Effects of selected repeated intravitreal chemotherapeutic agents

Vernot, Jackie; Peyman, Gholam A.; Gailitis, Ray P.; Fiscella, Richard G.; Woodhouse, Martha; Weinberg, David V.

doi:10.1007/bf00137646

Cited by 8 publications

(8 citation statements)

References 15 publications

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“…11,12 However, some antimetabolites have been shown to be safe. Methotrexate has been shown to be clinically nontoxic when injected into human eyes at doses of 400 µg.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Velez

Yuan²,

Sung³

et al. 2001

Arch Ophthalmol

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To investigate the pharmacokinetics and toxicity of intravitreal chemotherapeutic agents in the rabbit eye for the potential treatment of primary intraocular lymphoma and other intraocular malignancies. Methods:The ocular pharmacokinetics of intravitreal methotrexate sodium (400 µg) was studied in 10 New Zealand white rabbits, and a single-compartment, firstorder elimination model was used to calculate the drug half-life. With the use of these data, a treatment schedule using serial injections of intravitreal methotrexate and single injections of fluorouracil and dexamethasone sodium phosphate was developed. This schedule was studied in 4 New Zealand white rabbits to explore the combined toxicity of these agents.Results: Methotrexate vitreous levels, following a 400-µg intravitreal injection, remained therapeutic (Ͼ0.5µM) in the rabbit eye for 48 to 72 hours. Intravitreal methotrexate, combined with fluorouracil and dexamethasone, showed no evidence of drug toxicity as determined by electroretinography and histopathologic examination.Conclusions: A treatment schedule for primary intraocular lymphoma consisting of methotrexate intravitreal injections every 48 to 72 hours provides therapeutic drug concentrations in the vitreous and, in combination with fluorouracil and dexamethasone, appears to be safe in the rabbit eye.Clinical Relevance: Although responsive to conventional chemotherapy or radiotherapy, recurrence of ocular involvement with primary central nervous system lymphoma occurs in more than 50% of treated cases. Anecdotal reports of the use of intravitreal chemotherapy for primary intraocular lymphoma have been encouraging. However, animal data on the pharmacokinetics and toxicity of combined intravitreal agents for the treatment of this disease are lacking.

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“…11,12 However, some antimetabolites have been shown to be safe. Methotrexate has been shown to be clinically nontoxic when injected into human eyes at doses of 400 µg.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Velez

Yuan²,

Sung³

et al. 2001

Arch Ophthalmol

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“…The optic nerve and medullary rays also appeared intact in both the treated and control eyes [65] . Another study determined the retinal toxicity of combined chemotherapy in rabbit eyes, which consisted of: 5-FU, 375 g; doxorubicin, 3 g; neomycin, 15 g; thiotepa, 12 g; etoposide, 150 g, and MTX, 600 g. This combination regimen caused a severe ERG decrease (decrease in b-wave amplitude to less than 25%) and retinal changes (generalized thinning of the retina, disorganization of retinal layers and loss of photoreceptor outer segments) [71] .…”

Section: Antiviral Agentsmentioning

confidence: 99%

“…As early as 1985, it has been shown that 600 g MTX combined with other chemotherapeutic agents such as doxorubicin, 5-FU and bleomycin enhanced the risk of retinal toxicity [71] . However, in one recent study, the ocular pharmacokinetics and retinal toxicity of intravitreal MTX sodium at 400 g were studied in New Zealand white rabbits.…”

Section: Enzymes and Fibrinolyticsmentioning

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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“…Some of the reported examples of MTX neurotoxicity are: acute transient cerebral dysfunction (32), death of nerve cells in the brain stem (33) and degeneration of the autonomic nerve fibers in the small intestine (34). Severe toxicity on retina resulted as evaluated by electroretinography (35). A survey of the literature reveals that many, if not all, anticancer drugs can inhibit different enzymes in vitro and in vivo (22-24, 36, 37).…”

mentioning

confidence: 99%

Kinetics for Camel (Camelus dromedarius) Retina Acetylcholinesterase Inhibition by Methotrexate In Vitro

Al‐Jafari

Al-Khwyter

Kamal

et al. 1996

Japanese Journal of Pharmacology

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ABSTRACT-This work addresses the kinetic analysis of the interaction of methotrexate (MTX) with camel retina acetylcholinesterase (AChE, EC 3.1.1.7). It was found that the MTX effect was reversible in nature. The IC50 was determined, by two methods, to be 1.362 mM. The Michaelis-Menten constant (Ks) for the hydrolysis of acetylthiocholine iodide (ASCh) by AChE was 0.123 mM in the control system, and the MTX-treated systems showed a 10-35% decrease in this value. The Vmax was 0.789 pmol/min/mg protein for the control system, while it was decreased by 23 -76% in the MTX-treated systems. The LineweaverBurk plot, Dixon plot and their secondary replots indicated that the inhibition was a linear mixed type; i.e., uncompetitive and noncompetitive.The values of K; and KI were estimated as 0.782 and 0.404 mM, respectively. The use of camel retina as a model for the study of human retina may open new avenues for studying various aspects of AChE.

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Effects of selected repeated intravitreal chemotherapeutic agents

Cited by 8 publications

References 15 publications

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

Pharmacokinetics and Toxicity of Intravitreal Chemotherapy for Primary Intraocular Lymphoma

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

Kinetics for Camel (Camelus dromedarius) Retina Acetylcholinesterase Inhibition by Methotrexate In Vitro

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