A review of topical and intralesional cidofovir.
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Abstract:
Cidofovir is a potent nucleoside analog antiviral drug approved for the treatment of cytomegalovirus (CMV) retinitis in patients with the Acquired Immune Deficiency Syndrome (AIDS). It is currently available only for intravenous infusion. Several small studies and case reports describe the successful use of cidofovir applied either topically or by intralesional injection in several virally induced cutaneous diseases. Available information demonstrates that cidofovir is a potent antiviral agent with activity against several DNA viruses that cause cutaneous disease when applied topically or administered by intralesional injection. No significant systemic side effects have been noted, although application site reactions are common and can occasionally be severe. The effective use of topical and intralesional cidofovir for the treatment of diseases of the skin caused by DNA viruses has been demonstrated in animals and a limited number of patients including those infected with human immunodeficiency virus (HIV). This article reviews the pharmacology of cidofovir and the utility of topical and intralesional cidofovir for the treatment of viral infections caused by human papillomavirus, herpesviruses (including acyclovir resistant strains), Kaposi's sarcoma-associated herpesvirus, molluscum contagiosum and monkeypox.Keywords:
Cidofovir
Foscarnet
Cytomegalovirus retinitis
Molluscum contagiosum
Nucleoside analogue
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To the Editor. —Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS) and tends to occur after CD4+cell counts decrease to less than 0.10X 109/L.1Although anti-CMV therapy with ganciclovir, foscarnet sodium, or cidofovir initially leads to inactivation of the retinitis in the majority of patients, the disease later progresses in most patients despite continued therapy due to inadequate control of the replicating virus. Without therapy, the median time to detection of progression of CMV retinitis is approximately 2 to 3 weeks2,3; resolution of active retinitis without anti-CMV therapy rarely if ever occurs in immunosuppressed patients. Two recent studies have shown that treatment with highly active combination antiretroviral therapy, consisting of nucleoside analogs and protease inhibitors, has led to decreased human immunodeficiency virus (HIV) loads and increased CD4+cell counts.4,5We present 4 patients with AIDS and
Cidofovir
Foscarnet
Cytomegalovirus retinitis
Cytomegalovirus
Combination therapy
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Advances in ganciclovir and foscarnet therapies for treating cytomegalovirus retinitis, including ocular implants and injections, alternating use of foscarnet and ganciclovir, oral ganciclovir use, cidofovir treatment, and injecting either ganciclovir or foscarnet directly into affected eyes, are discussed. Interactions and adverse side effects for both drugs are listed. Final comments discuss efforts made by Isis Pharmaceuticals and their clinical testing of an antisense drug for CMV.
Foscarnet
Cidofovir
Cytomegalovirus retinitis
Cytomegalovirus
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Untreated cytomegalovirus (CMV) retinitis is progressive and generally leads to blindness within 6 months. Intravenous (i.v.) therapies such as foscarnet and ganciclovir, which were the first agents approved for the treatment of CMV retinitis, are effective in suppressing CMV replication, but they delay rather than prevent reactivation of CMV infection resulting in relapse of the disease. Furthermore, studies have shown that the time between subsequent reactivations becomes shorter, with each relapse producing more serious disease that may be more difficult to manage. This clinical failure may be caused in part by drug resistance; ∼10% of all patients receiving systemic treatment with these agents may harbor drug-resistant viral strains. With three systemic therapies (ganciclovir, foscarnet, and cidofovir) now available for the treatment of CMV retinitis, several options exist for patients who have failed therapy with one of these drugs: reinduction with the same i.v. agent, switching therapies, or combining therapies. Resistant or relapsing CMV retinitis may also be treated by local therapies such as intraocular injections of ganciclovir and foscarnet or with a sustained-release ganciclovir implant. However, local therapy is ineffective in controlling extraocular or fellow eye CMV disease. It is likely that the integration of both local and systemic therapies will be required to halt the relentless progression of this debilitating disease, particularly when clinical resistance is encountered.
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Cidofovir
Cytomegalovirus retinitis
Cytomegalovirus
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Cytomegalovirus (CMV) retinitis, a common complication of the acquired immunodeficiency syndrome (AIDS), is increasing in frequency as patients infected with the human immunodeficiency virus (HIV) live longer.In recent years, the lifetime risk for CMV disease in HIV-infected persons has increased from 24.9% to 44.9%. Cytomegalovirus retinitis is usually diagnosed clinically: Almost all patients are CMV seropositive and have CD4+ counts less than 50 cells/mm3. Specific diagnostic tests that use antigen detection or quantitation of circulating nucleic acid to detect CMV are being developed, but they have not been validated for routine clinical use. Such tests would help predict disease, diagnose acute retinitis, and monitor therapy.
Cytomegalovirus retinitis
Cytomegalovirus
Cytomegalovirus infections
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Cidofovir
Foscarnet
Cytomegalovirus retinitis
Regimen
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Cidofovir is a potent nucleoside analog antiviral drug approved for the treatment of cytomegalovirus (CMV) retinitis in patients with the Acquired Immune Deficiency Syndrome (AIDS). It is currently available only for intravenous infusion. Several small studies and case reports describe the successful use of cidofovir applied either topically or by intralesional injection in several virally induced cutaneous diseases. Available information demonstrates that cidofovir is a potent antiviral agent with activity against several DNA viruses that cause cutaneous disease when applied topically or administered by intralesional injection. No significant systemic side effects have been noted, although application site reactions are common and can occasionally be severe. The effective use of topical and intralesional cidofovir for the treatment of diseases of the skin caused by DNA viruses has been demonstrated in animals and a limited number of patients including those infected with human immunodeficiency virus (HIV). This article reviews the pharmacology of cidofovir and the utility of topical and intralesional cidofovir for the treatment of viral infections caused by human papillomavirus, herpesviruses (including acyclovir resistant strains), Kaposi's sarcoma-associated herpesvirus, molluscum contagiosum and monkeypox.
Cidofovir
Foscarnet
Cytomegalovirus retinitis
Molluscum contagiosum
Nucleoside analogue
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Purpose.: To evaluate the intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV), the hydrolysis product of HDP-cyclic-CDV, a long-lasting intravitreal cidofovir prodrug for cytomegalovirus (CMV) retinitis. Methods.: HDP-cyclic-CDV was suspended in phosphate-buffered saline (PBS) at 37°C and formation of HDP-CDV was monitored by high-performance liquid chromatography (HPLC) analysis for 30 weeks. The safety and pharmacokinetics of HDP-CDV intravitreal injections were studied using New Zealand Red rabbits and 14C labeled HDP-CDV. Ocular tissues from five time points (1, 3, 7, 14, and 35 days) were analyzed by scintillation counting and HPLC to characterize the pharmacokinetics. Results.: During the hydrolysis study, approximately 35% of the HDP-cyclic-CDV was converted to HDP-CDV. Evaluation of safety found no toxicity after intravitreal injection of HDP-CDV up to 28 μg/eye. Intravitreal pharmacokinetics of HDP-CDV in the retina, choroid, and vitreous followed a two-phase elimination process and elimination half-lives of 8.4 days (retina), 6.9 days (choroid), and 6.2 days (vitreous). In the retina, cidofovir and an unknown metabolite were detected in the first 2 weeks, and the maximum metabolite concentrations were present 48 hours after the maximum HDP-CDV concentration. Conclusions.: HDP-cyclic CDV, under simulated physiologic conditions, slowly converts to HDP-CDV, another potent anti-CMV prodrug that may be taken up by retinal cells and metabolized further to the active antiviral metabolite, cidofovir diphosphate. Taken together, these observations help to explain the ability of a single intravitreal dose of HDP-cyclic-CDV to prevent viral retinitis for up to 68 days in a rabbit model.
Cidofovir
Choroid
Cytomegalovirus retinitis
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Antiviral drug
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Cytomegalovirus (CMV) retinitis has become one of the most common manifestations of active CMV infection in patients with acquired immunodeficiency syndrome (AIDS). If left untreated, it results in complete loss of vision. At present, three systemic antiviral agents—ganciclovir, foscarnet, and cidofovir—are available for treatment of CMV retinitis. Unfortunately, reactivation of retinitis will occur with all three agents, and almost all patients eventually experience disease progression while receiving treatment. Therefore, our primary therapeutic challenge is to develop a means of preventing reactivation of CMV retinitis. Another challenge is to develop drugs that can be easily administered. Thus far, oral formulations have not succeeded in effectively meeting this challenge. Direct delivery of an antiviral agent into the vitreous of an infected eye, although easily performed and more effective in delaying time to progression, is unable to prevent or delay the progression of extraocular CMV disease. The ideal antiviral agent would have high central nervous system and tissue penetration, would suppress viral replication and mutation, would be administered orally, and would be inexpensive.
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Foscarnet
Cytomegalovirus retinitis
Cytomegalovirus
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Cidofovir
Molluscum contagiosum
Cytomegalovirus retinitis
Vidarabine
Foscarnet
Nucleoside analogue
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Cidofovir
Cytomegalovirus retinitis
Foscarnet
Cytomegalovirus
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