Browsing by Subject "eye"
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(2015)Posterior segment ocular diseases, such as age-related macular degeneration and diabetic retinopathy, can cause irreversible damage to the retina and visual impairments. Topical eye drop administration can be used for the treatment of anterior segment diseases, but it is not possible to get therapeutic drug concentrations in the posterior segment of the eye via topical route. Currently, intravitreal injections and implant are widely used for the treatment of posterior segment diseases. However, intravitreal administration can cause pain and discomfort, and frequent intravitreal administration can lead to, for example, retinal detachment and endophthalmitis. Therefore, safer and more patient friendly drug delivery method would be needed. After systemic administration, blood-aqueous barrier and bloodretinal barrier hinder the diffusion of drugs to the intraocular tissues. The aim of the experimental part was to develop a pharmacokinetic simulation model that could be used to predict the distribution of drugs into the eye after systemic administration. Such a model would be a very useful tool in drug development. The prediction accuracy of the model was tested with ten drugs. Concentrations in the vitreous and blood after systemic administration in rabbits has been published for these drugs. On average the prediction accuracy of the model was quite good: the simulated AUC of the drug concentration in the vitreous was 125 % and Cmax 117 % of the measured reference value. However, there was a significant amount of variation in the results. The lowest simulated AUC was 15 % and the highest simulated AUC was 403 % of the measured reference value. Therefore, the model is not yet realiable enough to be used as a tool in drug development. It might be possible to increase the prediction accuracy of the model by incorporating active transport into it and by using 2-compartment model to simulate systemic pharmacokinetics.
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(2021)Canine uveal melanoma (UM) usually manifests as a slowly developing, darker pigmented and well distinguishable mass in the iris. Less than a third of them are considered malignant, which is much less than with other melanocytic cancers. In contrast, in humans, 90% of UM occurs in the choroid and half of the patients eventually develop aggressive and often lethal metastases. Understanding the disease process and genetic background in dogs might also help us further the knowledge and improve the treatment options of humans. There is a hereditary component to the oncogenesis of the UM: the disease is more common in a Caucasian race and is also found in certain families. It is also more prevalent in certain dog breeds; Labrador Retrievers seem to be overrepresented. Several susceptibility genes have been identified in humans. One with the strongest association with UM is a tumor suppressor gene BAP1, which is dysfunctional or missing in nearly half of the human uveal melanomas. This gene is a so-called secondary driver of the UM and mutations in it spark the metastasizing process. There is a germline mutation of BAP1 in fourth of Finnish UM families and these mutations are also connected to various other cancers. Moreover, BAP1 shows over 98% protein product homology and almost 80% mRNA homology between dogs and humans, making it an appealing study target also for canines. Should a single variant account for high UM risk, a DNA test could be developed to be used in breeding and veterinary diagnostics. In this work, I mapped the BAP1 germline mutations of seven Labrador Retrievers with diagnosed uveal melanomas or melanocytomas. It was found that four dogs shared the same set of five heterozygous single nucleotide variants (SNV). One of the SNVs within exon 17 was synonymous, g.37,363,076G>A, p.(Ser721Ser), while the other four SNVs were intronic, residing close to exons 4, 10, 11 and 14. In the future, variant comparisons with healthy Labradors are needed to study the role of the identified variants for the development of UM, as the SNVs now found could also just be a part of a common variation in the Labrador Retriever gene pool. To grasp a bigger picture of the UM tumor development, the tumors themselves should also be analyzed for somatic mutations. Moreover, when we know that the disease is likely affected by over a hundred genes, studying just one gene is unnecessarily self-restricting. Modern full genome sequencing techniques should be used for catching all the predisposing genes simultaneously.
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