Use of Intravitreal Ganciclovir (Dihydroxy Propoxymethyl Guanine) for Cytomegalovirus Retinitis in a Patient With AIDS

Henry, Keith; Cantrill, Herbert L.; Fletcher, Courtney V.; Chinnock, Barbara J.; Balfour, Henry H.

doi:10.1016/s0002-9394(14)74163-7

Cited by 187 publications

(50 citation statements)

References 30 publications

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“…GCV formed in vivo has lower rate of elimination compared with the prodrugs, thus improving the residence time of GCV in the vitreous chamber. In addition, it has been assumed that equilibrium is estab- lished between the vitreous humor and retina, and the drug levels become similar in both the tissues (Henry et al, 1987;Morlet et al, 1996). The in vitro tissue hydrolysis studies carried out in our laboratory showed that the prodrugs are hydrolyzed in the retina at a much faster rate compared with that in the vitreous humor.…”

Section: Ocular Disposition Of Gcv and Its Monoester Prodrugsmentioning

confidence: 98%

“…Other toxic effects include granulocytopenia, thrombocytopenia, azoospermia, and rise in the serum creatinine (Faulds and Heel, 1990). Relatively high systemic toxicity caused by intravenous therapy has lead to the intravitreal administration of GCV (Henry et al, 1987;Daikos et al, 1988;Ussery et al, 1988;Cantrill et al, 1989;Cochereau-Massin et al, 1991), which enabled considerable improvement and/or stabilization of HCMV retinitis in most (80 -100%) of the patients. Intravitreal administration has the advantage of maintaining high concentrations of the drug for effective control of ocular infections with minimal systemic adverse effects.…”

mentioning

confidence: 99%

“…Clinical trials reported good response rates to intravitreal induction therapy with GCV (Cochereau-Massin et al, 1991). However, very few studies have been carried out to date delineating the intravitreal pharmacokinetics of GCV (Henry et al, 1987;Ashton et al, 1992;Morlet et al, 1996). The major constraint to the development and assessment of posterior segment pharmacokinetics of drugs in animal models is the inaccessibility of the ocular fluids for continuous serial sampling.…”

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confidence: 99%

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Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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ABSTRACT:The present study was carried out to delineate the ocular pharmacokinetics of ganciclovir (GCV) following intravitreal administration. Another objective was to achieve sustained therapeutic concentrations of GCV in the vitreous over a prolonged period of time using its acyl monoester prodrugs (acetate, propionate, butyrate, and valerate). New Zealand albino male rabbits (2-2.5 kg) were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous using a 21-guage needle, and a linear microdialysis probe was implanted in the anterior chamber across the cornea using a 25-guage needle. The probes were perfused with isotonic phosphate buffer saline (pH 7.4) at a flow rate of 2 l/min. The drugs were administered (0.2 moles) intravitreally and the samples were collected every 20 min over a period of 10 h. The vitreal terminal elimination half-life (t 1/2 ␤) of GCV was found to be 426 ؎ 109 min. The hydrolysis rate and vitreal clearance of the prodrugs increased with the ascending ester chain length. The vitreal elimination half-lives (t 1/2k10 ) of GCV, acetate, propionate, butyrate, and valerate esters of GCV were 170 ؎ 37, 117 ؎ 50, 122 ؎ 13, 55 ؎ 26, and 107 ؎ 14 min, respectively. A parabolic relationship was observed between the vitreal elimination rate constant and the ester chain length. Mean residence time (MRT) of the regenerated GCV following prodrug administration was found to be three to four times the value obtained after GCV injection. In conclusion, these studies have shown that the ester prodrugs generated therapeutic concentrations of GCV in vivo, and the MRT of GCV could be enhanced by 3-to 4-fold through prodrug modification.

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Section: Ocular Disposition Of Gcv and Its Monoester Prodrugsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Macha¹,

Mitra²

2002

Drug Metab Dispos

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“…Initially, intravitreal ganciclovir was used in patients in whom the toxicity of intravenous ganciclovir was so severe that it could not be used. In initial, uncontrolled studies, favourable results were seen in most treated eyes (18,19) . The long term outcome of this strategy has been confirmed (20) .…”

Section: Intravitreal Gan Ciclovirmentioning

confidence: 99%

Treatment of Cytomegalovirus Retinitis: A Growing Number of Options

Shafran¹,

Conly²

1996

Canadian Journal of Infectious Diseases and Medical Microbiolog

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“…These problems and the difficulties of long-term intravenous therapy have prompted the investigation of other modes of treatment. Intravitreal administration of ganciclovir avoids myelosuppression and has stabilized vision in some patients (195,198). Oral therapy is also being investigated.…”

Section: Ganciclovirmentioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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Use of Intravitreal Ganciclovir (Dihydroxy Propoxymethyl Guanine) for Cytomegalovirus Retinitis in a Patient With AIDS

Cited by 187 publications

References 30 publications

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Ocular Disposition of Ganciclovir and Its Monoester Prodrugs following Intravitreal Administration Using Microdialysis

Treatment of Cytomegalovirus Retinitis: A Growing Number of Options

Antiviral therapy: current concepts and practices

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