Abstract
Purpose: :
To investigate the intraocular properties and highest nontoxic dose of hexadecyloxypropyl–cyclic–HPMPA(HDP–cHPMPA), a crystalline drug delivery system for long acting treatment of CMV retinitis. The compound was tested in–vitro in HFF cells infected with the AD–169 strain of human CMV (HCMV), followed by testing in the rabbit eye.
Methods: :
In vitro testing in HFF cells showed an EC–50 against HCMV of 0.003µM, representing antiviral activity which is 500– and 153–fold greater than that of ganciclovir and cidofovir respectively. Pigmented rabbits were used to test for toxicity . One eye of each animal was injected with the test compound and the fellow eye was injected with BSS as control. Three doses (55 µg/eye, 100 µg/eye and 550 µg/eye) were tested and each dose was tested in triplicate. After injection the eyes were monitored with slit lamp, tonopen, indirect ophthalmoscopy and electroretinography. Animals were sacrificed at 8 weeks after injection and the globes were processed for histology.
Results: :
All three eyes injected with highest drug dose showed optic disc edema and hyperemia, vitritis , aqueous cell and low intraocular pressure. Out of three eyes injected with the intermediate dose, two showed no toxicity and one showed mild optic disc hyperemia with no other abnormalities. All three eyes injected with 55 µg/eye of HDP–cHPMPA demonstrated completely normal morphology and structures of all ocular tissues. Intraocular pressure of the eyes with 55µg test dose versus the control eyes were 17±2 vs.15±4 mmHg (p=0.5). Implicit of b–wave and the amplitude from a–wave trough to b–wave peak of the eyes with 55µg test dose versus control eyes were 46±2.8 vs 44±0 ms (p=0.5) and 90±3.8 vs. 82±2 µV (p=0.1), respectively.
Conclusions: :
Intravitreal injection of 55 µg/eye of HDP–cHPMPA in rabbit eyes yields a calculated intravitreal concentration of 65µM (mol wt. 567.7) which is 21,529 fold greater than the EC–5O against HCMV(0.003µM). The drug dissolves slowly in the vitreous,and preliminary data suggests the duration of action will be over four months.
Keywords: retina • AIDS/HIV • drug toxicity/drug effects