Posterior segment involvement in ocular Behçet's disease.

PURPOSE: Posterior segment involvement, which can lead to blindness with recurrent inflammatory attacks, has a very important prognostic value in ocular Behçet's disease (BD). This study evaluated the frequency and characteristics of posterior segment involvement and the causes of visual impairment in patients with ocular BD. METHODS: We retrospectively evaluated 257 eyes of the 131 patients who were followed from 1993 to 2001 in the Uveitis and BD division of SSK Ankara Eye Hospital, Turkey. RESULTS: The mean follow-up was 49.2 +/- 27.4 months. Thirty-one of the palents were female (23.6%) and 100 male (76.4%). The mean age was 25.1 +/- 7.9. Fundus changes were observed in 213 (82.9%) eyes and were bilateral in 87%, and vitritis was present in 239 (93%) eyes. The most frequent fundus changes were vascular sheathing in 61 eyes (23.7%), optic atrophy in 46 (17.9%), macular edema in 29 (11.3%), retinal hemorrhage in 23 (9%), macular scar in 21 (8.2%), optic disc paleness in 19 (7.4%), retinal edema in 17 (6.6%), branch retinal vein occlusion in 15 (5.8%). The most common fluorescein angiography findings were diffuse vascular leakage in 98 (38%), hyperfluorescence of the optic disc in 38 (14.8%) and hyperfluorescence of the macula in 29 eyes (11.3%). Visual acuity was <1/10 in 85 (33%) of the eyes. Optic atrophy was the main cause (54.1%) of permanent visual impairment. CONCLUSIONS: Posterior segment involvement is the most serious ocular complication of BD, leading to blindness with recurrent attacks. Following patients closely, performing fluorescein angiography in all patients diagnosed as BD even they have no clinical ocular involvement, and early treatment are very important in the prognosis of the disease.

Central retinal artery occlusion associated with ocular Behçet's disease.

PURPOSE: To report a case of central retinal artery occlusion associated with ocular Behçet's disease (BD) and briefly discuss retinal vasculitis due to BD. CASE REPORT: A 52-year-old man, diagnosed as BD 22 years ago and followed up with ocular involvement for six years presented with sudden loss of vision. The clinical diagnosis was central retinal artery occlusion. RESULTS: No other associated systemic diseases were found and the case was classified as a complication of retinal vasculitis due to BD. CONCLUSIONS: Although the arteries are rarely affected in retinal vasculitis due to BD, it has to be considered in the differential diagnosis of retinal arterial occlusions especially in countries where the disease is prevalent. To our knowledge, this is the first reported case of ocular BD complicated with central retinal artery occlusion.

Factors influencing treatment results in pseudophakic endophthalmitis.

PURPOSE: To evaluate risk factors, therapeutic approaches and factors associated with the poor visual outcome in pseudophakic endophthalmitis. METHODS: Data related to 28 cases with the diagnosis of endophthalmitis after cataract surgery and IOL implantation were gathered retrospectively. RESULTS: Preceding surgery was extracapsular cataract extraction (ECCE) in 18, phacoemulsification in 8 and scleral fixated intraocular lens implantation in two cases. Posterior capsule rupture and diabetes mellitus were considered to contribute to the development of endophthalmitis because of their high incidences (50% and 25%) in the study group. Microbiological studies from aqueous and vitreous humour were done in 85% of the cases and 58% were positive. S. Epidermidis was the most common organism, accounting for 50% of the isolates. All cases were given topical and systemic antibiotics. Inflammation was controlled by addition of subconjunctival antibiotics to this regimen in two, intravitreal antibiotic injection in 14, pars plana vitrectomy, total capsular and lens extraction and intravitreal antibiotic injection in three, lens exchange, intracapsular and intravitreal antibiotic injection in three cases. Six (21%) cases eventually needed evisceration. Visual acuity of 20/40 or better was achieved in 25%, and 20/100 or better in 64%. CONCLUSIONS: Treatment delay (p=0.039), capsular rupture complicating cataract surgery, especially with extracapsular cataract extraction (p=0.015), and initial visual acuity worse than hand motion (p=0.003) were strong predictors of poor visual outcome. The risk of endophthalmitis was not different forplanned ECCCE (0.26%) andphacoemulsification (0.27%) but the prognosis was better with the latter.

Evaluation of the human choroidal melanoma rabbit model for studying microcirculation patterns with confocal ICG and histology.

The aim of this study was to develop consistently focal elevated choroidal masses of human choroidal melanoma in immunosuppressed rabbits and to correlate the visualization of prognostically significant microcirculation patterns from confocal indocyanine green angiography with histologic microcirculation patterns. A human choroidal melanoma cell line (OCM1) was implanted in the choroid of 40 rabbit eyes using three different techniques: transscleral choroidal injection of a cell suspension, injection of a cell suspension in a surgically induced cyclodialysis cleft, and implantation of solid tumor fragments in a surgically induced cyclodialysis cleft. The rabbits were immunosuppressed with daily injections of Cyclosporin A to prevent host versus graft reaction. The eyes were studied weekly with indirect ophthalmoscopy and fundus photography to monitor tumor growth and indocyanine green angiography using a confocal scanning laser ophthalmoscope to identify microcirculation patterns in vivo and correlate these findings with the histologic demonstration of tumor microcirculation patterns. A tumor mass was identified by indirect ophthalmoscopy in 16 of the 40 implanted rabbit eyes (40%). Each of these tumors was confirmed histologically to represent a focal elevated choroidal mass. All 16 elevated choroidal masses grow in eyes in which solid tumor fragments were implanted. In total, a melanoma was identified histologically in 28 of the implanted 40 eyes (70%). In addition to the 16 eyes where the melanoma appeared as a focal elevated choroidal mass, 4 eyes contained a focal elevated mass in the sclera and 8 eyes contained a flat choroidal tumor. Histologically, microcirculation patterns were identified only in the 16 eyes with focal elevated choroidal masses. Confocal indocyanine green angiography imaged microcirculation patterns in 13 of these 16 eyes (81%). The surgical implantation of small solid fragments of human choroidal melanoma in immunosuppressed rabbit eyes provides the best method to consistently obtain focal elevated choroidal masses. These focal elevated choroidal masses resemble booth the localization and the growth pattern of choroidal melanomas in humans. In addition, they also contain microcirculation patterns similar to those seen in humans that are detectable with confocal indocyanine green angiography. The use of indocyanine green angiography with this animal model may be especially useful in designing and evaluating anti-microcirculation treatments directed at uveal melanoma.

The utility of entoptic perimetry as a screening test for cytomegalovirus retinitis.

OBJECTIVE: To determine the sensitivity and specificity of entoptic perimetry as a noninvasive test for detecting retinal damage due to peripheral cytomegalovirus (CMV) retinitis. DESIGN: A masked study comparing entoptic perimetry with fundus photography under 4 experimental conditions (determined by increasing pixel sizes) on 2 separate testing sessions. SETTING: Acquired immunodeficiency syndrome Ocular Research Unit at the University of California, San Diego. PATIENTS: Twenty-four human immunodeficiency virus-positive and 8 human immunodeficiency virus-negative subjects; 21 eyes with documented CMV retinitis, and 26 eyes that were retinitis free. MEASUREMENTS: For each testing session, screening method, and condition, the presence of CMV retinitis was determined for each meridian (i.e., clock hour), each quadrant (consisting of 3 meridians), and each eye (consisting of all meridians); the amount of retinitis was defined as the percentage of meridians or quadrants with CMV retinitis. RESULTS: Entoptic perimetry was as sensitive and specific as fundus photography in determining the presence of CMV retinitis. Determination of the amount of CMV retinitis tended to be underestimated by perimetry for larger pixel sizes. CONCLUSION: Entoptic perimetry may be an effective and inexpensive alternative to fundus photography for CMV retinitis in hospitals and community clinics.

Effects of topical and subconjunctival cidofovir (HPMPC) in an animal model.

PURPOSE: To characterize the anterior segment effects of cidofovir, using an animal model. METHODS: Cidofovir drops, at concentrations of 0.04%, 0.4% and 4%, were instilled in eyes of guinea pigs once daily for 10 days. Fellow eyes (controls) received normal saline. The corneal epithelium was debrided at day one and then at every other day for 10 days. Subconjunctival injections of 20 microl of 4% cidofovir were given in another group of animals. A micromanometer was used to determine the intraocular pressure (IOP). Eyes were studied histopathologically at the conclusion of the study. RESULTS: There was no significant drop in IOP after 10 days, using the 0.04% concentration of cidofovir drops. Histology revealed mild corneal edema and inflammatory infiltrate; iris, ciliary body and retina were normal. There was a statistically significant drop in IOP in the eyes treated with 0.4% and 4.0% cidofovir eye drops at 10 days (p = 0.005 and p < 0.0001, respectively) compared to baseline. Morphological changes included moderate to severe corneal edema, vascularization and inflammatory infiltration. The iris and ciliary body revealed mild inflammatory changes only at the 4% cidofovir dose. No changes were seen in the retina with any doses. No change in IOP was observed following subconjunctival injections of 4% cidofovir, and histologically, only localized inflammatory changes in the conjunctiva were observed. CONCLUSIONS: The IOP-decreasing effect of cidofovir occurs at doses below those causing intraocular inflammation and is likely due to an effect on the anterior segment. The anterior segment effects of cidofovir in guinea pigs were similar to those in humans. Thus, the guinea pig appears to be a good animal model for studying the effects of cidofovir on the anterior segment structures.

Influence of intravitreal injections of HPMPC and related nucleoside analogues on intraocular pressure in guinea pig eyes.

PURPOSE: 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.

Intravitreal and plasma cidofovir concentrations after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis.

This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

Clinical failure of CMV retinitis with intravitreal cidofovir is associated with antiviral resistance.

OBJECTIVES: To determine the incidence of clinical resistance to intraocular cidofovir injection for treatment of acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis, and to identify virologic features associated with cidofovir treatment failure. PATIENTS AND METHODS: Clinical resistance to intravitreal cidofovir was examined in 64 patients with CMV retinitis who received at least 1 injection of 20 pg of cidofovir. Histopathologic examination, culture, and polymerase chain reaction were used to detect CMV in ocular specimens. Antiviral resistance was assessed by plaque reduction assay and DNA sequencing. RESULTS: Clinical resistance to intravitreal cidofovir injections was identified in 3 patients (5%) and was associated with prior oral ganciclovir or intravenous cidofovir use. Ganciclovir- and cidofovir-resistant CMV isolates were cultured from 2 patients and harbored resistance-associated mutations in the UL97 and polymerase genes. Resistance mutations were also detected by direct analysis of vitreous. In 1 patient, different resistance mutations were identified in ocular vs extraocular CMV strains. CONCLUSIONS: Clinical failure of intravitreal cidofovir occurs infrequently, but may be associated with cidofovir-resistant CMV selected by prior ganciclovir or cidofovir treatment. Ocular CMV disease can result from a localized infection with a resistant CMV strain, and antiviral resistance may develop at a local site of infection independently from resistance that develops systemically.

Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS).

OBJECTIVE: The purpose of the study is to evaluate the adverse events and autopsy findings in a series of consecutive 20-microg intravitreous cidofovir injections at a single institution. DESIGN: The study design was a nonrandomized, consecutive case series. PARTICIPANTS: Seventy-six patients with acquired immune deficiency syndrome with cytomegalovirus retinitis were studied prospectively. Sixty-three patients had 1 month's follow-up or longer, and this comprised the study group. In addition, histopathologic findings from 18 eyes of 9 patients were studied at autopsy. INTERVENTION: A total of 296 injections of 20 microg cidofovir were given in 115 eyes. Sixty-three patients who had 246 injections in 93 eyes had 1 month's follow-up or longer for the evaluation of adverse events. MAIN OUTCOME MEASURES: Postinjection chronic hypotony associated with permanent visual loss, transient hypotony, iritis, and its long-term sequela (posterior synechia and cataract, retinal detachment, extraocular cytomegalovirus involvement) were the outcomes of interest in this study. Additionally, light and electron microscopic studies of human eyes were performed. RESULTS: The most severe adverse event was postinjection chronic hypotony. This phenomenon was associated with permanent visual loss. This was observed in 1% of the injections and 3% of the eyes of the patients (95% confidence interval, 0%-6%). Transient hypotony associated with mild-to-moderate visual loss developed in 14%, but vision recovered to baseline levels in these eyes subsequently. Analysis showed that transient hypotony in the injected eye could predict postinjection chronic hypotony in the fellow eye (two-tailed Fisher's exact test, P = 0.02). The incidence of iritis was 32%; posterior synechia and cataract were the long-term sequela of the iritis and developed in 19% and 11% of the eyes, respectively. The incidence of retinal detachment was lower (6%). Histopathologic evaluation of the eyes showed mild-to-moderate atrophy of the nonpigmented epithelium of the ciliary body and no other evidence of intraocular toxicity. CONCLUSIONS: The most serious adverse event was postinjection chronic hypotony, which occurred in 3% of eyes. Episodes of transient hypotony appear to indicate that the fellow eye was predisposed to chronic hypotony. Therefore, it may be prudent to give intravitreous injections at least 2 weeks apart in the fellow eye to evaluate the clinical response of the injected eye.

Analysis of visual dysfunctions in HIV-positive patients without retinitis.

PURPOSE: To investigate visual dysfunctions in ophthalmoscopically normal human immunodeficiency virus (HIV)-positive patients and to correlate the results to the stage of HIV disease and neuropsychological status. METHODS: Fifty-one randomly selected eyes (26 right, 25 left) of 51 HIV-positive patients with visual acuity measurements of 20/20 or better and no ophthalmoscopically detectable disorders were prospectively examined using achromatic and short-wavelength automated perimetry, color vision testing, and contrast sensitivity testing. CD4+ T-lymphocyte count, presence of systemic infection, hemoglobin, hematocrit, serum beta 2-microglobulin levels, and results of neuropsychological testing were also analyzed. RESULTS: On achromatic automated perimetry, 21.6% (11/51) of patients performed abnormally according to the mean defect and 27.5% (14/51) according to the Glaucoma Hemifield Test; 29.4% (15/51) performed abnormally on short-wave-length automated perimetry according to the mean defect and 23.5% (12/51) according to the Glaucoma Hemifield Test. On contrast sensitivity, 5.9% (3/51) of patients performed abnormally in the 1.5-cycles per degree (cpd) line, 2.0% (2/51) in the 3-cpd line, 23.5% (12/51) in the 6-cpd line, 25.5% (13/51) in the 12-cpd line, and 33.3% (17/51) in the 18-cpd line. On the Farnsworth-Munsell 100-hue test, 29.4% (15/51) of patients performed abnormally. After correction for multiple correlations, two statistically significant correlations were found: sum of log contrast sensitivity with achromatic automated perimetry and sum of log contrast sensitivity with the Farnsworth-Munsell 100-hue test. CONCLUSIONS: A significant percentage of HIV-positive patients with visual acuity of 20/20 or better and no ophthalmologic evidence of retinitis performed abnormally on visual psychophysical tests. The severity of visual dysfunction was not correlated with the stage of HIV infection or the degree of neuropsychological dysfunction.

Intraocular pressure and aqueous humor dynamics in patients with AIDS treated with intravitreal cidofovir (HPMPC) for cytomegalovirus retinitis.

PURPOSE: To evaluate the decrease in intraocular pressure associated with cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate; HPMPC) intravitreal injections. METHODS: We followed up 97 eyes of 63 patients with acquired immunodeficiency syndrome (AIDS) who had cytomegalovirus retinitis and had been treated with up to nine 20-microgram intravitreal cidofovir injections. Measurements were taken at baseline, between 2 and 3 weeks, and at 5 to 6 weeks after injections. Anterior chamber fluorophotometry was studied in seven eyes (four patients) before and after injections. Ciliary body anatomy was evaluated in two patients. RESULTS: After the first intravitreal injection, mean intraocular pressure was 2.2 mm Hg lower than that at baseline at 2 to 3 weeks (P < .001) and 1.3 mm Hg lower than at baseline at 5 to 6 weeks (P = .0025). After the second injection, mean pressure was 2.6 mm Hg lower at 2 to 3 weeks (P = .0013) and 1.5 mm Hg lower at 5 to 6 weeks (P = .043). After subsequent injections, however, the decrease was less than 1 mm Hg, suggesting that a plateau had been reached. Pressure in eyes with anterior uveitis after the first injection was lower than that in eyes without anterior uveitis (P < .0001). The mean rate of aqueous flow decreased from 2.8 to 1.9 microliters per minute 2 to 4 weeks after injection (P < .015). Ultrasound biomicroscopy disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy. CONCLUSIONS: Intraocular pressure decreases after the initial 20-microgram cidofovir intravitreal injection. However, eyes stabilize (pressure plateaus) after three injections. Effects on the ciliary body are the main cause of the decrease after cidofovir injections.

Low-dose intravitreal cidofovir (HPMPC) therapy of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome.

PURPOSE: The authors have shown that long-term treatment of cytomegalovirus (CMV) retinitis with 20-microgram intravitreal injections of cidofovir (HPMPC) is highly effective but may be associated with iritis and profound hypotony. They evaluated the efficacy and safety of 10-microgram intravitreal injections of cidofovir and made comparisons with their findings of 20-microgram injections. METHODS: The current study was conducted as a nonrandomized consecutive case series at the AIDS Ocular Research Unit of the University of California at San Diego. Twenty-seven eyes of 18 patients were injected with 10 micrograms intravitreal cidofovir and had complete follow-up. These were compared with another consecutive series of 24 eyes of 17 patients injected with 20 micrograms of cidofovir. MAIN OUTCOME MEASURES: The main outcome in this study was the incidence of failure to respond to treatment with 10-microgram injections. The authors also compared the time to progression of CMV retinitis after the initial intravitreal injections of 10 micrograms and 20 micrograms of cidofovir. Secondary outcomes included incidence of iritis and changes in intraocular pressure (IOP) after cidofovir injections. RESULTS: The median time to retinitis progression was 45 days after a single intravitreal injection of 10 micrograms cidofovir compared with 55 days with the authors' series of 20-microgram injections. This difference was statistically significant (P = 0.033, log-rank test) and appeared to be due principally to a 26% incidence of primary failure in the 10-microgram group (progression > or = 750 microns within 28 days, P = 0.0017 Wilcoxon test). Progression after a second injection of 10 micrograms cidofovir was more rapid (32 days, P = 0.037). The incidence of iritis after 10-microgram injections was 2.2% compared with 23% with 20-microgram injections (P = 0.003, Fisher's exact test, two-tailed). There was less decrease in IOP between the baseline injection and subsequent visits in the 10-microgram group. CONCLUSIONS: Treatment of CMV retinitis with 10-microgram intravitreal cidofovir injection was not as effective as with 20 micrograms and may allow development of drug resistance, but there were fewer side effects with the 10-microgram dose. The drug appears to have a narrow therapeutic index, and other attempts at reducing the side effects while preserving the long-acting effect, such as liposome delivery, may be warranted.

Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis.

OBJECTIVE: To describe intraocular inflammation due to treatment with intravenous cidofovir dihydrate for cytomegalovirus retinitis. DESIGN: Retrospective cohort. SETTING: Three university outpatient ophthalmology clinics. PATIENTS: All patients treated with intravenous cidofovir therapy before October 31, 1996. INTERVENTION: Treatment with intravenous cidofovir was given according to standardized protocols. Intraocular inflammation was treated according to the best medical judgment. MAIN OUTCOME MEASURES: The presence of new intraocular inflammation, the severity of inflammation, visual acuity, and intraocular pressure. RESULTS: Eleven cases of iritis (26%) occurred among 43 patients. In 6 cases, the iritis was bilateral. Patients who experienced iritis were more likely to have been previously treated for cytomegalovirus retinitis (P = .03), to be diabetic (P = .05), or to be receiving protease inhibitors (P < .001). Four patients and 15 control subjects had also taken rifabutin (P = .70). The onset of iritis occurred at a mean (+/-SD) of 4.9 +/- 1.8 days after a cidofovir dose and after a mean (+/-SD) of 4.2 +/- 1.6 doses of cidofovir. Six eyes of 4 patients had hypotony. Five eyes of 5 patients had a persistent decrease in visual acuity of at least 2 Snellen lines. CONCLUSIONS: Acute intraocular inflammation may occur with or without hypotony after intravenous cidofovir therapy, similar to the reactions seen after intravitreous administration. Although the manifestations may be severe, they are manageable with topical corticosteroid therapy in most cases. Cidofovir therapy can be continued in some patients if medical necessity warrants, but recurrent inflammation or permanent hypotony may occur.

An animal model for cidofovir (HPMPC) toxicity: intraocular pressure and histopathologic effects.

Intravitreal cidofovir has been shown to be a long acting and highly efficacious treatment for CMV retinitis; however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concentrations of 25, 200, 625 and 2000 micrograms ml-1. Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 micrograms ml-1. A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 micrograms of cidofovir intravitreally (vitreous concentration of 25 micrograms ml-1) is the highest non-toxic dose in the guinea pig; the IOP was unchanged at two and four weeks after injection with this dose; histologically the eyes were normal. A single injection of 50 micrograms of cidofovir intravitreally (vitreous concentration of 200 micrograms ml-1) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 micrograms and 500 micrograms of cidofovir (vitreous concentrations of 625, and 2000 micrograms ml-1, respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 micrograms cidofovir intravitreally (vitreous concentration of 625 micrograms ml-1); retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 micrograms of cidofovir intravitreally (vitreous concentration of 2000 micrograms ml-1): retina was relatively well preserved. The guinea pig eye shows similar reduction in IOP and ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. However, the reduction of IOP caused by cidofovir occurs in the guinea pig eye at a concentration 40 times higher than was observed in the human eye.

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. CONCLUSION: 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.

Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis.

PURPOSE: To evaluate the efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5 to 6 weeks for the maintenance treatment of cytomegalovirus (CMV) retinitis. METHODS: A prospective consecutive case series of 53 eyes in 35 patients with acquired immune deficiency syndrome and CMV retinitis was treated with maintenance intravitreal injections of cidofovir (20 micrograms) at one referral center between April 1994 and September 1995. Twenty-four eyes received intravitreal cidofovir as their initial treatment for CMV retinitis (group A), and 29 eyes previously had received systemic therapy (group B). None of the patients in either group received systemic anti-CMV therapy at any time during the study period. Progression of retinitis was the primary end point. RESULTS: All eyes with active retinitis healed in response to treatment. None of the 24 eyes in group A demonstrated any progression during the study period. Four (14%) of the 29 eyes in group B had one episode each of retinitis progression (mean follow-up, 15 weeks; range, 0-58 weeks). In 1 (1.9%) of the 53 eyes, a retinal detachment developed. A mild iritis was observed after 14% of injections, which were prophylaxed with oral probenecid. Irreversible visually significant hypotony developed in two eyes (3.8%). CONCLUSION: Treatment and subsequent maintenance therapy of CMV retinitis with 20 micrograms intravitreally injected cidofovir, given at 5- to 6-week intervals, is highly effective, with only rare episodes of re-activation and progression.