cc-3052 and Disease-Models--Animal

To evaluate the effect of thalidomide analogue CC-3052 on corneal neovascularization in the rabbit model.. Corneal neovascularization was induced in 15 rabbits by a silk suture in the corneal stroma. At 1 week after suturing, 30 eyes were divided into 5 groups of 6 eyes each. Three groups were treated with topical CC-3052 at 3 different concentrations: 0.25% (group 1), 0.5% (group 2), and 1.0% (group 3). All treatments were performed twice a day for a week. A 0.5% concentration of CC-3052 was injected subconjunctivally once in group 4. In group 5, a topical balanced salt solution was added twice a day for a week as the experimental control group. Rabbit corneas were photographed by a digital camera and examined by the operating microscope. Half of the corneal specimens were analyzed histopathologically, and the other half were used to measure the concentration of tumor necrosis factor α and vascular endothelial growth factor (VEGF) messenger RNA by reverse transcriptase-polymerase chain reaction.. The neovascularized area was decreased in all treatment groups compared with the control group. There was a significant difference in the percentage and score of corneal neovascularization between the control and all treatment groups. Inflammation, fibroblast, neovascularization, and anti-VEGF antibody intensities were significantly lower in the control group. The concentration of VEGF and tumor necrosis factor α was significantly lower in the control group. There was no difference between the treatment groups.. Topical and subconjunctival administration of thalidomide analogue CC-3052 was found to be effective for the inhibition of corneal neovascularization.

Topics: Administration, Topical; Angiogenesis Inhibitors; Animals; Biomarkers; Corneal Neovascularization; Disease Models, Animal; Female; Male; Rabbits; Thalidomide; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

Topics: Animals; Antibiotics, Antitubercular; Bacterial Load; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Drug Interactions; Immunity, Innate; Isoniazid; Lung; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mycobacterium tuberculosis; Phosphodiesterase 4 Inhibitors; Thalidomide; Tuberculosis