Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus-1 retinitis.
BACKGROUND
Acyclovir diphosphate dimyristoylglycerol is a lipid prodrug of acyclovir that forms liposomes and provides substantial activity against herpes simplex virus, acyclovir-resistant strains of herpes simplex virus, and human cytomegalovirus. We therefore tested this promising new drug in a rabbit model of herpes simplex retinitis.


METHODS
A total of 22 pigmented rabbits were pretreated with either acyclovir diphosphate dimyristoylglycerol, ganciclovir, acyclovir, or buffer. Retinae then were inoculated with herpes simplex virus-1 or buffer 1 week after the injection of drug. In another experiment we compared the effects of acyclovir diphosphate dimyristoylglycerol and acyclovir diphosphate dioleoylglycerol on the optical clarity of vitreous.


RESULTS
Animals injected intravitreally with acyclovir diphosphate dimyristoylglycerol showed retinitis that was less severe than that in animals injected with ganciclovir, acyclovir, and buffer; differences in grading scores of the retinitis between animals injected with acyclovir diphosphate dimyristoylglycerol and those injected with buffer were statistically significant (P = 0.0015). Vitreous and optical media became clear 4 days after acyclovir diphosphate dioleoylglycerol injection compared with 10 days after with acyclovir diphosphate dimyristoylglycerol injections.


CONCLUSIONS
Acyclovir diphosphate dimyristoylglycerol had prolonged antiviral activity against herpes simplex virus-1 retinitis in a rabbit model. This drug delivery system, modified to improve optical clarity, may allow long-acting intravitreal treatment of cytomegalovirus retinitis and other retinal diseases.
Taskintuna
I
I
Department of Ophthalmology, University of California, San Diego, USA.
Banker
A S
AS
Flores-Aguilar
M
M
Bergeron-Lynn
G
G
Aldern
K A
KA
Hostetler
K Y
KY
Freeman
W R
WR
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D008081:Liposomes; D010715:Phosphatidylglycerols / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D011817:Rabbits; D012173:Retinitis / Q000188:drug therapy* / Q000821:virology; D018139:Simplexvirus / Q000502:physiology; D014779:Virus Replication
D000998:Antiviral Agents; D008081:Liposomes; D010715:Phosphatidylglycerols; D011355:Prodrugs; C084886:acyclovir diphosphate dimyristoylglycerol; D015774:Ganciclovir; D000212:Acyclovir