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S. S. Lee, H. F. Edelhauser, P. Sharma, I. Harutyunyan, D. Z. D'Argenio, R. A. Moats; Understanding Drug Gradients in the Human Vitreous Using MRI. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5950.
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Drug diffusion gradients have been described to occur in the vitreous humor of a number of animal species. However, there is often hesitation to conclude that this heterogeneous drug dispersion also occurs in the human vitreous because it becomes syneretic as result of disease and age. Furthermore, head and eye movements occur more frequently in humans than in animals, thereby contributing to increased drug dispersion in the human vitreous. To improve our understanding of drug gradients in the human vitreous, ex vivo magnetic resonance imaging (MRI) studies were performed on whole human globes to evaluate drug distribution following simulated eye movement.
Fresh (<24 hours post-enucleation) human globes of aged donors (average age 60 years) (Lions Eye Institute, Tampa, FL) each received 1 intravitreal injection of 5 µL of 0.05M Gd-DTPA (Magnevist, Berlex , Inc.) diluted in a crosslinked hyaluronic acid gel. Head and eye movement was simulated by securing the injected eye (n=2) on an orbital shaker at maximum tilt and frequency for 1 hour. Control eyes (n=2) were immediately imaged in a 7-Tesla MRI (Bruker Corp., Billerica, MA). Serial 3-D MRI scans were performed for up to 8 hours for each eye. Signal intensity was measured from the high intensity core and outwards to the periphery of the depot along the center axis of the injection site in 1 plane for each time point. Concentration of Gd-DTPA was estimated from the signal intensity and the slope of the concentration along the measured axis was determined to assess the steepness of the gradient.
Diffusion gradients were detected at the injection location in both control and movement simulated eyes at all time points imaged. The average steepness of the gradient in control eyes decreased from 3.7E-04 at 0.5 hr to 2.77E-.06 at 5 hr and 1.7E-04 at 2 hr to 1.2E-05 at 5 hr in movement simulated eyes. The gradient intensities of control and movement simulated eyes did not appear to be significantly different.
Drug diffusion gradients in the vitreous humor appear to persist in the movement-simulated aged human eye up to 8 hours following intravitreal injection. Shortly following intravitreal injection, drug is concentrated near the injection site, suggesting that injection placement within the vitreous may be important to optimize drug exposure to targeted tissues in the eye.
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