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      Clinical Evaluation of Local Ocular Toxicity in Candidate Anti-Adenoviral Agents in vivo

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          Abstract

          Background: Adenovirus causes ophthalmological nosocomial infections. Although cidofovir may be used systemically for immunocompromised patients in disseminated adenoviral infections, no specific anti-adenoviral agent has been established for the treatment of adenoviral ocular infection. It has been reported that cidofovir may cause lacrimal duct obstruction when used locally. We have reported that zalcitabine and stavudine showed anti-adenoviral activity in vitro. We now evaluate the side effects of these agents in eyes and ocular adnexa in an animal model. Methods: Cidofovir, zalcitabine and stavudine 1% solutions and balanced salt solution were given as eye drops to healthy female Japanese albino rabbits 4 times a day for 14 days. Clinical scores in the conjunctiva and eyelid were recorded, and lacrimal irrigation was carried out. The diameter of the lacrimal canaliculus was scanned with an ultrasonograph. Histopathological analysis was carried out in the cidofovir group. Results: In the cidofovir group, significant narrowing of lacrimal canaliculus, redness of eyelids and conjunctival injection were observed, but no obstruction of the lacrimal duct was found. Histology showed eosinophils, suggesting an allergic inflammation. Although zalcitabine and stavudine induced eyelid redness and conjunctival injection, no change was observed in the lacrimal pathway. Conclusions: These drugs may be possible candidates as eye drops for adenoviral conjunctivitis but further study is required to prove its safety.

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          Most cited references13

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          Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

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            Exemestane for breast-cancer prevention in postmenopausal women.

            Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).
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              Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study.

              Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
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                Author and article information

                Journal
                OPH
                Ophthalmologica
                10.1159/issn.0030-3755
                Ophthalmologica
                S. Karger AG
                0030-3755
                1423-0267
                2009
                July 2009
                05 March 2009
                : 223
                : 4
                : 233-238
                Affiliations
                aDepartment of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, bDepartment of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka, cDepartment of Ophthalmology, Akita University School of Medicine, Akita, and dDepartment of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan
                Article
                205585 Ophthalmologica 2009;223:233–238
                10.1159/000205585
                19262070
                7857ba2a-af9f-4e4c-bbdf-886060399a43
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 15 September 2008
                : 21 November 2008
                Page count
                Figures: 2, Tables: 4, References: 23, Pages: 6
                Categories
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Stavudine,Adenovirus,Nucleoside reverse-transcriptase inhibitor,Zalcitabine,Cidofovir,Antiviral agent,Eye drops

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