Current Pharmaceutical Design - Volume 24, Issue 41, 2018

Pharmacological adjuncts to vitrectomy surgery are useful tools to better deal with surgery. Their introduction has enriched the therapeutic choice before, during and after operations. Although several classifications could be made to frame adjuncts to vitrectomy, we preferred to divide the pharmacological adjuncts to vitrectomy surgery for therapeutic use in the pre-operatory procedure (neo-adjuvant), for intraoperative use and for post-operatory practice (adjuvant). This type of classification allowed us to explore all the adjuncts based on the timing of their use. The actual interest in vitrectomy surgery is giving rise to considerable interest in new molecules with and without the pharmacological effect that will soon be available for the aid of vitreoretinal surgery.

Background: Myopic choroidal neovascularization (CNV) is a common cause of central visual loss in patients with high myopia, and the most common form of CNV in younger individuals. Pharmacologic therapy is the current mainstay of treatment of these patients. Methods: Review of pharmacological treatment options for myopic CNV, which primarily involves intravitreal administration of anti-vascular endothelial growth factor (anti-VEGF) agents. Results: At this time, anti-VEGF therapy agents are the first-line therapy in these patients. Comparative trials have not identified any major differences in treatment outcomes between aflibercept, bevacizumab, and ranibizumab. Only ranibizumab is approved for this indication in the US. Best visual outcomes are associated with younger age, smaller lesion size, and absence of chorioretinal atrophy. Conclusion: Anti-VEGF therapy is generally very effective in the treatment of myopic CNV.

Exudative age-related macular degeneration (AMD) is a major indication for the administration of intravitreal injections of anti-VEGF agents, which have been established as a very effective pharmacotherapy for this disease. However, treatment with anti-VEGF agents requires several patient visits for monitoring and treatment. Strategies for achieving a longer duration of pharmacological action are currently being developed. These include the development of longer-acting drugs, and of novel technologies to increase the duration of action of administered agents. This manuscript will review the novel drugs and technologies currently being developed for achieving a longer-action pharmacotherapy for exudative AMD.

Background: Central serous chorioretinopathy (CSC) is the fourth most frequent retinal disorder in terms of prevalence. It typically occurs in young subjects and affects men more often than women. CSC is characterized by serous retinal detachment (SRD) involving mainly the macular area. The clinical course is usually selflimited, with spontaneous resolution within 3 months. The persistence of SRD or multiple relapse may result in a chronic form of CSC distinguished by permanent retinal pigment epithelium (RPE) and photoreceptor damage. As the pathogenetic mechanism of CSC primarily involves RPE and choroidal vascularization, the current therapeutic approaches aim to restore the normal functions of RPE and normal choroidal vascular permeability. In this review, the authors aim to summarize the current therapeutic approach to CSC. Methods: A comprehensive review of the literature was conducted in PubMed by searching for relevant studies on the current therapeutic options for CSC, including simple observation, conventional laser treatment, subthreshold laser treatment (SLT), photodynamic therapy (PDT) with verteporfin, treatment with mineralocorticoid receptor (MR) antagonists and treatment with anti-vascular endothelial growth factor drugs. Results: Since most cases resolve spontaneously, the most common initial CSC treatment is observation. Current evidence suggests that PDT and SLT are valuable in improving visual acuity, reducing subretinal fluid and maintaining long-term effectiveness. No clear evidence of efficacy has been achieved for anti-VEGF. MR antagonists might be a viable choice for the treatment of chronic CSC. Conclusion: The pathophysiology of CSC remains poorly understood and as a consequence, the gold standard of care for CSC is yet to be defined. To date, PDT and SLT continue to offer good clinical outcomes. Positive preliminary results seem to emerge from the studies of MR antagonists.

Vitreomacular traction occurs due to incomplete or anomalous posterior vitreous detachment. Over time, the vitreous pulls anteriorly and causes retinal distortion and eventually reduced vision. Traditionally, vitreomacular traction was treated with vitrectomy surgery. In the past few years, there is a paradigm shift towards pharmacologic vitreolysis, which involves the intravitreal injection of enzymatic and non-enzymatic agents that facilitate posterior vitreous detachment. Many agents have been investigated and trialled including plasmin, microplasmin (Ocriplasmin), hyaluronidase, nattokinase, chondroitinase and dispase. This review will focus on the progress and current status in this research.

Background: Choroidal neovascularization (CNV) in adults is most commonly associated with neovascular age-related macular degeneration (AMD) and pathologic myopia. Though less common, CNV can also develop from other conditions such as uveitis, central serous chorioretinopathy, angioid streaks, intraocular tumors, hereditary chorioretinal dystrophies, or can be idiopathic in origin. If left untreated, CNV may cause visual loss because of exudation of intraretinal or subretinal fluid, retinal or subretinal hemorrhage, or fibrosis involving the macula. It is well known that one of the main drivers of angiogenesis in CNV development is vascular endothelial growth factor (VEGF) and therefore inhibitors of VEGF might be an effective treatment for CNV. Methods: The goal of this review is to provide an overview and summary in the use of pharmacotherapy especially anti-VEGF therapy, in the treatment of CNV due to uncommon causes. Results: Results from uncontrolled case series and controlled clinical trials have reported good efficacy and safety in using anti-VEGF agents including bevacizumab, ranibizumab, aflibercept and ziv-aflibercept in the treatment of CNV due to uncommon causes. Anti-VEGF has also been used in combination with verteporfin PDT and anti-inflammatory agents for treating CNV of various causes. Conclusion: Pharmacotherapy with anti-VEGF agents is an effective treatment option for CNV due to uncommon etiologies.

Background: Pseudophakic cystoid macular edema (PCME) remains one of the most common visionthreatening complication of phacoemulsification cataract surgery (PCS). Pharmacological therapy is the current mainstay of both prophylaxis, and treatment of PCME in patients undergoing PCS. We aimed to review pharmacological treatment options for PCME, which primarily include topical steroids, topical nonsteroidal antiinflammatory drugs (NSAIDS), periocular and intravitreal steroids, as well as anti-vascular endothelial growth factor therapy. Methods: The PubMed and Web Of Science web platforms were used to find relevant studies using the following keywords: cataract surgery, phacoemulsification, cystoid macular edema, and pseudophakic cystoid macular edema. Of articles retrieved by this method, all publications in English and abstracts of non-English publications were reviewed. Other studies were also considered as a potential source of information when referenced in relevant articles. The search revealed 193 publications. Finally 82 articles dated from 1974 to 2018 were assessed as significant and analyzed. Results: Based on the current literature, we found that corticosteroids remain the mainstay of PCME prophylaxis in uncomplicated cataract surgery, while it is still unclear if NSAID can offer additional benefits. In patients at risk for PCME development, periocular subconjunctival injection of triamcinolone acetonide may prevent PCME development. For PCME treatment the authors recommend a stepwise therapy: initial topical steroids and adjuvant NSAIDs, followed by additional posterior sub-Tenon or retrobulbar corticosteroids in moderate PCME, and intravitreal corticosteroids in recalcitrant PCME. Intravitreal anti-vascular endothelial growth factor agents may be considered in patients unresponsive to steroid therapy at risk of elevated intraocular pressure, and with comorbid macular disease. Conclusion: Therapy with topical corticosteroids and NSAIDs is the mainstay of PCME prophylaxis and treatment, however, periocular and intravitreal steroids should be considered in refractory cases.

Background: Currently, diabetic retinopathy is the leading cause of permanent visual loss in workingage adults in industrialized nations. The chronic microangiopathic changes associated with diabetic retinopathy lead to the most common causes of severe permanent visual loss: diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Multiple studies have evaluated different pharmacotherapies for different levels of retinopathy. Methods: A review of the pathophysiology of diabetic retinopathy and current and emerging pharmacotherapies for diabetic retinopathy. Results: Historically, DME has been the primary focus of treatment in patients with nonproliferative diabetic retinopathy (NPDR). Due to the rapidly increasing number of agents and treatment options, management algorithms for DME have become increasingly complex. Furthermore, spectral domain optical coherence tomography (OCT) has allowed unparalleled sensitivity and specificity for detecting macular edema. All available intravitreal vascular endothelial growth factor (VEGF) inhibitors have demonstrated efficacy in the treatment of patients with DME and PDR. Intravitreal triamcinolone acetonide has also proven beneficial in diabetic retinopathy. Most recently, various corticosteroids have been designed as sustained-release intraocular implants in order to reduce the burden and risks associated with retreatment. Current research is focused on providing new agents that target alternate pathways and signaling molecules to provide patients with additional therapeutic tools, especially in patients who have an incomplete response to the current medications. Conclusion: Anti-VEGF therapy has revolutionized the medical management of diabetic retinopathy. The most important existing challenges in the treatment of diabetic retinopathy are improving visual outcomes and decreasing the treatment burden associated with repeated intravitreal injections. Combination therapy with anti-VEGF and corticosteroids with other previously available treatments, such as panretinal photocoagulation, may be a reasonable clinical strategy to reduce the intravitreal injections burden. Many exciting novel drugs that target newly discovered pathways hold clinical promise. The results of ongoing randomized clinical trials will answer the important concerns surrounding new drugs and delivery devices: safety and visual outcomes.

Blockade of PD-1/PD-L1 interactions using PD-1/PD-L1 pathway modulators has shown unprecedented clinical efficacy in various cancer models. Current PD-1/PD-L1 modulators approved by FDA are exclusively dominated by therapeutic antibodies. Nevertheless, therapeutic antibodies also exhibit several disadvantages such as low tumor penetration, difficulty in crossing physiological barriers, lacking oral bioavailability, high manufacturing costs, inaccessible to intracellular targets, immunogenicity, immune-related adverse events (irAEs). Modulation of PD-1/PD-L1 pathway using small molecules may be an alternative approach to mobilize immune system to fight against cancers. In this review, we focus on summarizing the recently disclosed chemical structures and preliminary structure-activity relationships (SARs) of small molecules as PD-1/PD-L1 modulators for cancer immunotherapy.

Fish despite their low collocation in the vertebrate phylum possess a complete immune system. In teleost fish both innate and adaptive immune responses have been described with melanomacrophage centers (MMCs) equivalent to mammalian germinal centers. Primary lymphoid organs are represented by the thymus and kidney, while spleen and mucosa-associated lymphoid tissues act as secondary lymphoid organs. Functions of either innate immune cells (e.g., macrophages and dendritic cells) or adaptive immune cells (T and B lymphocytes) will be described in detail, even including their products, such as cytokines and antibodies. In spite of a robust immune arsenal, fish are very much exposed to infectious agents (marine bacteria, parasites, fungi, and viruses) and, consequentially, mortality is very much enhanced especially in farmed fish. In fact, in aquaculture stressful events (overcrowding), microbial infections very frequently lead to a high rate of mortality. With the aim to reduce mortality of farmed fish through the reinforcement of their immune status the current trend is to administer natural products together with the conventional feed. Then, in the second part of the present review emphasis will be placed on a series of products, such as prebiotics, probiotics and synbiotics, β-glucans, vitamins, fatty acids and polyphenols all used to feed farmed fish. With special reference to polyphenols, results of our group using red grape extracts to feed farmed European sea bass will be illustrated. In particular, determination of cytokine production at intestinal and splenic levels, areas of MMCs and development of hepatopancreas will represent the main biomarkers considered. All together, our own data and those of current literature suggests that natural product administration to farmed fish for their beneficial effects may, in part, solve the problem of fish mortality in aquaculture, enhancing their immune responses.

Peptides and proteins are two classes of molecules with attractive possibilities for therapeutic applications. However, the bottleneck for the therapeutic application of many peptides and proteins is their short halflives in vivo, typically just a few minutes to hours. Half-life extension strategies have been extensively studied and many of them have been proven to be effective in the generation of long-acting therapeutics with improved pharmacokinetic and pharmacodynamic properties. In this review, we summarize the recent advances in half-life extension strategies, illustrate their potential applications and give some examples, highlighting the strategies that have been used in approved drugs and for drugs in clinical trials. Meanwhile, several novel strategies that are still in the process of discovery or at a preclinical stage are also introduced. In these strategies, the two most frequently used half-life extension methods are the reduction in the rate of renal clearance or the exploitation of the recycling mechanism of FcRn by binding to the albumin or IgG-Fc. Here, we discuss half-life extension strategies of recombinant therapeutic protein via genetic fusion, rather than chemical conjugation such as PEGylation. With the rapid development of genetic engineering and protein engineering, novel strategies for half-life extension have been emerged consistently. Some of these will be evaluated in clinical trials and may become viable alternatives to current strategies for making next-generation biodrugs.