Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idoxuridine which was first used in 1960 (Kaufman et al., 1962), has been for many years the only antiviral agent available in the treatment of herpetic keratitis. It is however no more successful than is mechanical removal of diseased epithelium (Patterson & Jones, 1967), and furthermore it may give rise to serious toxic side effects. The search for an alternative medication is therefore a pressing one. Trifluorothymidine (F3T) has, in recent years, been shown to be more effective than IDU and to be free from significant toxicity. Both of these drugs are pyrimidine nucleosides. Adenine Arabinoside or Arabinoside-A (Ara-A) is, by contrast, a purine nucleoside. It is thought to exert its antiviral effect by blocking DNA polymerase and ribonucleotide reductase.
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PMID:Treatment of herpetic keratitis. 41 44

Previous studies to determine the efficacy of new antiviral compounds in treating HSV ocular infections have used rabbit models. However, rabbits are expensive to purchase and maintain, and require the use of substantial amounts of test compounds. We have used the currently licensed antiviral trifluorothymidine in a murine model of HSV-induced ocular infection to demonstrate that the less expensive murine model can be used for the in vivo evaluation of potentially useful antiviral compounds. Treatment with TFT reduced the severity of blepharitis, vascularization of the cornea, stromal keratitis, and the percentage of animals developing symptoms. TFT treatment did not reduce the peak titers of infectious virus in the eyes of the infected animals, but did enhance clearance of virus from the tissues in a dose-dependent manner. Treatment with 1.0% TFT prevented the establishment of reactivatable latent infections. However, treatment with 0.01% or 0.1% TFT did not affect latency. The ED50 values for blepharitis, vascularization, and stromal keratitis ranged between 0.007% and 0.023%. These results are very similar to results obtained in rabbits and establish baseline data for comparing rabbit and murine models. This murine model provides a potentially less expensive alternative for in vivo drug testing.
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PMID:A murine model of herpes simplex virus-induced ocular disease for antiviral drug testing. 156 Jan 5

The present paper reviews the adverse side effects caused by topically applied antiviral agents in herpetic keratitis. The effective treatment of herpetic keratitis with IDU, a chemotherapeutic agent, was first reported in 1962. After its introduction into ophthalmic therapy for herpetic keratitis, drops of IDU were administered every hour by day combined with ointment every two hours by night. The therapy often continued for months or in some cases, even more than one year. Numerous reports on its side effects have appeared. The side effects can be classified into two categories. The first category is allergic contact blepharodermatitis, a type IV delayed hypersensitivity reaction. Its occurrence is difficult to foresee. This category I side effect rarely results in the destruction of the ocular tissues. The second category of side effects is a drug-induced toxic side effect resulting in punctate epithelial keratitis, papillary conjunctivitis or follicular hypertrophy and lacrimal punctal obstruction. After withdrawal of IDU, these ill effects usually subside soon. When IDU is further continued, the destructive change of the tissues will ensue. Conjunctival cicatrization, symblepharon, corneal neovascularization, cicatrization and irreversible punctal occlusion have been reported in cases with prolonged IDU treatment. In addition to IDU for therapy of herpetic keratitis, we are fortunate to have F3T, Ara-A and acyclovir. They show no cross sensitivity reaction nor any cross toxic reaction to each other. However, if administered more than several times daily and continued for a prolonged period of time, these antiviral agents, like IDU, can also result in reversible side effects and, further, irreversible tissue destruction. Conjunctival cicatrization and permanent punctal occlusion caused by prolonged administration of F3T have been reported. Prompt recognition of the untoward reactions and withdrawal of the antiviral agent will result in the subsidence of the toxic reaction changes and prevent the eye from irreversible destruction. The recognition, prevention and management of the untoward side effects also are discussed.
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PMID:[Adverse side effects caused by topically applied antiviral agents in herpetic keratitis]. 248 Apr 57

We developed an in vitro model for studying the cytotoxicity of pharmacologic agents on corneal epithelium employing 3H-thymidine incorporation. Primary rabbit corneal epithelial cell cultures were established, and the cells plated prior to each experiment. 3H-thymidine incorporation was measured after the addition of drug or vehicle to these confluent cells, and dose-response curves were generated. Marked inhibition of 3H-thymidine incorporation was reached at chemotherapeutic concentrations achieved clinically for cytosine arabinoside (10(-7) M), methotrexate (10(-3) M), and 5-fluorouracil (10(-6) M). A 10(-4) M concentration of 2-deoxycytidine, a naturally occurring competitive inhibitor of cytosine arabinoside, protected cells up to a concentration of 10(-5) M. We utilized these data to undertake an in vivo prophylaxis study in 13 leukemia patients receiving high-dose iv cytosine arabinoside. Topical deoxycytidine 10(-4) M and 1% prednisolone phosphate, given 12 hours prior to the start of antileukemic therapy, were effective in reducing symptoms and signs of keratitis; both were better than historical placebo-treated eyes. Ophthalmic preservatives were studied in vitro at concentrations used clinically: benzalkonium chloride (BAC) (0.004-0.02%) was the most toxic, thimerosal (TMS) (0.001-0.004%) intermediate, and chlorobutanol (CHB) (0.2-0.5%) the least toxic. Antiviral agents (final concentration) included: trifluridine (TFT) (1.0%), ethyldeoxuridine (EDU) (2.0%), and idoxuridine (IDU) (0.1%). Dose but not time-dependent concentrations of these 3 agents were noted to cause toxicity; however, (E)-5(2-bromovinyl)-2'-deoxyuridine (BVDU) (0.1%) was non-toxic. Similarly, tobramycin and amikacin were significantly less toxic than gentamicin and neomycin in this system. These in vitro cytotoxicity data correlate well with previous in vivo and pre-clinical corneal epithelial toxicity studies. Our model may be useful in the toxicologic study of future topical ophthalmic agents.
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PMID:An in vitro method which assesses corneal epithelial toxicity due to antineoplastic, preservative and antimicrobial agents. 248 34

Trifluridine (TFT) and a structurally related analogue, 5-fluoro-2'-deoxyuridine (FDU), were investigated for their efficacy in the topical treatment of experimental keratitis caused by thymidine kinase-positive (TK+) and thymidine kinase-deficient (TK-) herpes simplex virus type 1 (HSV-1) strains. Bromovinyldeoxyuridine (BVDU) was used as a reference compound. Both 0.2% BVDU and 0.2% TFT eyedrops produced a highly significant healing of TK+HSV-1 keratitis as compared to the placebo and 0.2% FDU eyedrops (P much less than 0.005), whereas the latter compound did not differ from placebo eyedrops. In the treatment of TK HSV-1 keratitis, none of the drugs exhibited a beneficial healing effect, although the virus strain used was inhibited in vitro by TFT and FDU at a very low concentration (0.02-0.04 microgram/mL).
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PMID:Experimental thymidine kinase-deficient HSV-1 keratitis: therapeutic attempts. 295 58

The present study examined the antiherpetic effect of 2'-nor-cGMP, a new cyclic phosphate derivative of 2'NDG, in vitro and in the mouse keratitis model. The 50% inhibitory dose (ID50) was determined with HSV-1 RE strain in Vero cell monolayers for 2'-nor-cGMP (6.9 mcg./ml), 2'NDG (.06 mcg/ml), and trifluridine (F3T) (.72 mcg/ml). Balb C mice underwent bilateral ocular inoculation with HSV-1 RE strain, and then were treated with different therapeutic regimens. The antiviral efficacy of each drug was evaluated by ocular virus titers, clinical grading of epithelial keratitis, and histological evaluation of stromal keratitis. 2'-nor-cGMP was the most effective drug (P = .0001) in reducing ocular viral titers. Both 2'-nor-cGMP and 2'NDG were significantly more effective (P = .0001) than F3T in reducing epithelial keratitis, and as effective as F3T in reducing stromal keratitis.
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PMID:2'-nor-cGMP, a new cyclic derivative of 2'NDG, inhibits HSV-1 replication in vitro and in the mouse keratitis model. 303 Jun 46

Various side effects due to antiherpetic drugs observed in the last ten years in our department were studied. A total of 132 patients were treated with 5-iodo-2'-deoxyuridine (IDU), 69 with trifluorothymidine (F3T), 58 with acyclovir (ACV) and 33 with adenine arabinoside (ara-A). Patch tests were routinely done when patients exhibited contact dermatitis. Of the patients treated with IDU, 3 (2.3%) showed contact dermatitis, 2 (1.5%) follicular conjunctivitis and 1 (0.8%) punctate keratopathy. Of the patients treated with F3T, 7 (10.1%) exhibited contact dermatitis and 1 (1.4%) follicular conjunctivitis. In the group treated with ACV, 2 (3.4%) patients showed punctate keratopathy. The patients who received ara-A did not show any side effects. We found that F3T caused contact dermatitis more frequently in Japanese people than Europeans. These side effects were resolved by switching to another anti-herpetic drug without the occurrence of cross-allergy. Therefore, switching to another drug is strongly recommended when patients exhibit side effects in the treatment of herpetic keratitis. Other complications were allergy to atropine and to drug preservative.
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PMID:Side effects in the treatment of herpetic keratitis. 310 84

Clinical resistance of herpetic keratitis to antiviral agents constitutes one of the reasons for failure of treatment after their administration. A retrospective study of 42 cases of superficial herpetic keratitis resistant to IDU, IDU and IDC, and Ara-A demonstrated that in 2 out of 3 cases this resistance appeared in patients previously treated locally with antiviral compounds for anterior ocular lesions. Patients resistant to IDU were then treated with Ara-A, and those not responding to Ara-A, with TFT. Resistance may be observed following this new treatment during the subsequent relapses.
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PMID:[Clinical resistance of herpetic keratitis to antiviral agents (author's transl)]. 626 Aug 50

The treatment of herpetic corneal ulcerations with trifluorthymidine (F3T) has been evaluated in a clinical trial. F3T was found to be an effective antiviral agent for herpetic keratitis and a valuable alternative to idoxuridine (IDU)-therapy. Clinically IDU-resistent herpetic ulcers responded favourably to treatment with F3T.
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PMID:Trifluorthymidine in the treatment of herpes simplex corneal ulcers. A clinical evaluation. 677 92

The modes of action of IDU and TFT were compared in tests employing them both as a monotherapy and in combination with iodine debridement in 60 patients suffering from superficial herpetic keratitis. The combination therapy was used for patients showing only dendritic stains in the corneal epithelium, while the monotherapy was used for patients who had additional lesions in the region of Bowman's membrane. Both with the monotherapies and the combination therapies the average duration of healing was shorter with TFT.
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PMID:[Clinical experience with different methods of treating herpes corneae (author's transl)]. 677 29


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