How did Daisy Ridley treat her PCOS



Summary:
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.

Summary:
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.

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