Successfully Improving Ocular Drug Delivery Using the Cationic Nanoemulsion, Novasorb

Topical ophthalmic delivery of active ingredients can be achieved using cationic nanoemulsions. In the last decade, Novagali Pharma has successfully developed and marketed Novasorb, an advanced pharmaceutical technology for the treatment of ophthalmic diseases. This paper describes the main steps in the development of cationic nanoemulsions from formulation to evaluation in clinical trials. A major challenge of the formulation work was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time. Then, toxicity and pharmacokinetic studies were performed showing that the cationic emulsions were safe and well tolerated. Even in the absence of an active ingredient, cationic emulsions were observed in preclinical studies to have an inherent benefit on the ocular surface. Moreover, clinical trials demonstrated the efficacy and safety of cationic emulsions loaded with cyclosporine A in patients with dry eye disease. Ongoing studies evaluating latanoprost emulsion in patients with ocular surface disease and glaucoma suggest that the beneficial effects on reducing ocular surface damage may also extend to this patient population. The culmination of these efforts has been the marketing of Cationorm, a preservative-free cationic emulsion indicated for the symptomatic treatment of dry eye

The Fitzgerald Institute for Entrepreneurial Studies Innovation Project

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modulation of inflammation related genes in the cornea of a mouse model of dry eye upon treatment with cyclosporine eye drops

ABSTRACTPurpose/Aim: Inflammation is recognized as playing an etiological role in dry eye disease. This study aimed to assess the efficacy of various topical cyclosporine A (CsA) formulations on co..

Artificial Tears: Biological Role of Their Ingredients in the Management of Dry Eye Disease

Dry eye disease (DED) is the most common ocular surface disease, characterized by insufficient production and/or instability of the tear film. Tear substitutes are usually the first line of treatment for patients with DED. Despite the large variety of tear substitutes available on the market, few studies have been performed to compare their performance. There is a need to better understand the specific mechanical and pharmacological roles of each ingredient composing the different formulations. In this review, we describe the main categories of ingredients composing tear substitutes (e.g., viscosity-enhancing agents, electrolytes, osmo-protectants, antioxidants, lipids, surfactants and preservatives) as well as their effects on the ocular surface, and we provide insight into how certain components of tear substitutes may promote corneal wound healing, and/or counteract inflammation. Based on these considerations, we propose an approach to select the most appropriate tear substitute formulations according to the predominant etiological causes of DED

Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å (1 Å=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P1′ residue with the unusual R configuration which, surprisingly, is accommodated by the large S2′ pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi–pi stacking interactions with the amino benzoyl group of the first molecule locking them in a ‘hand-shake’ conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors

Conjunctival Inflammatory Gene Expression Profiling in Dry Eye Disease: Correlations With HLA-DRA and HLA-DRB1

Purpose: In several multicenter clinical trials, HLA-DR was found to be a potential biomarker of dry eye disease (DED)'s severity and prognosis. Given the fact that HLA-DR receptor is a heterodimer consisting in an alpha and a beta chain, we intended to investigate the correlation of inflammatory targets with the corresponding transcripts, HLA-DRA and HLA-DRB1, to characterize specific targets closely related to HLA-DR expressed in conjunctival cells from patients suffering from DED of various etiologies.Methods: A prospective study was conducted in 88 patients with different forms of DED. Ocular symptom scores, ocular-staining grades, tear breakup time (TBUT) and Schirmer test were evaluated. Superficial conjunctival cells were collected by impression cytology and total RNAs were extracted for analyses using the new NanoString® nCounter technology based on an inflammatory human code set containing 249 inflammatory genes.Results: Two hundred transcripts were reliably detected in conjunctival specimens at various levels ranging from 1 to 222,546 RNA copies. Overall, from the 88 samples, 21 target genes showed a highly significant correlation (R > 0.8) with HLA-DRA and HLA-DRB1, HLA-DRA and B1 presenting the highest correlation (R = 0.9). These selected targets belonged to eight family groups, namely interferon and interferon-stimulated genes, tumor necrosis factor superfamily and related factors, Toll-like receptors and related factors, complement system factors, chemokines/cytokines, the RIPK enzyme family, and transduction signals such as the STAT and MAPK families.Conclusions: We have identified a profile of 21 transcripts correlated with HLA-DR expression, suggesting closely regulated signaling pathways and possible direct or indirect interactions between them. The NanoString® nCounter technology in conjunctival imprints could constitute a reliable tool in the future for wider screening of inflammatory biomarkers in DED, usable in very small samples. Broader combinations of biomarkers associated with HLA-DR could be analyzed to develop new diagnostic approaches, identify tighter pathophysiological gene signatures and personalize DED therapies more efficiently

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes