Compounds for treating ophthalmic diseases and disorders
A compound, technology for ocular diseases, for use in the field of intraocular DHODH inhibitor compounds, DHODH inhibitor compounds, administration of ophthalmic compositions, intravitreal administration, treatment of ophthalmic diseases and disorders, controlled release of therapeutically active agents, Ability to address unmet medical needs, low safety of therapies, etc.
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Embodiment 1
[0192] Example 1: Local Tolerability of Intravitreal Injection of PP-001
[0193] Intraocular (=topical) administration of drugs for uveitis is an ideal way of treatment avoiding systemic treatments, which often have severe side effects.
[0194] For this purpose, three different doses of PP-001 dissolved in phosphate-buffered saline (PBS) and a vehicle control containing only PBS were injected into the posterior chamber (=vitreous) of rat eyes. Eyes (anterior chamber) were examined daily with an ophthalmoscope, the experiment was terminated after 8 days, and the processed eyes were used for histological analysis (frozen section).
[0195] Eight Lewy mice (7-8 weeks old) were anesthetized subcutaneously with 0.5 mg / kg medetomidine. Obuvacaine 0.4% eye drops were administered for additional local anesthesia. After intraocular injection, subcutaneous injection of 2.5mg / kg atipamezole antisedation.
[0196] Monitored under an operating microscope, 10 μl of the solution was i...
Embodiment 2
[0204] Example 2: Prevention of recurrence of experimental autoimmune uveitis in a rat model by intravitreal injection of PP-001
[0205] Experimental autoimmune uveitis (EAU) of the Lewy rat is a model of endogenous uveitis in humans. The disease is mediated by CD4+ T lymphocytes of the T helper 1 (Th1) and Th17 subtypes. In Lewi mice, disease is induced by immunizing animals with retinal antigens, such as interphotoreceptor retinoid binding protein (IRBP), and an adjuvant. IRBP is also considered a human autoantigen.
[0206] Peptide R14, a 23mer from IRBP, is the most pathogenic epitope for Lewy mice. Immunization with these peptides emulsified in complete Freund's adjuvant (CFA) caused severe inflammation of the anterior chamber of the eye and destruction of retinal structures.
[0207] R14 causes relapsing remitting disease with early onset (around day 7) with peak EAU between days 10-14 and remission around days 17 / 18.
[0208] Twenty rats were immunized with 15 μg...
Embodiment 3
[0212] Example 3: Inhibition of choroidal neovascularization
[0213] Choroidal neovascularization is a known feature of posterior uveitis and is a major cause of retinal destruction and injury. To monitor the effect of PP-001 on neovascularization, the EAU model in Lewi rats was used.
[0214] In Lewi mice, disease is induced by immunizing animals with the retinal antigen PDSAg (14-mer derived from S-Ag). Immunization with peptide emulsified in complete Freund's adjuvant (CFA) caused severe inflammation of the anterior chamber of the eye and destruction of retinal architecture and choroidal neovascularization.
[0215] Induction with PDSAg caused a monophasic disease in which the first clinical signs of inflammation were observed between days 8-12 after immunization and reached a peak of disease between days 14-18. Inflammation in the anterior chamber did not subside until day 21-22 after immunization. Long-term effects, eg, choroidal neovascularization can be seen later...
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