Treatment or prevention of herpes simplex virus retinitis with intravitreally injectable crystalline 1-O-hexadecylpropanediol-3-phospho-ganciclovir.
OBJECTIVE
To evaluate an intraocular drug delivery system consisting of the crystalline ammonium salt of 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV) as a slow-release form of the drug.


METHODS
A dosage of 0.885, 1.57, 2.8, 4.486, or 8.85 micromol of ammonium salt HDP-P-GCV in 0.1 mL was intravitreally injected into rabbit vitreous. The toxicity and safety were evaluated with ophthalmoscopy, electroretinography, and pathology. Drug vitreous levels were determined at various time intervals by means of HPLC. The treatment efficacy and duration of efficacy were tested in a herpes simplex virus (HSV)-1 retinitis rabbit model.


RESULTS
Intravitreal injections of the compound revealed clear vitreous of optic axis, a desirable drug depot in the inferior vitreous cavity, and no clinical toxicity, except for variable mild local posterior subcapsular cataract and local retinal toxicity with high doses. HPLC analysis showed free ammonium salt of HDP-P-GCV in the upper vitreous at a level of 0.2 microM 12 weeks after the 2.8-micromol initial intravitreal dose. Drug concentration was still 1.95 microM 20 weeks after the 8.85-micromol initial intravitreal dose. These concentrations (0.2 and 1.95 microM) were 10 and 100 times higher, respectively, than the median inhibitory concentration (IC(50)) of HSV-1 (0.023 microM). Treatment with the highest nontoxic dose (2.8 micromol) and the highest dose (8.85 micromol) showed significant protection from HSV-1 infection (P < 0.05) and provided sustained antiviral effect after a single intravitreal drug injection.


CONCLUSIONS
The crystalline ammonium salt of HDP-P-GCV may be a very useful local therapy for herpes family viral retinitis.
Cheng
Lingyun
L
Shiley Eye Center, University of California San Diego, La Jolla, California 92093-0946, USA.
Hostetler
Karl Y
KY
Chaidhawangul
Sunan
S
Gardner
Michael F
MF
Beadle
James R
JR
Toyoguchi
Mitsuko
M
Bergeron-Lynn
Germaine
G
Freeman
William R
WR
D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D016503:Drug Delivery Systems; D004596:Electroretinography; D015828:Eye Infections, Viral / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006561:Herpes Simplex / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D018259:Herpesvirus 1, Human / Q000302:isolation & purification*; D007267:Injections; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D012173:Retinitis / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D012449:Safety; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism
C407662:1-O-hexadecyl-propanediol-3-phospho-ganciclovir; D011355:Prodrugs; D015774:Ganciclovir