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      Effectiveness and safety of 0.15% ganciclovir in situ ophthalmic gel for herpes simplex keratitis – a multicenter, randomized, investigator-masked, parallel group study in Chinese patients

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          Abstract

          Objectives

          Parallel comparison with 0.15% ganciclovir (GCV) ophthalmic gel to evaluate the effectiveness and safety of 0.15% GCV in situ ophthalmic gel for the treatment of herpes simplex keratitis (HSK).

          Methods

          This was a multicenter, randomized, investigator-masked, parallel group study. HSK patients were randomly divided into two groups, with the corresponding treatment of 0.15% GCV ophthalmic gel or 0.15% GCV in situ ophthalmic gel. Symptoms and signs were observed before administration, and 3 (±1), 7 (±1), 14 (±2), and 21 (±3) days after the administration. The clinical effective rate was considered as the primary outcome. The safety profile was evaluated by AEs, visual acuity, and ocular tolerance.

          Results

          The clinical effective rate in the per-protocol (PP) dataset for the treatment group and the control group were 95.10% and 93.00%, respectively ( P = 0.5282). The noninferiority test showed significant differences ( P = 0.000305, P < 0.025), indicating that the tested drug was noninferior to the control. Patients in the PP dataset of both groups experienced decreases in the total scores of clinical indicators. Ocular AEs were few but similar between the two groups. There were no significant differences between patients’ visions between the two groups before and after administration in the safety analysis set. In terms of drug tolerance, the rates of patients without transient blurred vision during all the visits in the treatment group were higher than those for the control group ( P < 0.05). During the third and fourth visits, the rates of patients with eye itching were 4.08% and 1.22% in the treatment group, and 13.59% and 8.14% in the control group, respectively ( P < 0.05). During the second visit, the rates of patients with eye irritation were 14.42% in the treatment group and 25.71% in the control group ( P < 0.05).

          Conclusion

          The 0.15% GCV in situ ophthalmic gel was effective and safe for the treatment of HSK, and was not inferior to 0.15% GCV ophthalmic gel. The 0.15% GCV in situ ophthalmic gel presented superior ocular tolerance.

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          Most cited references 23

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          A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery.

          The aim of the present work was to obtain an ophthalmic delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the treatment of ocular diseases. For this, an in situ forming gel comprised of the combination of a thermosetting polymer, poly (ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-PPO-PEO, poloxamer), with a mucoadhesive agent (chitosan) was developed. Different polymer ratios were evaluated by oscillatory rheology, texture and mucoadhesive profiles. Scintigraphy studies in humans were conduced to verify the retention time of the formulations developed. The results showed that chitosan improves the mechanical strength and texture properties of poloxamer formulations and also confers mucoadhesive properties in a concentration-dependent manner. After a 10-min instillation of the poloxamer/chitosan 16:1 formulation in human eyes, 50-60% of the gel was still in contact with the cornea surface, which represents a fourfold increased retention in comparison with a conventional solution. Therefore, the developed formulation presented adequate mechanical and sensorial properties and remained in contact with the eye surface for a prolonged time. In conclusion, the in situ forming gel comprised of poloxamer/chitosan is a promising tool for the topical treatment of ocular diseases. Copyright 2010 Elsevier B.V. All rights reserved.
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            Adenovirus infection in hematopoietic stem cell transplantation: effect of ganciclovir and impact on survival.

            Adenoviruses (ADV) are emerging as important causes of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In mainly non-T-cell depleted HSCT recipients, we analyzed the incidence of ADV infection, risk factors for infection, the effect of ganciclovir administered for prevention of cytomegalovirus (CMV), and the impact of ADV infection on survival. The overall incidence of ADV, irrespective of the method of detection, was 8.5% (450/5233) and 12.3% (43/348) after the first or second allogeneic HSCT, and 6.3% (78/1219) and 6.5% (5/77) after the first or second autologous HSCT, respectively. The most frequent sites of infection and disease were stool and gastrointestinal tract, respectively. Statistically significant risk factors associated with ADV infections among allogeneic recipients included younger age, grade II to IV graft-versus-host disease, year of transplantation, and a second allogeneic HSCT. Furthermore, allogeneic patients seronegative for CMV at transplantation and seropositive allogeneic patients who did not receive ganciclovir, either at engraftment or as pre-emptive therapy on CMV reactivation, were at higher risk of developing ADV infections compared with seropositive patients who received ganciclovir (odds ratio=1.8, 95% confidence interval (CI) 1.2 to 2.8, P=.005 and odds ratio=3.4, 95% CI 2.1 to 5.55, P<.0001, respectively). The hazard of overall mortality was higher in patients who contracted ADV compared with those who did not (hazard ratio 1.5, 95% CI 1.3 to 1.7, P<.0001). This study shows that ADV infections are associated with poor transplantation outcome in T-cell repleted HSCT recipients. Ganciclovir, given for CMV prevention, may have a protective effect. Controlled treatment and prevention studies are warranted.
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              Stress-induced glucocorticoids at the earliest stages of herpes simplex virus-1 infection suppress subsequent antiviral immunity, implicating impaired dendritic cell function.

              The systemic elevation of psychological stress-induced glucocorticoids strongly suppresses CD8(+) T cell immune responses resulting in diminished antiviral immunity. However, the specific cellular targets of stress/glucocorticoids, the timing of exposure, the chronology of immunological events, and the underlying mechanisms of this impairment are incompletely understood. In this study, we address each of these questions in the context of a murine cutaneous HSV infection. We show that exposure to stress or corticosterone in only the earliest stages of an HSV-1 infection is sufficient to suppress, in a glucocorticoid receptor-dependent manner, the subsequent antiviral immune response after stress/corticosterone has been terminated. This suppression resulted in early onset and delayed resolution of herpetic lesions, reduced viral clearance at the site of infection and draining popliteal lymph nodes (PLNs), and impaired functions of HSV-specific CD8(+) T cells in PLNs, including granzyme B and IFN-gamma production and the ability to degranulate. In knockout mice lacking glucocorticoid receptors only in T cells, we show that these impaired CD8(+) T cell functions are not due to direct effects of stress/corticosterone on the T cells, but the ability of PLN-derived dendritic cells to prime HSV-1-specific CD8(+) T cells is functionally impaired. These findings highlight the susceptibility of critical early events in the generation of an antiviral immune response to neuroendocrine modulation and implicate dendritic cells as targets of stress/glucocorticoids in vivo. These findings also provide insight into the mechanisms by which the clinical use of glucocorticoids contributes to altered immune responses in patients with viral infections or tumors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                29 April 2013
                : 7
                : 361-368
                Affiliations
                [1 ]Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, People’s Republic of China
                [2 ]Department of Biostatistics and Social Medicine, School of Public Health, Fudan University, Shanghai, People’s Republic of China
                [3 ]The School of Ophthalmology and Optometry Affiliated with Wenzhou Medical College, Wenzhou, People’s Republic of China
                [4 ]The Second Affiliated Hospital of Haerbin Medical University, Haerbin, People’s Republic of China
                [5 ]The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
                [6 ]General hospital of Shenyang Military Command, Shenyang, People’s Republic of China
                [7 ]Shenyang SINQI Pharmaceutical Co Ltd, Shenyang, People’s Republic of China
                Author notes
                Correspondence: Lan Gong, 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Tel +02 164 310 068, Fax +02 164 310 068, Email gong_lan70@ 123456yahoo.com.cn . Xing-huai Sun, 83 Fenyang Road, Shanghai, 200031, People’s Republic of China, Tel +02 164 310 068, Fax +02 164 310 068, Email xhsun@ 123456shmu.edu.cn
                Article
                dddt-7-361
                10.2147/DDDT.S42624
                3673863
                23761964
                © 2013 Lin et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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