Antiviral Agent for Treatment of Cytomegalovirus Retinitis

Human cytomegalovirus is a member of the herpesvirus family, which also includes the herpes simplex (discussed below), varicella zoster, and Epstein-Barr viruses (88,89). Cytomegalovirus (CMV) and herpes simplex are the most studied of the microorganisms responsible for the opportunistic infections associated with acquired immunodeficiency syndrome (AIDS) (90). Cytomegalovirus infection in AIDS patients is most commonly manifested as retinitis (CMV retinopathy) and is the most common cause of blindness in AIDS patients (90).

Foscarnet (trisodium phosphonoformate) inhibits all human herpes viruses in vitro, including CMV (91), and intravenously administered fos-carnet is currently available for treatment of CMV infections and/or retinitis (92,93). The treatment regimen for CMV retinitis consists of an initial induction dose (180 mg/kg of body mass per day for 2 weeks) followed by a maintenance dose (120 mg/kg/day indefinitely) (92,93). Since foscarnet prevents replication of the viral DNA but does not eliminate the virus from the tissues, CMV eventually reactivates and the lesions enlarge so that higher doses of the drug have to be administered. This mode of administering foscarnet may result in serious systemic toxicity (92,93). Intravitreal injection of foscarnet has been reported but also suffers from many of the same complications (endophthalmitis, increased intraocular pressure, retinal detachment, etc.) associated with other modes of ocular injection (94-96). Foscarnet is an ideal candidate for iontophoresis, since it is ionized at the physiological pH of the eye, is soluble in water, and has a molecular weight of 300.1 (91,97).

Sarraf et al. (97) studied the vitreous pharmacokinetics of foscarnet (24 mg/mL solution) after transscleral iontophoresis into normal rabbit eyes. The iontophoretic probe was applied perpendicular over the conjunctiva 1-3 mm posterior to the corneoscleral limbus. The surface area of the probe was ~0.2 mm2. The current applied was 1.0 mA for a 10-minute duration. Intravitreal samples were obtained at 12 time points (15 and 30 min and 1, 2, 4, 8, 16, 24, 32, 40, 48, and 60 h) after iontophoresis or subconjunctival injection and analyzed by HPLC. Mean vitreous concentrations of foscarnet were within the therapeutic range (25-800 mM) (91) for inhibition of CMV as early as 15 minutes posttreatment. A peak vitreal foscarnet concentration of 200 ± 311 mM was observed 4 hours after ionto phoresis. This concentration is well below the concentration reported to cause retinal toxicity (>2000 mM) (94). Therapeutic levels of foscarnet for CMV retinitis were maintained for up to 60 hours posttreatment. These levels were well above the range (10-25 mM) at which foscarnet is active against HIV (93). No toxic effects to the sclera, cornea, anterior chamber, or lens were observed by biomicroscopy.

Yoshizumi et al. (98) characterized the utility of foscarnet iontophoresis for the treatment of CMV retinitis. The possible retinotoxic effects of transscleral iontophoresis of foscarnet were examined by slit-lamp biomicro-scopy, indirect ophthalmicroscopy, light and electron microscopy, and elec-troretinography (ERG) (98). Slit-lamp examination (SLE) revealed no toxic effects for any of the treated eyes. Indirect ophthalmicroscopy showed retinal and choroidal burns 1-3 mm in diameter at the site of iontophoresis. Light and electron microscopy showed focal retinal, retinal pigment epithelial, and choroidal necrosis at the site of iontophoresis but no abnormalities elsewhere. ERG studies showed no changes in the response between foscar-net-treated eyes and saline-treated control eyes. The lesions reported were minimal and judged to be equivalent to or less than those that would have been created by an intravitreal injection or surgical implantation of an intraocular drug delivery device (99).

Another study from Yoshizumi's group (100) demonstrated that ocular iontophoresis of foscarnet could supplement intravenous injection of foscarnet in the management of CMV retinopathy. Foscarnet (120 or 180 mg/kg) was injected intravenously into one group of rabbits and peak concentrations in the serum and vitreous were determined at 1, 4, 8, 24, 60, and 120 hours after injection. A second group of rabbits, injected with the same dose of foscarnet, received ocular foscarnet iontophoresis 1 hour after the injection. Vitreous humor samples were obtained at the same time points as for group one. Maximum serum and vitreous humor concentrations were obtained 1 hour after each intravenous dose. Peak vitreous humor concentrations were obtained 4 hours after the 120 mg/kg intravenous dose plus iontophoresis and 8 hours after the 180 mg/kg intravenous dose plus iontophoresis. Vitreous humor levels of foscarnet were significantly higher in eyes receiving intravenous foscarnet plus ocular foscarnet iontophoresis than in those receiving intravenous foscarnet alone (126.77 mM vs. 7.63 mM for the group receiving 120 mg/kg; p < 0.00001 and 86.92 mM vs. 7.43 mM for the group receiving 180 mg/kg; p < 0.00001). The difference in vitreous humor levels observed in eyes receiving the intravenous dose plus iontophoresis (either 120 or 180 mg/kg) was not significant (p < 0.1). Although the intravenous dose was administered 1 hour prior to ocular iontophoresis, it did not significantly affect the levels obtained after ocular iontophoresis (p < 0.1). The authors concluded that the increased foscarnet concentra-

tions obtained with ocular iontophoresis could be a valuable adjunct to intravenous injection in the treatment of CMV retinitis.

A subsequent study from Yoshizumi and associates examined the ocular toxicity of multiple applications of foscarnet iontophoresis (101). They performed multiple ocular iontophoretic applications of foscarnet at the same paralimbal site for a total of seven treatments over a period of 21 days (one treatment every 3 days). This was done to mimic the repeated treatments that may be necessary for long-term iontophoretic therapy for treatment of CMV retinitis and/or AIDS (92,93). The mean concentration of foscarnet in the vitreous humor 4 hours after the seventh ocular iontophoresis was 189 ± 50.6 mM. These levels are clearly within the therapeutic range (25-800 mM) needed for treatment of CMV retinitis (91). Moreover, the values are comparable to those obtained in eyes treated with only a single foscarnet iontophoresis. Electroretinography and slit-lamp examination revealed no evidence of ocular toxicity. Examination of the retinas and choroid revealed a single small burn in the retina and choroid corresponding to the iontophoresis probe contact site, which was similar to the lesion resulting from a single iontophoretic application (98). These results suggest that repeated ocular iontophoresis of foscarnet could be an effective means of achieving enhanced, localized treatment of CMV retinitis in humans.

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