Influence of intravitreal injections of HPMPC and related nucleoside analogues on intraocular pressure in guinea pig eyes.
OBJECTIVE
Cidofovir (HPMPC) is a potent long-acting anticytomegalovirus agent. In humans, its dose-limiting intravitreal toxicity results in the lowering of intraocular pressure (IOP). The purpose of the present study was to determine the effects of HPMPC and various acyclic nucleoside phosphonate (ANP) analogues when administered intravitreally in guinea pig eyes and to establish the structural and functional relation of these compounds in connection with their effects on the ciliary body and retina.


METHODS
Ninety-six guinea pig eyes were injected with various doses of HPMPC and ANP analogues.


RESULTS
Severe lowering of IOP with structural alterations of the ciliary body was observed when doses were administered that achieved final intravitreal concentrations greater than 25 microg/ml HPMPC, 200 microg/ml cyclic HPMPC (cHPMPC), 25 microg/ml (S)-HPMPA, and 625 microg/ml PMEG. Concentrations of 25 microg/ml HPMPC, 200 microg/ml cHPMPC or less, and all concentrations of (R)-HPMPA, HPMPU, PMEA, PMEC, PMEDAP, (R)-PMPA, and (S)-PMPA did not lower IOP significantly, nor did they cause significant histologic changes.


CONCLUSIONS
Of the HPMP series, the cyclic analogue of HPMPC (cHPMPC) and HPMPC are the least toxic of the compounds that show potent anti-human cytomegalovirus activity (HCMV). PMEG, the most potent anti-HCMV compound of the PME series, is toxic at higher doses. Further evaluation of lower doses is needed. Compounds of the PMP series are not toxic, but they show no anti-HCMV activities. The IOP-lowering effect of these compounds appears to be associated with an effect on the ciliary body.
Banker
A S
AS
Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
De Clercq
E
E
Taskintuna
I
I
Keefe
K S
KS
Bergeron-Lynn
G
G
Freeman
W R
WR
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D000077404:Cidofovir; D002924:Ciliary Body / Q000187:drug effects* / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D015814:Ocular Hypotension / Q000139:chemically induced; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D013329:Structure-Activity Relationship; D014822:Vitreous Body
D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir