synthesis of Lactone-opened Derivatives of anti and syn Head-to-Head Coumarin Dimers, Bull. Chem. Soc. Jpn. 1983, 56, 367-368.
  79. DM Birney, JA Berson, Synthesis of the covalent benzene-carbon monoxide cycloadduct, norborna-2,5-dien-7-one: Correlation of kinetic and thermodynamic stabilities in cycloreversion reactions, Tetrahedron 1986, 42 (6), 1561 - 1570.
  80. A. Willmes, paperback chemical substances: elements -inorganics -organics -natural substances -polymers, Verlag Harri Deutsch, 2007.
  81. C. Doubleday, Tetramethylene Optimized by MRCI and by CASSCF with a multiply Polarized Basis Set., J. Phys. Chem 1996, 100, 15083-15086.
  82. K. K., The application of cocaine to the eye as an anesthetic, Wein Med Bl Oct 1884, 23, 1352-1355.
  83. R. B. Woodward, R. J. Hoffmann, The Conservation of Orbital Symmetry, Angew. Chem. Int. Ed. 1969, 8, 781-853.
  84. R. B. Woodward, R. H. Eastman, The Dimerization of 6-Methoxy-3,4-dihydronaphthalene, Journal of the American Chemical Society 1944, 66 (5), 674-679.
  85. Pesudovs, K., Elliot, D. B., The evolution of cataract surgery., Optom. Today 2001, 41, 30-32.
  86. C. S. Pearlstein, S. S. Lane, R. L. Lindstrom, The incidence of secondary posterior capsulotomy in convex-posterior vs. convex-anterior posterior chamber intraocular lenses, Journal of Cataract and Refractive Surgery 1998, 14 (5), 578-580.
  87. E. Miller, The metabolism and pharmacology of 5-fluorouracil, Journal of Surgical Oncology 1971, 3 (3), 309-315.
  88. H. I. Bernstein, W. C. Quimby, The Photochemical Dimerization of trans-Cinnamic Acid, Journal of the American Chemical Society 1943, 65 (10), 1845-1846.
  89. J. Liese, N.A. Hampp, Thermal [2 + 2] -cycloreversion of a cyclobutane moiety via a biradical reaction, JPC A 2011, accepted.
  90. J. Carnduff, J. Iball, G. Leppard, J. N. Low, The Structure of the anti Head-to-head Photodimer of 1,1-Dimethyl-2 (1H) -naphthalenone, Chem. Comm. 1969, 1218-1219.
  91. T. Mukai, T. Oine, H. Sukawa, Three Photodimers of 1,1-Dimethyl-2 (1H) -naphthalenone, Chem. Comm. 1970, 271-272.
  92. H.-C. Kim, S. Härtner, M. Behe, T. Behr, N. A. Hampp, Two-photon absorption-controlled multidose drug release: a novel approach for secondary cataract treatment, J. Biomed. Opt. 2006, 11, 119.
  93. L. Parma, N. Omenetto, Two-photon absorption of 7-hydroxycoumarine, Chemical Physics Letters 1978, 54 (3), 541-543.
  94. W. Kaiser, C. G. B. Garrett, Two-Photon Excitation in CaF2: Eu2 +, Physical Review Letters 1961, 7, 229.
  95. H.-C. Kim, S. Kreiling, A. Greiner, N. Hampp, Two-Photon-Induced Cyclore- version of Coumarin Photodimers., Chemical Physics Letters 2003, 372, 899.
  96. R. N. Beale, E. M. F. Roe, Ultra-violet absorption spectra of trans- and cis-stilbenes and their derivatives. Part I. Trans- and cis-stilbenes, J. Chem. Soc 1953, 2755-2763.
  97. T. K. Dobbs, D. V. Hertzler, G. W. Keen, E. J. Eisenbraun, R. Fink, M.B. Hossain, D. Van der Helm, Regioselective acid-catalyzed cyclodimerization of 1,2-dihydronaphthalenes. Mechanism of formation and single-crystal x-ray analysis of two octahydrobenzo [j] fluoranthenes, The Journal of Organic Chemistry 1980, 45 (23), 4769-4774.
  98. World Health Organization, Prevention of Blindness and Visual Impairment: Priority eye diseases - Cataract 2011.
  99. R. Dahm, Between crystal clear and cataracts: Augenlinse, Biologie in our Zeit 2003, 33, 366–374.
  100. D. B. Longley, D. P. Harkin, P. G. Johnston, 5-Fluorouracil: mechanisms of action and clinical strategies, Nat Rev Cancer 2003, 3, 330-338.
  101. R. W. Carr, W. D. Walters, The Thermal Decomposition of Cyclobutane, J. Phys. Chem. 1963, 67, 1370-1372.
  102. J. Daviel, A new method of curing cataract by extraction of the lens., Memoires de L'Academie Royale de Chirurgie 1753, 2, 337-354.
  103. N. H. L. Ridley, Intraocular acrylic lenses after cataract extraction, Lancet 1952, 19, 118-129.