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Biomedical subjects

Robert N Frank

Publications and source records attributed to Robert N Frank.

8 recordsLinked to original sources
PubMed2006

Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial.

Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Adenoviridae↗
PubMed2004

Temporal variation in diabetic macular edema measured by optical coherence tomography.

PURPOSE: To determine, by optical coherence tomography (OCT), whether there is a quantitative decrease in macular edema in diabetic subjects over the course of a day. STUDY DESIGN: Observational case series. PARTICIPANTS: Ten subjects with diabetic macular edema in 1 or both eyes. METHODS: Subjects were admitted to the hospital the evening before the study so that they would remain in the recumbent position until immediately before study measurements began. They then underwent 4 OCT measurements of macular thickness in both eyes, at 8:00 am, 11:00 am, 2:00 pm, and 5:00 pm. At each of these times, they also had refractions and visual acuity measurements using the Early Treatment Diabetic Retinopathy Study protocol. Macular thickness measurements determined by the Zeiss-Humphrey (Dublin, CA) optical coherence tomograph for each eye of each subject were plotted as a function of time. MAIN OUTCOME MEASURES: Temporal changes in retinal thickness in each of the 9 macular sectors defined by the OCT protocol and in the entire macula of each eye, averaged from all 9 sectors; temporal changes in refractive error and visual acuity. RESULTS: Four of the 10 subjects showed consistent decreases in macular thickness over the course of the day in 1 or more of the retinal sectors in 1 or both eyes. When macular thickness values were averaged over all 9 sectors for all subjects, both eyes showed consistent declines in mean thickness throughout the day. By t test, the 8 am value in each eye was significantly higher (P<0.0005) than any of the 3 later values, which did not differ significantly from each other. However, comparison of all 4 values by analysis of variance showed no significant differences. With the exception of 1 subject, there were no consistent changes in refractive error or in best-corrected visual acuity over the course of the study. CONCLUSIONS: This study, using quantitative OCT determinations, seems to confirm the much earlier report by Sternberg et al, which used more subjective methods, that macular edema might vary over the day. That the 8 am value, obtained just after waking, was higher than the 3 later values (highly significant by 1 test) suggests that the decrease in macular thickness is most likely due to the shift from recumbent to upright body position, although our study protocol did not exclude other possible mechanisms. Although changes in macular thickness over the course of the day did not occur in all subjects, therapeutic studies for macular edema that use OCT as an outcome measure should control for time of day when these measurements are carried out.

Aged↗
PubMed2004

Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression.

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy.

Animals↗
PubMed2003

Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats.

The study addressed the role for aldose reductase (AR) in 1) retinal oxidative stress and vascular endothelial growth factor (VEGF) overexpression in early diabetes, and 2) high glucose-induced oxidative stress in retinal endothelial cells. In vivo experiments were performed on control rats and diabetic rats treated with or without low or high dose of the AR inhibitor (ARI) fidarestat (2 or 16 mg. kg(-1). day(-1)). In vitro studies were performed on bovine retinal endothelial cells (BREC) cultured in either 5 or 30 mmol/l glucose with or without 1 micro mol/l fidarestat. Intracellular reactive oxygen species were assessed using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) probe and flow cytometry. Both low and high doses of fidarestat (i.e., the doses that partially and completely inhibited sorbitol pathway hyperactivity) arrested diabetes-induced retinal lipid peroxidation. This was achieved due to upregulation of the key antioxidative defense enzyme activities rather than changes in reduced glutathione, oxidized glutathione, ascorbate and dehydroascorbate concentrations, and the glutathione and ascorbate redox states. Diabetes-associated 2.1-fold VEGF protein overexpression (enzyme-linked immunosorbent assay; ELISA) was dose-dependently prevented by fidarestat, whereas total VEGF mRNA and VEGF-164 mRNA (RT-PCR) abundance were not affected by either diabetes or the ARI. In BREC, fidarestat corrected hyperglycemia-induced increase in H(2)DCFDA fluorescence but not oxidative stress caused by three different pro-oxidants in normoglycemic conditions. In conclusion, increased AR activity contributes to retinal oxidative stress and VEGF protein overexpression in early diabetes. The findings justify the rationale for evaluation of fidarestat on diabetic retinopathy.

Aldehyde Reductase↗
PubMed2002

Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors.

PURPOSE: To review the evidence supporting a role for the beta (beta) isoform of protein kinase C (PKC) in the pathogenesis of diabetic retinopathy and the possible therapeutic benefit of inhibiting this enzyme. DESIGN: Brief literature review of research suggesting the potential use for systemic inhibitors of the beta isoform of PKC as a medical therapy to prevent the progression of diabetic retinopathy. Brief consideration is given to previous, primarily clinical, studies dealing with other therapies for this disease. RESULTS: Kinases transfer the terminal, "high energy," phosphate group of ATP to a site on a target protein, thereby activating the protein, which may be an enzyme, cell membrane receptor, or ion transport channel. The PKC family is a group of such enzymes that require specific activator molecules, including diacylglycerol, whose intracellular concentration is substantially increased during the hyperglycemia of diabetes. Protein kinase Cbeta is present at high levels in the retina. Increased activation of this enzyme, perhaps by producing tissue hypoxia, leads to increased expression of vascular endothelial growth factor, a mitogen that increases proliferation of vascular endothelial cells leading to neovascularization and enhances breakdown of the blood-retinal barrier, perhaps resulting in macular edema. CONCLUSIONS: By interfering with the above biochemical pathways, PKC inhibitors may retard or prevent the development and progression of diabetic retinopathy. Because members of the PKC family are found throughout the body, a generalized inhibitor is likely to be toxic. However, an inhibitor specific for PKCbeta may act effectively within the retina and have a favorable toxicity profile. Two phase III randomized controlled clinical trials of such an inhibitor are now in progress, attempting to evaluate the efficacy of this approach to preventing the progression, or inducing regression, of "nonclinically significant" diabetic macular edema and of severe nonproliferative diabetic retinopathy.

Clinical Trials, Phase III as Topic↗