Ophthalmology clinics of North America最新文献

VEGF plays a pivotal role in the neovascularization of the choroid in AMD. Anti-VEGF agents have been developed to target VEGF itself or its receptor signal transduction pathway, and have shown promising results in clinical trials. The combination of anti-VEGF strategies with established treatment modalities may have additional efficacy. Safe and effective drug-delivery systems are also required for the successful anti-VEGF therapies for AMD and other ocular diseases with CNV.

A wide variety of mediators likely contribute to ocular NV and these can serve as potential targets for the treatment of ocular NV. Several targets have already been validated in preclinical models and are being explored in clinical studies. In addition, targeting other processes besides angiogenesis, such as inflammation and apoptosis, may be beneficial in the treatment of ocular NV. Combined approaches with the use of several angiogenesis inhibitors or anti-inflammatory agents may show synergistic effects in treating ocular NV.

Repeated Macugen intravitreal injections, well tolerated and safe when performed according to protocol, is the first successful pharmacotherapy for wet AMD. Macugen has already had a significant impact on neovascular AMD management, in regard to both individual patients with AMD lesions that would become amenable to treatment, and in its effects on visual function and its preservation in the aging United States population. Although results and delivery method are not optimal, the positive outcomes indicate the beginning, and not the limit, of pharmacotherapy for AMD. The benefits of Macugen therapy for AMD strongly outweigh the risks. It is pointed out by some that the overall magnitude of the efficacy results is very similar to the PDT trials and question why there is so much enthusiasm about a treatment that entails intravitreal injections every 6 weeks instead of PDT every 12 weeks. In all fairness, PDT is not equally efficacious across the lesion subtypes and sizes, whereas Macugen has effect with all lesion subtypes. In addition, these studies widen the armamentarium and open up the possibility of combination therapy in attacking neovascularization through multiple ways.

Corticosteroids have been traditionally used for treatment of inflammatory disorders, but recently their angiostatic properties have been explored in neovascular ocular diseases. New corticosteroid compounds designed specifically to target angiogenesis are being developed, along with novel delivery methods and therapeutic regimes. Corticosteroids are gaining widespread acceptance, particularly in the treatment of retinal diseases, and new advances are being made in understanding their mode of action, optimal administration, and safety. Recent basic and clinical findings about the effectiveness and mechanisms of angiostatic corticosteroids are reviewed in this article.

Squalamine lactate inhibits angiogenesis by a long-lived, intracellular mechanism of action. The drug is taken up into activated endothelial cells through caveolae, small invaginations in the cellular membrane. Subsequently, the drug binds to and "chaperones" calmodulin to an intracellular membrane compartment and blocks angiogenesis at several levels. A series of basic investigations, preclinical studies, and human clinical trials have begun to establish the proof of concept, efficacy, and safety parameters for use of squalamine lactate as a therapeutic agent for exudative age-related macular degeneration and several types of malignancies.

Ranibizumab therapy is the first treatment for neovascular AMD to improve vision for most patients. The benefits apply to all angiographic subtypes of neovascular AMD and across all lesion sizes. Although the pivotal phase III trials (MARINA and ANCHOR) used monthly injections of ranibizumab for 2 years, the ongoing PIER, PrONTO, and SAILOR trials are investigating less frequent dosing regimens, and preliminary results from the PrONTO study suggest that fewer injections will most likely result in visual acuity improvements similar to the results from the phase III trials. When comparing the ANCHOR results with the FOCUS results, it also becomes apparent that the combination of ranibizumab with PDT does not necessarily result in better visual acuity outcomes, and the use of PDT may even reduce the visual acuity benefits achieved with ranibizumab alone (see Figs. 1-3). It seems unlikely that combination therapy provides any significant advantage over ranibizumab alone unless the combination of PDT and ranibizumab can decrease the need for frequent retreatment. The results from the PrONTO Study already suggest that less frequent treatment with ranibizumab is possible by using a variable dosing regimen with OCT. Ranibizumab also seems to be safe, with the 2-year MARINA data showing no increase in the incidence of systemic adverse events that could be associated with anti-VEGF therapy, such as myocardial infarction and stroke. There was a hint of a safety concern, however, in the pooled 1-year safety results from the MARINA and ANCHOR trials. Although the combined rate of myocardial infarction and stroke during the first year of the ANCHOR and MARINA trials was similar in the control and the 0.3-mg ranibizumab arms (1.3% and 1.6% respectively), these adverse events were slightly higher in the 0.5-mg ranibizumab arm (2.9%). These differences are not statistically significant, however, and probably do not represent a dose-dependent increase in risk because the 2-year results from the MARINA trial with the same monthly injection regimen showed no increased risk of thromboembolic events. In December 2005, Genentech submitted a Biologics License Application to the FDA for the use of ranibizumab in the treatment of neovascular wet AMD based on 1-year clinical efficacy and safety data from the two pivotal phase III trials, ANCHOR and MARINA, and the phase I-II FOCUS trial. Genentech has been granted a 6-month Priority Review from the FDA with a decision anticipated 6 months from the December submission date or by the end of June 2006 [29]. By the summer of 2006, this revolutionary therapy should be available for the treatment of neovascular AMD. At that time, the major dilemma facing most retina specialists will be whether to use intravitreal ranibizumab or intravitreal bevacizumab, the low cost alternative, for the treatment of neovascular AMD.

Although there have been treatments and pharmacologic agents approved in the last several years to treat advanced stages of AMD, these treatments do not halt disease progression. Furthermore, it is clear that when dry AMD progresses to CNV in one eye, there is a substantial risk that it will progress in the other eye. Sight-preservation at early stages of the disease should be a key goal of research, yet there are no approved therapies for halting the progression of early stages of AMD. Patients may be encouraged to use vitamin supplements, cease smoking, and eat a healthy diet; however, these recommendations are not appropriate for all patients, nor are they embraced by everyone. A pharmacologic agent capable of targeting the early stages of AMD would be a welcome addition to the armamentarium of options for managing AMD. Trials are ongoing to evaluate the role of anecortave acetate as a prophylactic treatment to slow the progression of the early stages of AMD. Completed clinical studies have demonstrated that anecortave acetate possesses a mechanism of action that decreases CNV growth irrespective of the inciting angiogenic stimulus, has a dosing-interval that allows its use as prophylactic therapy, and is safe. The economic benefits associated with prevention and progression to advanced AMD, in even a small proportion of cases, is significant and could result in substantial cost savings to society as a whole while providing countless benefits to individual patients in terms of continued independent function, self-sufficiency, and improved quality of life.

VEGF-A is a critical regulator of ocular angiogenesis and vascular permeability and is involved in the pathogenesis of several ocular diseases involving neovascularization or increased vascular permeability, such as neovascular AMD, diabetic ME, and diabetic retinopathy. Currently available therapies for neovascular AMD, such as laser photocoagulation, PDT with verteporfin, and pegaptanib sodium, slow visual loss but do not improve vision for most patients. In contrast, an emerging anti-VEGF agent, ranibizumab, improved vision in 25% to 34% of treated patients in one clinical trial, rather than slowing visual loss and is the first treatment for neovascular AMD to demonstrate visual improvement in a substantial number of patients. This represents a major advance in the treatment of ocular diseases involving neovascularization or increased vascular permeability and provides hope to patients with these debilitating diseases. Since the submission of this article, ranibizumab was approved by the FDA for the treatment of neovascular AMD.

RNA interference is a new technology that allows the production of therapeutic double-stranded RNA molecules (siRNA) that can specifically prevent the production of a particular gene product in a potent and efficient manner. It accomplishes this task by activating a native cellular defense mechanism, which when triggered results in the prevention of gene product production before the protein is made. Because of this amplification, only small quantities of siRNA are required to produce a silencing of gene production. siRNA designed to reduce production of angiogenic molecules provides potent therapies for ocular neovascularization in patients with age-related macular degeneration or diabetic retinopathy.

Orbital regional anesthesia is a useful and safe modality for providing excellent operating conditions for the surgeon and painless, pleasant circumstances for the patient. It is especially suited for patients who are extremely sensitive and who could not tolerate topical anesthesia or a sub-Tenon's block without deep sedation. Both intraconal and extraconal techniques can be used safely and effectively if proper precautions are taken to enter the safest areas of the orbit and to avoid the vascular areas and the deep orbit where structures are tightly packed and thus more easily harmed. Thorough knowledge of orbital anatomy and understanding of the globe-orbit relationship of every patient are necessary to perform this form of regional anesthesia. In addition, knowledge of the effects and side effects of the anesthetics and adjuvants is also required.