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1.  Successfully Improving Ocular Drug Delivery Using the Cationic Nanoemulsion, Novasorb 
Journal of Drug Delivery  2012;2012:604204.
Topical ophthalmic delivery of active ingredients can be achieved using cationic nanoemulsions. In the last decade, Novagali Pharma has successfully developed and marketed Novasorb, an advanced pharmaceutical technology for the treatment of ophthalmic diseases. This paper describes the main steps in the development of cationic nanoemulsions from formulation to evaluation in clinical trials. A major challenge of the formulation work was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time. Then, toxicity and pharmacokinetic studies were performed showing that the cationic emulsions were safe and well tolerated. Even in the absence of an active ingredient, cationic emulsions were observed in preclinical studies to have an inherent benefit on the ocular surface. Moreover, clinical trials demonstrated the efficacy and safety of cationic emulsions loaded with cyclosporine A in patients with dry eye disease. Ongoing studies evaluating latanoprost emulsion in patients with ocular surface disease and glaucoma suggest that the beneficial effects on reducing ocular surface damage may also extend to this patient population. The culmination of these efforts has been the marketing of Cationorm, a preservative-free cationic emulsion indicated for the symptomatic treatment of dry eye.
PMCID: PMC3313063  PMID: 22506123
2.  Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis 
BMC Ophthalmology  2010;10:31.
Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours.
A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated.
Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels.
Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD.
PMCID: PMC3009619  PMID: 21144031
3.  Gene expression profiling in autoimmune non-infectious uveitis disease 
Non-infectious uveitis is a predominantly T cell mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with non-infectious uveitis, peripheral blood mononuclear cells (PBMCs) were isolated from 50 patients with clinically characterized non-infectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real time PCR array for further confirmation. Sixty-seven inflammation and autoimmune associated genes were found differentially expressed in uveitis patients with twenty-eight of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20 and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared to the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provides the first evidence that a sub-set of IL-10 family genes are implicated in non-infectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.
PMCID: PMC2631441  PMID: 18802119
human; autoimmunity; non-infectious uveitis; microarray; peripheral blood mononuclear cells
4.  High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, noninfectious uveitis 
Journal of autoimmunity  2008;31(2):91-97.
This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis.
Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8 mg/kg at day 0 and 4 mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2 mg/kg every 4 weeks for 52 weeks. The primary outcome assessed was a 2-step decrease in vitreous haze at day 21. Secondary outcomes evaluated included best-corrected visual acuity, retinal thickness as measured by optical coherence tomography, retinal vascular leakage assessed by fluorescein angiography, anterior chamber and vitreous cellular inflammation.
4 male patients and 1 female patient were enrolled. Diagnoses included birdshot retinochoroidopathy (2 patients), Vogt-Koyanagi-Harada's disease, bilateral idiopathic panuveitis and bilateral idiopathic intermediate uveitis. By the 4th week, four of five patients demonstrated a 2-step decrease in vitreous haze. The other participant did not meet this criterion until week 20, but all 5 patients maintained stability in vitreous haze grade throughout their follow-up periods. At enrollment, mean visual acuity (10 eyes in five patients) was 69.2 ETDRS letters and following treatment was 78.2 letters (p < 0.12). Anterior chamber cell, vitreous cell, and vitreous haze also improved in the majority of eyes. Adverse events were generally mild except for one episode of left-lower lobe pneumonia requiring hospitalization and treatment.
This is the first demonstration that high-dose daclizumab can reduce inflammation in active uveitis. Daclizumab was well-tolerated but there may be a potential increased risk of infection associated with immunosuppression. All five patients demonstrated a decrease in vitreous haze and measures of intraocular inflammation at final follow-up. The results of this small, nonrandomized pilot study support the consideration of high-dose daclizumab therapy in cases of active posterior uveitis.
PMCID: PMC2742388  PMID: 18571896
daclizumab; posterior uveitis; panuveitis; intermediate uveitis; interleukin-2
5.  Intravitreal Methotrexate Resistance in a Patient with Primary Intraocular Lymphoma 
To describe the clinical course of a patient with multiple recurrences of primary intraocular lymphoma (PIOL).
Interventional case report,
Retrospective chart review.
A 57-year-old female treated with multiple intravitreal methotrexate injections became refractory to intravitreal methotrexate after a year. Lymphoma cells evaluated using immunocytochemistry and confocal microscopy showed aberrant multidrug resistance-related protein (MRP) and decreased reduced folate carrier (RFC) and folate binding protein (FBP) expression compared to PIOL cells from another patient clinically responsive to methotrexate.
This case suggests that alterations in the transport of methotrexate across the cell membrane might contribute to resistance following repeated intravitreal injections.
PMCID: PMC2561282  PMID: 18379939
CNS lymphoma; cytokine; drug resistance; methotrexate; multidrug resistance protein
6.  A Double-masked, Randomized Study to Investigate the Safety and Efficacy of Daclizumab to Treat the Ocular Complications Related to Behçet’s Disease 
To investigate the safety and efficacy of daclizumab (Zenapax, humanized anti-Tac, HAT) in controlling the ocular manifestations of Behçet’s disease.
Randomized, placebo-controlled, double-masked clinical trial.
Seventeen participants with Behçet’s disease experiencing at least two prior ocular attacks and requiring treatment with immunosuppressive agents for the ocular complications of Behçet’s disease.
Participants received either intravenous placebo or daclizumab (1 mg/kg) infusions every two weeks for six weeks, then every four weeks while continuing their standard immunosuppressive regimens. If clinically indicated, tapering of the standard immunosuppressive medications was allowed after six months of study enrollment. Complete ocular and physical examinations and an adverse event assessment were performed at baseline and prior to each study infusion.
Main Outcome Measures
Primary safety endpoints were the development of a life-threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of systemic immunosuppressive medications required during the study, including the ability to taper concomitant immunosuppressive therapy.
Nine participants randomized to daclizumab and eight to placebo were followed monthly. Follow-up ranged from one to 34 months, with a median follow-up of 15 months. Two participants randomized to daclizumab discontinued study therapy prior to the end of the study for personal reasons. No participant experienced a safety endpoint, and visual acuity remained stable in all participants during the course of the study. Ten participants (six daclizumab, four placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (median 1.27 vs. 0.17 attacks/year, respectively). Participants in the placebo arm also experienced a greater reduction in the immunosuppressive medication score compared to participants receiving daclizumab (median −4.0 vs. −1.0, respectively).
The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for the management of the ocular complications of Behçet’s disease. In our small study, there was no suggestion that daclizumab was beneficial in comparison with placebo. However, the low observed attack rate limited our ability to make a definitive treatment group comparison.
PMCID: PMC1950583  PMID: 17558830
Behcet’s disease; uveitis; daclizumab; clinical trial
7.  Detection of the bcl-2 t(14;18) Translocation and Proto-Oncogene Expression in Primary Intraocular Lymphoma 
Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells.
Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis.
Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger.
PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lympho-mas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profil-ing, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.
PMCID: PMC1945012  PMID: 16799010
8.  Primary Testicular and Intraocular Lymphomas: Two Case Reports and a Review of the Literature 
Survey of ophthalmology  2006;51(1):41-50.
Testicular lymphoma is a rare neoplasm of the testis that is most commonly seen in older patients. It metastasizes preferentially to extranodal sites, including the skin, central nervous system, Waldeyer ring, contralateral testis, and lung. Two case reports of patients with a history of testicular lymphoma who developed involvement of the vitreous and retina are presented. These are interesting cases as the testis, central nervous system, and eye are all immune privileged organs, which may account for occurrence of disease in these sites. Histopathologic examination of diagnostic vitrectomy specimens from both cases showed atypical lymphoid cells with immunoglobulin heavy chain (IgH) gene rearrangements, consistent with the diagnosis of intraocular B-cell lymphoma. The results of a literature review of all reports of ocular involvement with testicular lymphoma are discussed. Patients with testicular lymphoma are at risk for relapse, particularly in the central nervous system. Clinicians should be suspicious for intraocular lymphoma in patients with a history of testicular lymphoma who present with vitritis or retinal lesions.
PMCID: PMC1930146  PMID: 16414360
immune privileged organ; immunohistochemistry; intraocular lymphoma; microdissection; PCR; retina; testicular lymphoma; vitreous

Results 1-8 (8)