Therapy In Ophthalmology Research Articles

Glutathione-dependent formaldehyde dehydrogenase (ADH3) and low km mitochondrial aldehyde dehydrogenase (ALDH2). New evidence for differential expression in the rat retina in response to oxidative stress

Objectives: Epidemiological and experimental studies support the involvement of lipid peroxidation (LPO) in retinal diseases. In addition to other pathogenic mechanisms not fully understood, the possibility remains that peroxidic aldehydes, acting as cytotoxic chemicals, mediate in the progression of chronic ocular disorders. Methods: To test proper mechanisms involved in removing peroxidic aldehydes from the retina, in an attempt to understand long-lasting changes induced by LPO, the oxidative and antioxidant enzymatic activities, as well as the retinal distribution and activity of glutathione-dependent formaldehyde dehydrogenase (ADH3) and low km mitochondrial aldehyde dehydrogenase (ALDH2), were studied and compared with induced LPO sites in the adult rat retina. Biochemical enzymatic-colorimetric assays, histochemical and immunocytochemical analyses were carried out in the mature rat retinal tissues. Statistics were performed by the SPSS 15.0 program. Results: Data revealed (1) the noticeable LPO and glutathione (GSH) enzymatic system retinal and optic nerve activities; (2) the retinal expression and distribution of both the ADH3 and ALDH2; and (3) the co-localisation of iron/nicotine adenine dinucleotide phosphate (Fe/NADPH)-induced LPO, mainly in the outermost and innermost retinal strata, as compared to the rest of the retinal layers (p < 0.001). Conclusions: Changes in the GSH and GSH enzymatic system, and in the ADH3 and ALDH2 retinal expression and distribution might be crucial in assessing the intrinsic mechanisms of LPO-mediated retinopathies. Further research is needed to evaluate these findings and their application to new ophthalmological therapy.

Ergebnisse einer Expertenbefragung zum Einsatz der VEGF-Inhibitoren in der Augenheilkunde

VEGF inhibition is an important treatment option for patients with eye diseases like wet AMD or diabetic eye diseases. Concerning VEGF inhibition in Germany's ophthalmology there is lack of health-care data. A standardised telephone survey addressing treating ophthalmologists in Germany was used to acquire information in terms of VEGF inhibitors in ophthalmology. 44.9% considered ranibizumab (Lucentis®) and bevacizumab (Avastin®) as equal regarding efficacy and safety. Even so ranibizumab captured with 69.8% regarding patients under treatment the greatest market share. 26.1% estimated that less than 10% of patients with diabetic eye diseases are under treatment while 23.4% assumed that at present all treatable patients are under treatment. The integration of IVI into the EBM is recommended by only 9.4%. Using the content of one vial for the treatment of more than one patient is challenged by 66.4% of all participating ophthalmologists. 50.7% of these would accept the splitting procedure on condition that proof of drug quality in terms of efficacy and safety is given. The dominance of ranibizumab is based upon a forensic discussion about off-label use of drugs and liability of the treating physicians. In this connection it should not be forgotten that at the end of 2009 the approval of pegaptanib (Macugen®) and ranibizumab covers exclusively the indication "neovascular AMD". Since Novartis gained new indication for Lucentis in EU for vision loss due to diabetic macular edema (DME) it is to be expected that VEGF inhibition will become first line for patients with DME. The cost effectiveness of the anti-VEGF therapy in ophthalmology is based upon the treatment of several patients with one drug package. The integration of IVI into the EBM is not recommended by the majority of Germany's ophthalmologists because neither would the patients benefit nor would the health-care data transparency increase. To evaluate the ophthalmological anti-VEGF market in Germany and to identify and secure the treatment quality a recurring acquisition of health-care data with following management actions is needed.

Gene Therapy in Ophthalmology: Validation on Cultured Retinal Cells and Explants from Postmortem Human Eyes

Gene therapy studies in primates can provide important information regarding vector tropism, specific cellular expression, biodistribution, and safety prior to clinical trials. In this study, we report the assessment of transduction efficiency of recombinant adeno-associated virus (rAAV) vectors using human postmortem retina. Transductions were performed using two in vitro models prepared from human tissue: dissociated cell cultures and retinal explants. These models were used to assess cellular tropism and selectivity of rAAV vectors encoding for fluorescent proteins under the control of different promoters. These promoters were a ubiquitous cytomegalovirus promoter and a cell type-specific promoter targeting expression in ON bipolar cells. The results demonstrate that this in vitro approach can limit the use of living primates for the validation of gene therapy in vision and ophthalmology.

Redefining tissue engineering for nanomedicine in ophthalmology

Working at the nanoscale means to completely rethink how to approach engineering in the body in general and in the eye in particular. In nanomedicine, tissue engineering is the ability to influence an environment either by adding, subtracting or manipulating that environment to allow it to be more conducive for its purpose. The goal is to function at the optimum state, or to return to that optimum state. Additive tissue engineering replaces cells or tissue, or tries to get something to grow that is no longer there. Arrestive tissue engineering tries to stop aberrant growth which, if left uncontrolled, would result in a decrease in function. Nano delivery of therapeutics can perform both additive and arrestive functions influencing the environment either way, depending on the targeting. By manipulating the environment at the nanoscale, the rate and distribution of healing can be controlled. It infers that potential applications of nanomedicine in ophthalmology include procedures, such as corneal endothelial cell transplantation, single retinal ganglion cell repair, check of retinal ganglion cell viability, building of nanofibre scaffolds, such as self-assembling peptides, to create a scaffold-like tissue-bridging structure to provide a framework for axonal regeneration in the case of optic nerve reconnection or eye transplantation, and ocular drug delivery. Examples of potential arrestive therapies include gene-related treatment modalities to inhibit intraocular neovascularization and to block retinal cell apoptosis. Looking towards the future, this review focuses on how nanoscale tissue engineering can be and is being used to influence that local environment.

Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B

Present limitations in the management of ophthalmic fungal infections include the inability to provide long-term extraocular drug delivery without compromising intraocular structures and/or systemic drug exposure. In the present study, the potential of Eudragit RS 100 nanoparticles (NPs) as a new vehicle for the improvement of the delivery of drugs to the ocular mucosa was investigated. Amphotericin B (AmB) was chosen as a model compound because of its potential usefulness for the treatment of fungal diseases. A solvent displacement technique was used to produce AmB-loaded Eudragit NPs. These NPs had a mean size range of 150–290 nm and a zeta potential of +19–28 mV. Even after 6 months of stability study, results were unchanged, indicating the good potential for ocular application. In vitro release studies revealed that a maximum amount of drug was released within 24 hours (60%). The results obtained from microbial assay showed that the antifungal activity of drug-loaded NPs was equal to or slightly lower than that of free-AmB solution. In vivo experiments showed that, following topical instillation of nanosuspension to a rabbit's eye there was no irritation. From these results we can conclude that Eudragit RS 100 nanosuspension may represent an efficacious vehicle to deliver the drug into the eye. From the Clinical Editor Amphotericin B encapsulated into Eudragit, a mildly cationic nanoparticle, was shown to have 6 month stability, release 60% of its drug payload in dissolution within 24 hours, and elicited no irritation when instilled into rabbit eyes. The concept is being considered for local ophthalmologic therapy of fungal disease.

O9 Chlorin e6 photosensitizer as a fluorescence marker for fluorescence diagnostics during photodynamic therapy in ophthalmology

A relationship is presented which permits a determination of the quantity Γϱ2/Γ, where Γϱ and Γ are the particle (proton) and total widths, respectively, of an isolated resonance of which the total spin and channel spin mixing parameter are known. The analysis depends upon observation at a zero of the relevant Legendre polynomial, and hence only resonances for which ≠ can be analysed. Since the relationship is independent of instrumental resolution, it can be expected to yield better values of the parameters than the usual curve fitting procedure. The results are independent of target thickness, counter efficiency and solid angle, and current integrator precision. The formula given is valid if there is no appreciable l-mixing, no overlap of resonances, and if the “hard-sphere” correction to the Rutherford scattering is negligible. Tables are given showing where the latter approximation may be expected to break down. The restriction on l-mixing can be removed if the parity allowed l's are odd, since observation at 90° (C.M.) makes all interference terms vanish. If the allowed l's are even it is still possible to apply the formula given if an angle of observation can be found where the interference terms vanish. In both cases difficulty will be encountered in evaluating the results since the l-mixing parameter must be known. It is also shown that if the off-resonant scattering can be quantitatively compared to the Rutherford scattering, the range of application of the formula can be extended to cover all well-separated resonances. The extended formula depends, however, on the constancy (not the absolute value) of target thickness, counter efficiency and solid angle, and current integrator calibration. The analysis is applied to published data on the elastic scattering at a bombarding energy of 1.286 MeV in the 23Na (ϱ, ϱ) reaction.

068 Qualité de vie : De la théorie à la pratique

Introduction Quality of life (QoL) plays an increasingly important role in clinical studies and for the assessment of new technologies. It is directly relevant for evidence based individual patient treatment. Therefore the current study aims to summarize the impairment of vision-related QoL in selected diseases and their treatments. Materials and methods A short review based on the methods of assessing quality of life is given. Focussing on important retinal diseases like age related macular degeneration, diabetic retinopathy and disorders of the vitreoretinal interface (macular holes, ERM) the impairment of vision-related QoL by the diseases and changes by treatment are illustrated. Implications for clinical practice are discussed and recommendations are given. Observation While in some conditions visual acuity transfers well into visual QoL, this is frequently not the case and sometimes there is only weak or no correlation. Visual QoL is a more comprehensive endpoint including many other factors that influence vision such as visual field impairment, metamorphopsia or color perception. The visual QoL is also an expression of the visual preference of the individual patient. Discussion As patient perceived quality of vision may be considered the real goal of ophthalmologic therapy, it should also be considered more systematically in daily practice. Visual quality of life has a different information value than visual acuity. Evidence based study results of large patient numbers can be applied to decide on the most suitable therapeutic regimen for the individual patient. Conclusion Visual QoL has increasing importance not only in clinical studies but also in actual therapeutic decision making for the individual patient, although on many points further research is needed.

Gene therapy in ophthalmology

It has been more than a year since ophthalmologists and scientists under Dr. Robin Ali′s team at the Moorsfield Eye Hospital and the Institute of Ophthalmology, University College London, successfully treated patients with a severely blinding disease, Leber′s congenital amaurosis (LCA) using gene therapy. This success does not look to be transient, and this achievement in gene replacement therapy clinical trial for LCA has instilled hope in numerous families with patients suffering from this and similar retinal degenerative diseases, for whom restoration of lost vision has remained a distant dream so far. The encouragement that this success has given is expected to also lead to start of clinical trials for other blinding ocular diseases for which gene therapy experiments at the laboratory and animal levels have been successful. This article reviews the various studies that have led to the understanding of gene therapy outcomes in human ocular diseases and attempts to provide a brief sketch of successful clinical trials.

The possible involvement of nasal allergy in allergic keratoconjunctivitis

Allergic keratoconjunctivitis coexists regularly with allergic rhinitis. However, little is known about the relationship between these conditions. The purpose of this study was to investigate the possible involvement of nasal allergy in keratoconjunctivitis by means of nasal challenge with allergen (NPT), in combination with recording of the ocular symptoms. In 26 patients suffering from atopic (n=15) or vernal (n=11) keratoconjunctivitis showing positive history and skin tests, but responding insufficiently to the local ophthalmologic therapy, 71 NPTs with inhalant allergens were performed and combined with the recording of the ocular response. In 11 control subjects with allergic rhinitis, but without ocular disease history, 11 positive NPTs were repeated and supplemented with the registration of the ocular features. Of the 26 patients, 24 developed 51 positive nasal responses (NRs; P<0.01), 43 of which were accompanied by significant ocular response (P<0.01). No ocular responses were measured during the 26 PBS control challenges (P>0.05) or during 11 repeated NPTs in control subjects (P>0.2). These results give evidence for possible involvement of nasal allergy in some cases of keratoconjunctivitis. They also show diagnostic value of nasal challenges with allergen in combination with registration of the ocular symptoms in such patients, allowing then consideration of additional therapeutic measures concerning the nasal allergy.

Ultrahigh speed Spectral / Fourier domain OCT ophthalmic imaging at 70,000 to 312,500 axial scans per second

We demonstrate ultrahigh speed spectral / Fourier domain optical coherence tomography (OCT) using an ultrahigh speed CMOS line scan camera at rates of 70,000 - 312,500 axial scans per second. Several design configurations are characterized to illustrate trade-offs between acquisition speed, resolution, imaging range, sensitivity and sensitivity roll-off performance. Ultrahigh resolution OCT with 2.5 - 3.0 micron axial image resolution is demonstrated at approximately 100,000 axial scans per second. A high resolution spectrometer design improves sensitivity roll-off and imaging range performance, trading off imaging speed to 70,000 axial scans per second. Ultrahigh speed imaging at >300,000 axial scans per second with standard image resolution is also demonstrated. Ophthalmic OCT imaging of the normal human retina is investigated. The high acquisition speeds enable dense raster scanning to acquire densely sampled volumetric three dimensional OCT (3D-OCT) data sets of the macula and optic disc with minimal motion artifacts. Imaging with approximately 8 - 9 micron axial resolution at 250,000 axial scans per second, a 512 x 512 x 400 voxel volumetric 3D-OCT data set can be acquired in only approximately 1.3 seconds. Orthogonal registration scans are used to register OCT raster scans and remove residual axial eye motion, resulting in 3D-OCT data sets which preserve retinal topography. Rapid repetitive imaging over small volumes can visualize small retinal features without motion induced distortions and enables volume registration to remove eye motion. Cone photoreceptors in some regions of the retina can be visualized without adaptive optics or active eye tracking. Rapid repetitive imaging of 3D volumes also provides dynamic volumetric information (4D-OCT) which is shown to enhance visualization of retinal capillaries and should enable functional imaging. Improvements in the speed and performance of 3D-OCT volumetric imaging promise to enable earlier diagnosis and improved monitoring of disease progression and response to therapy in ophthalmology, as well as have a wide range of research and clinical applications in other areas.

Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses: a pilot study

Local photodynamic therapy (PDT) is a novel cancer therapy in veterinary ophthalmology. A prospective pilot study seeking to demonstrate proof of principle and safety for the treatment of equine periocular squamous cell carcinoma (PSCC) was therefore conducted. We hypothesized that surgical excision with adjunctive local PDT is an effective and safe treatment for equine PSCC. Nine horses (10 eyes) with PSCC were treated with surgical resection, local infiltration of resulting wound beds with 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) and irradiation with 665-nm wavelength diode laser. Regular follow-up ophthalmic examinations were performed. Surgical resection and PDT yielded disease-free intervals of 25-68 months in our study horses as of January, 2008. These results were obtained following a single treatment in seven horses and two treatments in one horse. In one horse, carcinoma in situ developed 2.5 months after partial surgical excision and PDT, requiring local excision under standing sedation. Preliminary results suggest that surgical resection and adjunctive local PDT is a safe and effective novel treatment for PSCC in horses. More research is needed before PDT for the treatment of equine PSCC can be adequately compared with other current modalities. Important to future investigations regarding PDT, tumor recurrence rate, length of hospitalization, number of treatment episodes required to effect tumor remission, and total treatment costs should be examined in a controlled manner. Our present results and experiences suggest that this treatment may be useful in the treatment of equine PSCC.

The efficiency of ophthalmologic interventions and occupational therapy in children with cerebral palsy and poor vision

The efficiency of ophthalmologic interventions and occupational therapy in children with cerebral palsy and poor vision

Photodynamic therapy: basic principles and potential uses for the veterinary ophthalmologist

Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light and oxygen. PDT, while now commonly used in physician ophthalmology and oncology, is uncommonly used for the veterinary ophthalmic patient. It is an emerging new therapy in veterinary ophthalmology for the treatment of periocular tumors. This article reviews the basic principles of PDT to provide the veterinary ophthalmologic community with a succinct reference for this emerging treatment modality in our field.

Endogenous Bone Marrow–Derived Cells Express Retinal Pigment Epithelium Cell Markers and Migrate to Focal Areas of RPE Damage

The aim of the present study was to investigate whether bone marrow-derived cells (BMCs) can be induced to express retinal pigment epithelial (RPE) cell markers in vitro and can home to the site of RPE damage after mobilization and express markers of RPE lineage in vivo. Adult RPE cells were cocultured with green fluorescence protein (GFP)-labeled stem cell antigen-1 positive (Sca-1(+)) BMCs for 1, 2, and 3 weeks. Cell morphology and expression of RPE-specific markers and markers for other retinal cell types were studied. Using an animal model of sodium iodate (NaIO(3))-induced RPE degeneration, BMCs were mobilized into the peripheral circulation by granulocyte-colony stimulating factor, flt3 ligand, or both. Immunocytochemistry was used to identify and characterize BMCs in the subretinal space in C57BL/6 wild-type (wt) mice and GFP chimeric mice. In vitro, BMCs changed from round to flattened, polygonal cells and expressed cytokeratin, RPE65, and microphthalmia transcription factor (MITF) when cocultured in direct cell-cell contact with RPE. In vivo, BMCs were identified in the subretinal space as Sca-1(+) or c-kit(+) cells. They were also double labeled for GFP and RPE65 or MITF. These cells formed a monolayer on the Bruch membrane in focal areas of RPE damage. Thus, it appears that BMCs, when mobilized into the peripheral circulation, can home to focal areas of RPE damage and express cell markers of RPE lineage. The use of endogenous BMCs to replace damaged retinal tissue opens new possibilities for cell replacement therapy in ophthalmology.

This Issue of Acta

This Issue of Acta

Gene therapy in ophthalmology. Review of options and trends in corneal diseases

Gene therapy has gained increasing attention and a number of ongoing clinical trials have been initiated. This article provides current perspectives and limitations on gene therapy in ophthalmology. Since a number of comprehensive studies on gene therapy for retinal diseases already exist, we focus attention to the treatment of anterior segment disorders of the eye. We undertook a reference search (DIMDI, PubMed) of articles published between (1989-2000) using the key words cornea, conjunctiva, eye, gene therapy, and keratoplasty. The search was restricted to publications in English, French and German. In addition, we incorporated some results of our recent experiments on cytokine gene transfer to the cornea. Attention to gene therapy in ophthalmology is currently focused on retina and choroidea (40 articles) however, an increasing number of publications includes the cornea (12 articles). The majority of these contributions deals with improvements in the design of gene therapy vectors in particular for targeted application. Gene therapy to the cornea may offer interesting new venues. Currently, insufficient gene transfer technologies and safety concerns prevent the broad application in humans. However, a broad spectrum of applications can be supposed.

Treatment of Advanced Glaucomas Using Leksell Gamma Knife (LGK)--A Pilot Clinical Study

The use of radiosurgery in treatment of the glaucomas is a completely new way of treating advanced stages of this treacherous disease. Up to now, the most common indications for the LGK therapy in ophthalmology at our department are malignant melanoma, vascular diseases, intraocular and intraorbital metastasis, and glioma of the optic nerve. Our pilot study shows that focal irradiation of the ciliary body in advanced glaucoma can ameliorate the main symptoms and thus prevent the otherwise inevitable enucleation of the eye. We treated in 12 patients, 13 very painful eyes, who were blind or with very diminished vision, and where the conventional treatment was ineffective. The ocular pain was alleviated in all patients and their intraocular pressure was reduced or normalized. There were no early side effects. Further studies are needed to elucidate the best treatment parameters and the involved pathophysiological mechanisms. However, it is evident that gamma knife radiosurgery can be considerably extended in this way.

Loss of visual acuity under dopamine substitution therapy

Visual dysfunction is a well-known feature of Parkinson’s disease. Dopamine has been shown to be a functional modulator at many levels of the visual system. We report on a parkinsonian patient, suffering concurrently from various ophthalmological conditions including glaucoma and cataracts and displaying objectively measurable loss of visual acuity and blurring of vision while under medication with an MAO-B inhibitor and multiple ergolene-derived dopamine agonists. Various studies have investigated the effects of different D1- and D2-agonists and -antagonists on visual function and found that the presynaptic dopaminergic autoreceptor involved in the modulation of dopamine release in the retina displays characteristics of D2-receptors. We conclude that the observed phenomenon represents either an inhibition of dopamine release due to excessive stimulation of presynaptic D2-autoreceptors, leading to an insufficient stimulation of postsynaptic dopaminergic receptors and thus impeding retinal signal conduction, or a heretofore unclear interaction between the patient’s ophthalmological pathologies and dopaminergic therapy, possibly due to excessive stimulation of postsynaptic dopamine receptors, leading to faulty retinal information processing.

A population pharmacokinetic metabolism model for individualizing ciprofloxacin therapy in ophthalmology

A population pharmacokinetic metabolism model for individualizing ciprofloxacin therapy in ophthalmology

Chemotherapy for retinoblastoma: a current topic.

Retinoblastoma is the most common primary intraocular tumour in children, with an incidence of 1 in 15,000 live births. Treatment strategies for retinoblastoma have gradually evolved over the past few decades. There has been a trend away from enucleation (removal of the eye) and external beam radiation therapy toward focal 'conservative' treatments. Every effort has been made to save the child's life with preservation of eye and sight, if possible. Primary enucleation continues to be the commonly used method of treatment for retinoblastoma. It is employed in situations where eyes contain large tumours, long standing retinal detachments, neovascular glaucoma and suspicion of optic nerve invasion or extrascleral extension. Most of these eyes either have or are expected to have no useful vision. Radiation therapy continues to be an effective treatment option for retinoblastoma. However, external beam radiotherapy has unfortunately been associated with secondary non-ocular cancers in the field of radiation (primarily in children carrying the RB-1 germline mutation). Ophthalmic plaque brachytherapy has a more focal and shielded radiation field, and may carry less risk. Unfortunately, its applicability is limited to small to medium-sized retinoblastomas in accessible locations. Cryotherapy and transpupillary thermotherapy (TTT) have been used to provide control of selected small tumours. TTT is an advanced laser system adapted to the indirect ophthalmoscope which provides flexible nonsurgical treatment for small retinoblastomas. Recent research in the treatment of retinoblastoma has concentrated on methods of combining chemotherapy with other local treatment modalities (TTT, radiotherapy, cryotherapy). This approach combines the principle of chemotherapeutic debulking in paediatric oncology with conservative focal therapies in ophthalmology. Termed chemoreduction, intravenous or subconjunctival chemotherapy is used to debulk the initial tumour volume and allow for local treatment with TTT, cryotherapy and plaque radiotherapy. Cyclosporin has been added to the chemotherapy regimen in several centres. Other clinical settings where chemotherapy is considered are situations where the histopathology suggests a high risk for metastatic disease and where there is extraocular extension. There is no consensus that chemotherapy is needed when choroidal invasion is observed on histopathology. However, in patients where the retinoblastoma is noted beyond the cut end of the optic nerve or if there is disruption of the sclera with microscopic invasion of the orbital tissue, treatment has been helpful. Systemic and intrathecal chemotherapy with local and cranial radiotherapy has improved the survival of these patients. Most recently, the use of new chemotherapy modalities with haematopoietic stem cell rescue or local radiotherapy has increased the survival of patients with distant metastasis. Nevertheless, the prognosis of patients with central nervous system involvement is still poor.