Soft Corticosteroids Research Articles

Preventing and Managing Iatrogenic Dry Eye Disease during the Entire Surgical Pathway: A Study Focusing on Patients Undergoing Cataract Surgery

Patient expectations for cataract surgery are continuously increasing, and dry eye disease (DED) represents a major cause of patient dissatisfaction in eye surgery. The present opinion paper aims to provide useful insights to improve the entire pathway of a patient undergoing cataract surgery, from the preoperative setting to the postoperative one. The available evidence from main clinical trials published on this topic is presented in association with experience-based points of view by the authors. Ocular surface disease (OSD) is common in patients presenting for cataract surgery, and more than half of these patients have DED and meibomian gland dysfunction (MGD), even in the absence of symptoms. Therefore, there is a need to encourage preoperative assessments for the risk of DED development or worsening in all patients as a routine approach to cataract surgery. New all-in-one diagnostic machines allow for fast and noninvasive screening of the ocular surface status. Once a preoperative diagnosis of DED/OSD is reached, ocular surface optimization should be obtained before surgery. In the case of unresolved OSD, the decision to delay surgery should be considered. The surgical procedure can be optimized by avoiding large incisions, limiting microscope light intensity and exposure, and avoiding an aspirating speculum or preserved eye drops. Postoperatively, the continued avoidance of preserved agents is advisable, as well as a limited exposure to epitheliotoxic antibiotics and nonsteroidal anti-inflammatory drugs. Short-term, preservative-free, soft corticosteroids may be useful for patients with extensive or persistent inflammation.

Development and clinical success of novel soft drugs

Retrometabolic drug design combines the structure-activity and structure-metabolism relationships, allowing the effective separation of drug action and side effects. This combination results in significant improvement of the therapeutic index. The main aim is not only to study the metabolism but to build into the drug molecule the desired metabolic route, in addition to the therapeutic activity. There are two basically different approaches to achieve this aim. Both use designed-in metabolism. The 1. chemical drug-targeting systems (CDS) and 2. soft drug, both control the drug targeting and action by strategically designed metabolism. In the case of the soft drugs, we want to rely on hydrolytic enzymes, avoiding the oxidative processes. In the present work, we focus on the clinical successes of the soft drugs designed in our laboratories. In order to show the difference, we briefly present a brain-targeted delivery system, where the originally inactive molecular construct undergoes sequential metabolism to allow specific concentration of the active drug in the brain. Among the soft drugs first we present the highly successful soft corticosteroids. Loteprednol etabonate has been used worldwide for over twenty years, and its use is constantly growing. In addition to the dramatically improved therapeutic index, the specific, serious ophthalmic side effects (elevation of intraocular pressure; glaucoma and cataract formation) were completely eliminated. Similarly designed second generation of soft corticosteroids are also presented, where the soft pharmacophore is structurally unexpected. The most recent soft drug design involves anticholinergics. Sofpironium bromide, a highly effective molecule but without the typical anticholinergic side effects, was first developed to treat hyperhidrosis, an unmet need. Phase III clinical studies were successfully completed and its marketing approval is pending. Since the soft drug design principles, methods and rules are general and specific in nature, a computerized expert system was also developed. Orv Hetil. 2020; 161(10): 363-373.

A corneal-penetrating eye drop formulation for enhanced therapeutic efficacy of soft corticosteroids against anterior uveitis

Eye drop administration suffers from low bioavailability due to inadequate preocular retention and tissue penetration, which leads to multiple administration to achieve ocular therapeutic concentration. We tested the hypothesis that a cluster bomb releasing corneal-penetrating bomblet of drug assembles would increases drug bioavailability and reduce the administration frequency of corticosteroids in uveitis treatment. The microparticulate drug delivery system was obtained from host-guest assembly of (2-hydroxypropyl)-γ-cyclodextrin with loteprednol etabonate, a hydrophilic polymer, hydroxypropyl methylcellulose, and a stabilizer, caffeine, and polysorbate 80. The pharmacokinetics and pharmacodynamics studies of the proposed microparticles were performed on normal and on experimental uveitis model of New Zealand White rabbits, respectively. In comparison to the commercial microparticulate formulation Lotemax®, our formulation showed 5.4 and 3.5-fold increase of maximum drug concentration in aqueous humor and iris/ciliary body (target tissue of anterior uveitis) in vivo, respectively, while the intraocular pressure remains normal. Along with the enhanced drug exposure in target tissue, the drug dosing frequency can be reduced into half with a comparable outcome to the typical steroid treatment against autoimmune-induced uveitis by using our eye drop formulation. The microparticulate drug delivery system was developed to provide a potential solution to increase drug bioavailability in ocular tissues and with which the administration frequency could be reduced. Our results suggest that these goals could be successfully achieved by using the proposed eye drop formulation.

17β-carboxamide steroids – in vitro prediction of human skin permeability and retention using PAMPA technique

In this paper, twenty-two 17β-carboxamide steroids were synthesized from five corticosteroids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone) in two steps. The first step was periodic acid oxydation of these corticosteroids to corresponding cortienic acids and the second step was amidation of thus obtained cortienic acids with esterified l-amino acids. These compounds are potential soft corticosteroids with local anti-inflammatory activity in the skin. Parallel artificial membrane permeability assay (PAMPA) was applied in order to predict permeability and retention of these compounds in human skin. Comparison of permeability and retention parameters between 17β-carboxamide steroids and corresponding corticosteroids was performed. Compounds with significantly higher retention were identified and the derivative that does not have significantly higher permeability was underlined. Molecular structures of all compounds were optimized by use of Gaussian semiempirical/PM3 method. Geometrical, thermodynamic, physicochemical and electronical molecular parameters of the optimized structures were calculated and quantitative structure–property relationship (QSPR) analysis was performed in order to explain permeability and retention of these compounds. ANN-, PLS- and MLR-QSPR models were created. Quality of these models was evaluated by commonly used statistical parameters and the most reliable models were selected. Analyzing descriptors in the selected models, main molecular properties that influence permeability and retention in the PAMPA artificial membrane were identified. Based on these data, further structural modifications could be applied in order to increase retention without significant increase of permeability, which can positively affect potential local anti-inflammatory activity of these compounds. Selected QSPR models could be used as in silico tool for predicting human skin permeability and retention of novel 17β-carboxamide steroids without performing PAMPA experiments.

Retrometabolic drug design: Principles and recent developments

Abstract Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs (SDs) and of chemical delivery systems (CDSs). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and -metabolism relationships; however, they achieve it by different means: whereas SDs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. General principles and recent developments are briefly reviewed with various illustrative examples from different therapeutic areas with special focus on soft corticosteroids and on brain targeting.

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

Inhaled and intranasal corticosteroids (ICSs) still are the most effective treatment available for allergic airway diseases and are likely to remain the cornerstone of managing persistent asthma/allergic rhinitis in the foreseeable future. Even if the therapeutic index of this class increased significantly with the introduction of newer corticosteroids, and even if new therapeutic potentials are beginning to emerge with our increasing understanding of the mechanisms of asthma, chronic obstructive pulmonary disease, and rhinitis, corticosteroid development still remains a very important field for drug designers. After a brief review of issues related to the structure-activity relationships of glucocorticoids and the main determinants of their receptor-binding affinity at the glucocorticoid receptor, the main focus of the present article will be on the development of soft corticosteroids, as they are particularly well suited to separate local activity from systemic side effects, which still is an important issue for ICSs. Design consideration required in the search for safe and effective soft drugs on one hand, and safe and effective ICSs on the other hand, will be briefly discussed and illustrated with a number of cases, in particular, with that of loteprednol etabonate and etiprednol dicloacetate, soft corticosteroids that are being developed for a full spectrum of therapeutic applications including asthma and allergic rhinitis.

Tear film, pharmacology of eye drops, and toxicity.

Various new topical ophthalmic drug delivery systems show promise for increasing bioavailability, reducing epithelial toxicity, and improving patient compliance. Microparticulates are drug-containing polymeric particles that are placed in the fornix and release ocular medication by diffusion, chemical reaction, polymer degradation, or ion exchange and can be used to deliver many topical ophthalmic medications, including antibiotics and antimetabolites. Soft drugs are activated enzymatically at the site of application and are rapidly converted to inactive metabolites when exposed to the ocular environment, improving bioavailability at the target site, and reducing the potential for ocular and systemic side effects. Applications include soft beta-blockers, soft corticosteroids, and soft anticholinergics. Collasomes are made up of collagen pieces suspended in a viscous vehicle; this formulation is similar to that of corneal collagen shields, but is more useful for chronic therapy because the collasomes can be instilled by the patient and cause less blurring of vision. Potential uses include delivery of hydrophobic antimetabolites such as cyclosporine to prevent graft rejection and delivery of lipids for the therapy of dry eyes. Ideal replacements for dysfunctional tear layers, especially the lipid layer, have not yet been developed. The toxic effects of preservatives in topical ocular medications, particularly in artificial tears, often outweigh the benefits and preservative-free tear preparations are almost always preferable.

Designing safer ophthalmic drugs by soft drug approaches.

There are two major novel metabolism-based drug design concepts which have significant advantages when used in the design of safe, specific ophthalmic drugs. One is based on predictable enzymatic activation processes by enzymes found exclusively or preferentially at the site of action--in this case, within the eye, primarily in the iris-ciliary body. The second major retrometabolic design technique involves soft drug approaches. Among the various soft drug design strategies, it was found that the "inactive metabolite" and the "soft analog" approaches are the most useful for designing safe and selective ophthalmic drugs. In the first case, the design process starts with a known (or predicted) inactive metabolite (Mi) of the drug (D). This Mi is then structurally modified in the "chemical activation" stage to the soft drug (SD), which is isosteric and/or isoelectronic with D to produce activity at the target receptors, similar to that of D. By design, however, SD is also subject to a facile, predictable (generally hydrolytic) metabolism leading in one step to the starting inactive Mi. As this deactivation takes places everywhere in the body, the desired activities are produced virtually exclusively at the target site at or near the place of application. Successful use of this general concept has led to soft beta-blockers as safe antiglaucoma agents, soft anticholinergics as short acting mydriatic agents, and soft corticosteroids as a type of novel, safe anti-inflammatory agents, which due to their unique design, do not elevate intraocular pressure IOP and do not produce other systemic and local side effects.