Current Drug Targets - Volume 12, Issue 2, 2011

The Literature Search using as keyword “Age Related Macular Degeneration” (AMD) has identified more than 13,000 articles in Medline from 1960 to 2009. This apparently high number of articles, which surely does not account for the importance of the disease, became plethoric in the last decade, with more than two-thirds of totally published papers. AMD represents the leading cause of blindness in industrialized countries in people aged 65 years or older. Even in developing nations, AMD is gaining attention due to increased life expectancy and improved visual care facilities. The clinical presentation of AMD ranges from a few soft drusen and normal visual acuity to subfoveal choroidal new vessels (CNV) with disciform scarring and legal blindness. Rarely, patients have profound visual loss caused by extensive subretinal and vitreous hemorrhage [1]. It initially occurs in a “dry” or atrophic form, and can progress to geographic atrophy or convert to exudative or “wet” AMD, characterized by CNV [2]. The prevalence of AMD markedly increases with aging, but it is uncommon before the age of 50 years, whereas by age 90, one in four persons will sure to lose vision [3]. The natural course of AMD varies extremely between individuals. However, reliable factors for the explanation of this variability have so far not been established. The substantial variety in presentation, natural history of progression and associated risk factors suggest that several phenotypes of AMD may exist and different patterns of disease progression and functional impairment may reflect distinct underlying aetiologies. While our understanding of molecular events presaging AMD has grown in the last decade, its pathogenesis is yet a conundrum. In fact, genetic factors, oxidative stress, hydrodynamic changes, senescence of retinal pigment epithelium, hemodynamic changes, angiogenesis and subclinical inflammation [4] have been -from time to time- considered as the primum movens of the disease. The study of AMD pathogenesis as well as the therapeutic advances are hampered by the absence of an animal model that faithfully resembles every phase of AMD. The primary locus of insult for Age-Related Macular Degeneration remains in dispute. The hallmarks of the disease are; diffuse and focal thickening of Bruch's membrane (drusen) together with the development of hypo- and hyper-pigmented areas of RPE, the former signifying areas of RPE cell loss [5]. Although an array of risk factors has been epidemiologically related to AMD, their role in the progression of the disease remains unclear. Still, thanks to a greater understanding of AMD aetiology therapeutic strategies which have been moved beyond the initial limited approach of thermal laser photocoagulation. Photodynamic therapy with verteporfin (PDT-V) represents such a milestone in new options, but it too has restricted benefits. The therapeutic effect of PDT-V is achieved by a laser-light-induced thrombosis of CNV that has been photosensitized by the administration of verteporfin [6]. The individually variable efficacy of standardized PDT-V is clearly noticeable by reviewing the outcomes of Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP), Visudyne in Photodynamic Therapy (VIP), and Visudyne in Minimally Classic Choroidal Neovascularization studies [7-9]. Several gene mutations can affect the balance between pro and anticoagulant mechanisms, accounting for the occurrence of thrombophilic or hemorrhagic diatheses. The therapeutic effect of PDT-V is based on a photochemical perturbation of the hemostasis and coagulation within the neovascular complex. However, only recently the presence of a predictive correlation between peculiar coagulation-balance gene polymorphisms and different levels of PDT-V responsiveness in AMD patients with classic or predominantly classic CNV has been documented. These findings have provided a pharmacogenetic relationship between coagulation-balance genetic backgrounds and different levels of PDT-V effectiveness [6, 10-13]. Triamcinolone acetonide (TA) has been the first compound used for the treatment of CNV secondary to AMD. TA modulates the permeability and adhesion of in vitro cultured endothelial cells, down-regulates cytokine-induced expression of the intercellular adhesion molecule, as well as the matrix metalloproteinase and interferon gamma-induction of vascular permeability [14]. Lastly, Ciulla et al. have shown that triamcinolone inhibited laser-induced choroidal neovascularization in rats [15]. TA has the peculiar characteristics of being safe and well tolerated by the ocular tissues and consistently effective, thanks to its capability to remain active for many months after a single intravitreal injection. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment for several ocular diseases such as uveitis, macular oedema secondary to retinal vasculature disease, neovascularization and vitreous-retinopathy. IVTA treatments may slow down the natural course of AMD. No significant improvement of visual functions has been recorded in patients with exudative AMD, whereas a decrease of leakage in fluorescein angiography (FA) and a lack of further loss in visual functions have occurred. However, in the long-term follow-up IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect was observed in the short-term follow-up. Consequently, the synergistic combination of IVTA with photodynamic therapy (PDT), has been reported to improve vision and to reduce the number of PDT re-treatments [16]. Intraocular pressure (IOP) elevation has been reported in 19%- 43% of eyes after IVTA. It occurs most often between one and three months after the injection. Jonas et al. [17] reported IOP greater than 21, 30, 35 and 40 mmHg in 41.2%, 11.4%, 5.5% and 1.8% patients, respectively. Rise in IOP is well controlled with one or two topical anti-glaucoma medications; approximately 3% needs filtering surgery. The introduction of anti-vascular endothelial growth factor (VEGF)-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a high proportion of patients, previously limited to minimizing vision loss. Multiple studies have suggested that VEGF increases vascular permeability and is involved in the pathogenesis of neovascularization in human eye disease [18]. Current approaches to inhibit VEGF involve binding it to a molecule that prevents receptor 0-ligand interaction, thus incapacitating the effect of VEGF on the local environment. Options currently include either a full-length recombinant monoclonal antibody (bevacizumab), a humanized antibody fragment (ranibizumab), or a pegylated aptamer (pegaptanib sodium). Anti-VEGF therapies are an important breakthrough in exudative AMD, but they present issues that need to be explained. First, the risk for the development of endophthalmitis, which - although not so high - represents a potential devastating complication. Second, the rate of treatment, which presumes to be a monthly administration. Third, the cost of treatment, directly due to the compound and indirectly due to the need to re-examine the patient at each check. Fourth, the potential to develop cardiovascular and cerebral acute accident following prolonged exposure to anti VEGF drugs; in fact, these compounds have many essential functions, including the formation of collateral vessels after ischemia, as well as neurotrophic properties. Despite intra-vitreous injection, systemic absorption occurs and long-term treatment with repeated injections may cause chronic inhibition of the VEGF and its associated adverse effects [19]. Lastly, the resistance to anti-angiogenic therapy, i.e. why some patients do not respond to the treatment. Treatments for CNV can target either the vascular components of CNV (the new vessels that proliferate and leak blood and fluid) or the angiogenic components (that lead to the development of the condition). The combination of vPDT, (targeting the vascular components) and the anti-VEGF therapy (targeting key mediators of the angiogenic cascade), may have an additive or synergistic effect in reducing the frequency of treatment [20]. Moreover, the expression of VEGF is increased after PDT therapy and contributes to the re-growth of CNV. The combination therapy may be a cost effective alternative to monotherapy by reducing the need for re-treatment. A meta-analysis of randomized clinical trials comparing approved pharmacological treatments for neovascular AMD has shown that ranibizumab was the most effective treatment compared to PDT and pegaptanib....

In Western Countries, the occurrence of choroidal neovascularization (CNV) secondary to different forms of macular degeneration represents a common cause of blindness. Particularly, age-related macular degeneration (AMD) and pathologic myopia (PM) are the most frequent diseases related to CNV development. At present, the combined employment of drugs acting against vascular endothelial growth factor (anti-VEGF) and photodynamic therapy with verteporfin (PDT-V) is a promising therapeutic strategy for neovascular macular degenerations. However, this approach inevitably leads to an increase in health-resource utilization. In several clusters of patients treated for CNV, correlations among common gene polymorphisms implicated in coagulation- or complement-cascade and different levels of, respectively, post-PDT-V or post-anti-VEGF benefit have been reported. Factor XIII-A G185T substitution (rs5985), a frequent anti-thrombophilic genetic variant of Caucasian ethnic groups, unequivocally influences a worsening of the CNV responsiveness to PDT-V in patients affected by either AMD- or PM-related CNV. These coherent pharmacogenetic findings point out the opportunities to: i. optimize the eligibility criteria of PDT-V and, ii. customize the interventional strategy against CNV, for finally minimizing the socio-economic burden of neovascular macular degenerations.

Triamcinolone acetonide (TA) is one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The most important effects of TA consist in the stabilisation of the blood-retinal barrier and the down-regulation of inflammation. TA also has antiangiogenic and anti-fibrotic properties. The peculiar characteristic of being well tolerated by ocular tissues and the capability to remain active for many months after a single intravitreal injection, make this drug a safe and effective alternative. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment of several ocular diseases such as uveitis, macular edema secondary to retinal vasculature disease, neovascularisation and vitreoretinopathy. In this paper, we review all the available evidence of its use in AMD as mono-therapy or in combination with other treatments, and we discuss which role TA will play in the treatment of AMD in the future. The first experiences with IVTA as monotherapy for the treatment of exudative AMD reported a positive outcome in transiently reducing the leakage from CNV. However, in the long-term follow-up, IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect found 3 months after the treatment. Consequently, studies using the combination of IVTA and photodynamic therapy (PDT), which acts synergistically, were performed. They reported to improve vision and to reduce the number of re-treatments with PDT. A large number of publications confirmed the positive synergic role of combining TA and PDT (therapies) for the treatment of all types of CNV: classic or predominantly classic, occult or minimally classic and RAP (Retinal Angiomatous Proliferation) lesions. The advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Nevertheless, cataract surgery may stimulate the development of CNV (result in stimulating CNV). However, in large, randomized, clinical trials on combination therapy of TA and PDT, visual acuity failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone. Some authors reported an increased risk of developing macular atrophy after the combination therapy with IVTA and PDT. Reduction of the PDT fluence rate in association with the use of steroids resulted in reducing the risk of macular atrophy and in a better visual acuity outcome. The introduction of anti-VEGF-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a higher proportion of patients, previously limited to minimizing vision loss. Anti-VEGF therapy also resulted in superior visual improvement compared to all types of combination therapy with IVT and PDT. Nevertheless, anti-VEGF monotherapy also has many limitations due to the need of repetitive treatments, increased costs and tachyphylaxis. Treatment regimens involving TA in combination therapy with anti-VEGF and PDT may preserve benefits for substantially longer periods. A question remains open on whether a combination treatment with anti-VEGF, triamcinolone and/or PDT may be a treatment option in patients with exudative AMD, by offering, with one cycle of therapy, functional VA benefits comparable to those observed with continued monthly anti-VEGF therapy. Further trials, of higher scientific significance, are needed to study the potential of these treatment options.

Age-related macular degeneration (AMD) is the leading cause of blindness among elderly patients in developed countries. Although the pathogenesis of AMD is still largely unknown, it is now well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels (i.e. choroidal neovascularization, CNV) which characterizes the “wet form” of this ocular disease. Therefore, inhibiting VEGF has turned out to be a good way of more effectively controlling neovascular AMD. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Currently two anti-VEGF compounds have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD: pegaptanib and ranibizumab. Off-label usage of bevacizumab, an anti-VEGF agent similar to ranibizumab, has also become fairly common. The substantial improvement of visual acuity noticed in patients treated with ranibizumab has made this drug the gold standard for AMD therapy. However, as with many new therapies, there are unresolved issues, including safety, cost, and dosing frequency. This review describes in details the properties and efficacy of the three anti-VEGF agents in use in clinical practice. Promising emerging anti-VEGF strategies (VEGF-trap, small interfering RNA, tyrosine kinase inhibitors) which aim to improve outcomes, safety and treatment burden through novel mechanisms of action are also discussed.

Background: Age-related macular degeneration (AMD) is a condition that accounts for 75% of cases of legal blindness in individuals over the age of 50. Objectives: The objective of this review has been to evaluate the clinical effectiveness of available combined treatments modalities in the treatment of neovascular AMD. Data Sources: Central and Medline were searched for original research studies (Phase I, II, III), abstracts, and review articles concerning combination therapies for the control of neovascular AMD. We included randomized controlled trials (RCTs). Results: The results of therapeutic trials focused on the actual options in the management of neovascular AMD are discussed. Intravitreal treatment with substances targeting all isotypes of vascular endothelial growth factor (VEGF) results in a significant increase in visual acuity in patients with neovascular AMD. The combination with occlusive therapies like verteporfin photodynamic therapy (V-PDT) potentially offers a reduction of re-treatment frequency rate and long-term maintenance of the benefit reached. Despite the promise from combining anti-VEGF therapies with V-PDT, other combinations to improve outcomes with V-PDT deserve attention. Corticosteroids demonstrated an antiangiogenic effect and targeted the extravascular components of CNV, such as inflammatory cells and fibrocytes. Nevertheless, the study on the clinical application of corticosteroids will require a better understanding of the potential complications. Further developments interacting with various steps in the angiogenic cascade are under clinical or preclinical evaluation and may soon become available. In AMD the goal of a combination regimen is to address the therapy toward neovascular, inflammatory, and proliferative components of the disease. Conclusions: Combined treatments strategies are an obvious step providing disease control when it is not achieved with a single therapeutic approach. One risk of using a single therapy to control AMD is a rebound induced by compensatory stimulation of other pathogenetic pathways. Combination therapy is a logical approach to address mechanisms of disease progression that appear to be self-sustaining once initiated.

Purpose: This review summarizes the data reported in peer-reviewed literature on the effects of submacular surgery for age-related macular degeneration (AMD) associated with choriodal neovascularization (CNV). Methods: A review of the MEDLINE database has been performed in order to examine the therapeutic effects of submacular surgical treatments in patients affected by AMD. Results: The multicenter studies conducted by the Submacular Surgery Trials Research Group compare the removal of the CNV complex, both with (336) and without blood (454), with observation in patients affected by AMD. At a 1-year follow-up, no benefit in preventing visual loss had been shown. Furthermore, complications occurred in the surgery arm such as retinal detachment and lens opacification. No differences have been found between submacular surgery and laser photocoagulation in terms of visual acuity and quality of life. As yet, there are no randomized controlled trials concerning retinal pigment epithelium and choroid translocation or macular translocation, but only prospective, non-controlled case series with low quality of evidence. Conclusions: No evidence of potential benefit from submacular removal of the CNV complex due to AMD has been shown. Randomized clinical trails (RCT) concerning other submacular surgical approaches are not available. There are sufficient non-comparative data on retinal pigment epithelium (RPE) graft to warrant an RCT especially in patients with large subretinal haemorrhages, RPE rip or in Anti-VEGF non-responders.

Retinal angiomatous proliferation (RAP) is a distinct form of choroidal neovascularization which may complicate a wet age related macular degeneration (AMD). This exudative-AMD has a peculiar clinical history and prognosis. RAP accounts from 8% to 22% of newly diagnosed cases among patients previously diagnosed as exudative AMD, and up to 25% of the occult or minimally classic CNV. The disease is more prevalent in women (90% of cases) and in elderly patients (around 75 years), and is characterized by a very poor prognosis. The neovascular process, whose retinal or choroidal origin is still object of discussion, often hesitates in the formation of a disciform scar, that evolves into a severe loss of central vision. Treatment for RAP is not yet well established; herein are described the most used therapeutic strategies, starting from laser photocoagulation until the nearest anti VEGF. The opportunity of combination among various treatments to obtain a better effectiveness and a lower frequency of recurrence is also discussed.

Polypoidal Choroidal Vasculopathy (PCV) is a condition characterized by chronic, multiple, recurrent serous and/or hemorrhagic detachments of the retinal pigment epithelium (RPE) and neurosensory retina. Although it has been described to more often affect Asians and individuals of pigmented races, PCV may also be present in white patients who present with the clinical appearance of age related macular degeneration (AMD). PCV and its treatment are discussed, including the use of combination therapy.

Objective: To investigate the use of mixed treatment comparison (MTC) meta-analysis models to summarize results from randomized clinical trials (RCTs) on approved pharmacological treatments for neovascular age-related macular degeneration (AMD). Methods: The number of patients with visual loss or visual gain of 3 or more lines of visual acuity (15 ETDRS letters) at 1 year was extracted from 10 RCTs including patients with neovascular AMD and comparing at least one of the following drugs to sham treatment (1080 control patients, 8 studies) or to each other: verteporfin photodynamic therapy (PDT, 1124 patients, 4 studies), pegaptanib (904 patients, 2 twin studies), ranibizumab (984 patients, 4 studies). Both frequentist and Bayesian methods were used to conduct MTCs. Results: Direct and indirect evidence was available and found to be overall in good agreement for the comparisons: PDT vs. control, ranibizumab vs. control, ranibizumab vs. PDT. Bayesian model fit was better for a model including a covariate coding for the PIER study ranibizumab regimen, i.e. quarterly injections after three initial monthly doses. In the MTC model, monthly ranibizumab was superior to PDT and pegaptanib, and could not be shown to be better than PIER ranibizumab regarding visual loss, being estimates imprecise. Ranibizumab PIER retreatment regimen was better than PDT and pegaptanib regarding visual loss, whereas an advantage over them regarding visual gain was suggested by a frequentist MTC approach, but not by a Bayesian approach, which was more conservative. A limitation of our MTC model was that only two twin studies connected pegaptanib to the treatment network, and only one study was available for the PIER ranibizumab regimen. Conclusion: The clinically heterogeneous and sparse typology of the evidence is a limitation to carry out MTC metaanalysis of approved pharmacological treatments for neovascular AMD. Ranibizumab was found to be the most effective treatment compared to PDT and pegaptanib, although this superiority cannot be demonstrated regarding visual gain for the PIER ranibizumab regimen in a Bayesian analytic setting. We did not find RCTs which investigated the current ranibizumab as needed retreatment regimen approved in Europe.

Age-related macular degeneration (AMD) is the leading cause of central blindness or low vision among the elderly in industrialized countries. AMD is caused by a combination of genetic and environmental factors. Among modifiable environmental risk factors, cigarette smoking has been associated with both the dry and wet forms of AMD and may increase the likelihood of worsening pre-existing AMD. Despite advances, the treatment of AMD has limitations and affected patients are often referred for low vision rehabilitation to help them cope with their remaining eyesight. The characteristic visual impairment for both forms of AMD is loss of central vision (central scotoma). This loss results in severe difficulties with reading that may be only partly compensated by magnifying glasses or screen-projection devices. The loss of central vision associated with the disease has a profound impact on patient quality of life. With progressive central visual loss, patients lose their ability to perform the more complex activities of daily living. Common vision aids include low vision filters, magnifiers, telescopes and electronic aids. Low vision rehabilitation (LVR) is a new subspecialty emerging from the traditional fields of ophthalmology, optometry, occupational therapy, and sociology, with an ever-increasing impact on the usual concepts of research, education, and services for visually impaired patients. Relatively few ophthalmologists practise LVR and fewer still routinely use prismatic image relocation (IR) in AMD patients. IR is a method of stabilizing oculomotor functions with the purpose of promoting better function of preferred retinal loci (PRLs). The aim of vision rehabilitation therapy consists in the achievement of techniques designed to improve PRL usage. The use of PRLs to compensate for diseased foveae has offered hope to these patients in regaining some function. However, in a recently published meta-analysis, prism spectacles were found to be unlikely to be of substantial benefit in people with age-related macular degeneration. Prescription filters are one of the most beneficial visual aids for people with macular degeneration. In principle, one aims both at reducing short-wavelength light to reduce glare and at identifying light with specific wavelengths (colours) preferred by the patient for viewing. In both instances, such interventions result in apparent improved contrast sensitivity and better visual acuity. Although specific tests are performed to determine the best colour, tint, lens material, and type of frame for the patient's need, no scientific protocol has been developed so far to assist in prescribing tinted or selective transmission lenses. Magnifying optical lenses are available in a wide range of dioptric powers and are made from materials that correct for weight (plastic), thickness (high index), spherical aberrations (aspherical), and variable light intensities (photochromatic). These lenses can be used as loose lenses, mounted on optical frames, or used with a wide variety of attachments. As the dioptric power of plus lenses increases, the viewing distance of the target decreases, hence their usefulness mainly for tasks requiring near resolution acuity, like reading. Magnification can also be achieved with the use of telescopic devices that are built of two or more plus and (or) minus (minifying) optical lenses. Normal resolution acuity levels can be achieved with these devices for all viewing distances. Therefore, all telescopic devices are useful only for stationary patient tasks that do not require mobility and orientation. Electronic magnification has the great advantage over plus lenses of producing an acuity reserve enabling reading skills for almost all levels of visual acuity. The additional benefit provided is preservation of binocularity, even at high levels of visual disparity between the two eyes. Vision rehabilitation can help patients to maximize their remaining vision and adapt to activities of daily living. The support of the patient's social network is critical to patient's well-being as patients adjust to being partially sighted.

Vision loss secondary to Choroidal Neovascularization (CNV) is becoming a major disease condition in the developed world. CNV is typically secondary to Age-related Macular Degeneration (AMD) and these conditions are major, and also substantially increasing, causes of blindness among aged people. Several therapeutic options are currently available to treat CNV with variable efficacy on disease progress. Among existing treatments there are laser photocoagulation, photodynamic therapies, local corticosteroids and, more recently, the use of anti-angiogenic factors. Although by these treatments very effective results are obtained and their further improvement is still possible, it is also reasonable and necessary to look for more successful and definitive alternatives. The research in this direction is already very active and it can be expected that applications of the more recent molecular technologies will bring important advances also for CNV. These will likely regard the use of gene therapy and of new target specific factors. Gene therapy methodologies are rapidly becoming closer to current clinical use and, since the eye is a particularly favorable organ for drug delivery, their ocular use is probably going to be among the first successful applications of these techniques. In addition to its specific technology, gene therapy requires the knowledge of specific genes to be modulated to adequately affect pathogenesis and progression of the disease for which it has to be applied. This will also be true for the use of novel target specific drugs such as antibodies and other molecules able to affect cellular factors and pathways also related to disease development. For this reason, a major direction of future CNV therapies will be the identification of specific gene, gene products, metabolic pathways and metabolites related to the disease. This information, in addition to be suitable for gene and target specific therapies, will also allow the development of new procedures to improve diagnosis and/or prognostic evaluation of the disease.

Post-stroke cognitive impairment has a high prevalence in stroke patients and is associated with poor short and long term outcomes, including a negative impact on functional recovery. There is evidence that post-stroke impairment is the direct result of stroke induced neurological injury. Gray matter atrophy has been implicated in the development of post-stroke cognitive impairment and is the result of a series of neurochemical processes that are activated by ischemia. Lithium, traditionally used as a mood stabilizer, has been recognized in the last 10 years for its robust neuroprotective and neurotrophic effects against diverse insults, such as ischemia, both in vitro and in vivo. This has generated several preclinical and clinical studies of lithium treatment for managing neurodegenerative diseases and cerebral ischemia. Evidence suggests that lithium may protect against the cerebral atrophy and neuronal degeneration induced by the neurochemical processes and pathways known to regulate cell death and atrophy after an ischemic event. Lithiummediated neurotroprotective and neurotrophic effects involve mechanisms highly relevant to the post-stroke population including the increased expression of brain-derived neurotrophic factor (BDNF) and Bcl-2, and inhibition of GSK-3β. Lithium-induced increases in human gray matter have been reported and occur within a time frame consistent with the known effects of lithium through increased expression of BDNF, Bcl-2 and GSK-3β inhibition. This article reviews the evidence to support the use of lithium to reduce neuronal damage post-stroke through 1) mechanisms of excitotoxicity and post-ischemic inflammation; and 2) neurotrophic signaling cascades. Lithium's relevant actions in preclinical and clinical studies will be reviewed and presented to support the neuroprotective and neurotrophic effects of lithium as well as other clinical considerations in using lithium in the post-ischemic stroke population.

Sepsis is a common and frequently a fatal syndrome. Though, there is steady progress in the management of sepsis, further reduction of its mortality is still hampered by the lack of specific remedies. Recent advances in the understanding of the pathophysiology of sepsis and innovations in drug design have enabled researchers to develop new strategies for the treatment of this complicated condition in a more efficient way. Among these, a variety of small synthetic compounds with the molecular weight lower than 1000Da are emerging rapidly. This review highlights the advances of these small molecules in the treatment of sepsis, which are categorized into the following seven groups according to their pharmaceutical targets: LPS sequestrants and TLR4 antagonists, C5a receptor antagonists, inhibitors of macrophage migration inhibitory factor, inhibitors of QseC signaling, A3 adenosine receptor agonists and A2A adenosine receptor antagonists, estrogen receptor β agonists and caspase inhibitors. Most of the compounds have shown effectiveness in preclinical studies and displayed little or no toxicity. These small molecular compounds are potential candidates for further therapeutic development of sepsis.

Atrial fibrillation (AF) is an emerging clinical problem with multifaceted issues: current and expected prevalence, significant morbidity, potentially fatal outcome (e.g., stroke) and gaps in therapeutic approaches. Current antiarrhythmic strategies not only fail to guarantee effective rhythm control, but also cause “on target” (i.e., pro-arrhythmia, namely torsade de pointes) and “off target” (i.e., extra-cardiac toxicities) side effects. Although a number of drugs have just come out of the pipeline with promising results (e.g., dronedarone), the question arises whether channel-targeted drugs represent the only viable approach. A body of evidence has emerged supporting structural remodeling as the main arrhythmogenic substrate perpetuating AF. Fibrosis, inflammation and oxidative stress appear strongly interconnected in the pathogenesis of remodeling-induced abnormalities. Moreover, insights into extracellular matrix network strongly suggested an active cross-talk within the cardiac microenvironment, which should be further investigated as promising “anti-remodeling” approach. Therefore, pharmacological modulation of non-ionic targets (the so called “upstream” therapy) has gained interest as a preventive strategy in AF. At the present state of knowledge, renin-angiotensinaldosterone system blockers and statins offer evidence for potential clinical exploitation, while several remodeling targeted therapies have been tested only experimentally or failed when studied for human validation. Fascinating and innovative strategies have been proposed (e.g., miRNAs modulation), but the actual benefit is debated. This review will provide mechanistic insights into structural remodeling and highlight emerging upstream strategies in AF management.