Lack of retinal toxicity of the anti-CMV drug (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC)

Dolnack, D.R.; Munguai, D.; Bergeron–Lynn, Germaine; Wiley, Clayton A.; Clercq, E. De; Boscher, C; Connor, James D.; Freeman, W.R.

doi:10.1016/0166-3542(91)90287-2

Cited by 6 publications

(9 citation statements)

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“…A single intravitreal injection of cidofovir was able to prevent progression of herpes simplex virus type 1 retinitis for an almost 10 times longer period of time than with a single intravitreal injection of ganciclovir in a rabbit model [46][47][48][49][50] . No signs of retinal toxicity were found at the doses ^ 100 g/eye injected intravitreally in rabbits and Papio cynocephalus monkeys [48] . Phase I/II clinical studies showed that a single intravitreal injection of 20 g of cidofovir was safe and efficacious against CMV retinitis in human eyes for a median time of 55 days.…”

Section: Antiviral Agentsmentioning

confidence: 99%

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

et al. 2010

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Aims: Retinal pharmacotherapy has gained great importance for the treatment of various retinal diseases. An increasing number of drugs have been constantly released into the market, especially for wet age-related macular disease and diabetic macular edema. In this review, the issues concerning the toxicity of current and new classes of drugs are discussed. Methods: An extensive search of the literature was performed to review various aspects of drug toxicity in retinal pharmacotherapy. The different major classes of drugs, such as corticosteroids, antibiotics, antimetabolites, antineoplastic agents, monoclonal antibodies (mAbs), nonsteroidal anti-inflammatory drugs, enzymes, fibrinolytics, miscellaneous anti-inflammatory and antiangiogenic agents, as well as toxicity unrelated to the drug were identified and discussed. Results: Corticosteroids like fluocinolone, dexamethasone or triamcinolone at low dose cause little damage to the retina, but at high doses signs of toxicity have been well documented. Complications like cataract and glaucoma are quite common with corticosteroids. Aminoglycosides showed differences in the type and doses associated with toxic reactions, thereby the following order of toxicity can be described (from most toxic to least toxic): gentamicin > netilmicin = tobramycin > amikacin = kanamycin. Vancomycin at the usual dose of 1 mg is not toxic to the retina, while further studies are necessary in order to clarify the safety of new-generation quinolones. 5-Fluorouracil has been shown to be nontoxic to the retina after an injection of 2.5 mg in animals. mAbs like ranibizumab and bevacizumab were demonstrated to be safe to the retina in cell culture, animals and humans at high doses. The exact biocompatibility of nonsteroidal anti-inflammatory agents like diclofenac needs further evaluation. Preservatives like benzyl alcohol and changes in pH or osmolarity exert an influence on the toxic effects of intravitreally applied drugs. Conclusions: A great number of drugs are now used mainly intravitreally without relevant retinal toxicity.

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Section: Antiviral Agentsmentioning

confidence: 99%

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

et al. 2010

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“…Intravitreal injection of cidofovir has been utilized in humans to decrease systemic exposure and nephrotoxicity while continuing to provide effective local levels of the drug. Twenty micrograms of intravitreal cidofovir is well tolerated by the human eye . At this dosage, a statistically significant decrease in the mean IOP compared with baseline at two and 4 weeks postinjection was noted.…”

Section: Introductionmentioning

confidence: 86%

Intravitreal cidofovir injection for the management of chronic glaucoma in dogs

Low

Landis

Peiffer

2013

Veterinary Ophthalmology

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“…Twelve New Zealand White rabbits were used for this study. Toxicity was assessed by electroretinography, weekly indirect ophthalmoscopy and slit-lamp examinations, and light and electron microscopy as previously described (6). Twelve eyes of six New Zealand White rabbits were used for each time point.…”

Section: Animalsmentioning

confidence: 99%

“…After being anesthetized as described above, the animals were euthanized with an intracardiac injection of 1.0 ml of pentobarbital sodium (390 mg/ml). Both eyes underwent triple fixation as previously described (6,10,31). The selected calottes were vertically sectioned through the optic nerve-inferior retina, which was prepared for thin-section light microscopy and electron microscopy.…”

Section: Animalsmentioning

confidence: 99%

Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine

Besen

Paz

Tatebayashi

et al. 1995

Antimicrob Agents Chemother

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Compound 2242, also known as 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, is the first known antivirally active nucleoside analog with the side chain substituted at the N-7 position of the purine ring system. Our purpose was to evaluate its retinal toxicity and assess the efficacy of its highest nontoxic concentration in a rabbit model of herpes simplex retinitis. Concentrations of the drug from 0.5 to 2,000 M were injected intravitreally in twelve New Zealand White rabbits. Fundoscopic, histologic, and electrophysiologic data revealed no evidence of toxicity even at the highest dose of the compound. Dutch pigmented rabbits (n ‫؍‬ 34) had their left eyes injected with herpes simplex virus type 1 3 days after, concurrently, or 3 days before intravitreal injection of either 2,000 M compound 2242 or 480 M ganciclovir (final concentration in the eye). Both compound 2242 and ganciclovir were equally effective compared with saline when administered simultaneously with the virus (P < 0.0001). In the 3-day pretreatment paradigm, compound 2242 was superior to ganciclovir (P < 0.04), but there was no clear difference between the two with regard to their effects on an established infection. The pharmacokinetics of compound 2242 in 10 rabbits injected intravitreally with 30 M showed an intravitreal half-life of 8 h. This compound, which may be orally active in its pro form, has a very high therapeutic index in the eye and is more efficient than ganciclovir in this animal model of herpes retinitis.Administration of ganciclovir or foscarnet is a useful treatment for patients with cytomegalovirus (CMV) retinitis (8,16,18,28). However, both drugs can cause serious systemic toxicity, and during therapy with either drug, clinically resistant retinitis may develop in a significant proportion of these patients (9). For some patients, a change from one drug to the other does not ameliorate the retinitis, and combination therapy must also be used (22). Local intraocular antiviral therapy has been widely used for patients unable to tolerate systemic therapy (2,4,5,14,17,32). Unfortunately, both ganciclovir and foscarnet have short intravitreal half-lives and durations of action, making weekly injections necessary, with all the risks associated with frequent procedures (11,30). A recently developed intravitreal ganciclovir implant is capable of releasing ganciclovir for up to 8 months, but surgery with potential complications is required, and experience with the use of the device is quite limited (1,24,29). Although the systemic role of CMV is not yet clear, another concern with local therapy is that it does not treat possible clinically inapparent infection with CMV. In addition, strains of the virus resistant to both drugs have been isolated (7, 21). A continuing need for an orally administered drug for the management of CMV retinitis exists, and a safe intravitreal compound that would allow for the control of retinitis with infrequent injections is required.Since the discovery of the selective antiherpes action of acyclovir, a...

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Lack of retinal toxicity of the anti-CMV drug (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC)

Cited by 6 publications

References 0 publications

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

Retinal and Ocular Toxicity in Ocular Application of Drugs and Chemicals – Part II: Retinal Toxicity of Current and New Drugs

Intravitreal cidofovir injection for the management of chronic glaucoma in dogs

Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine

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