Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Epithelial-mesenchymal transition as a therapeutic target for prevention of ocular tissue fibrosis

Fibrotic diseases are characterized by the appearance of myofibroblasts, the key cell type involved in the fibrogenic reaction, and by excess accumulation of extracellular matrix with resultant tissue contraction and impaired function. Myofiborblasts are generated by fibroblast-myofibrobalst conversion, and in certain tissues through epithelial-mesenchymal transition (EMT), a process through which an epithelial cell changes its phenotype to become more like a mesenchymal cell. Although inflammatory/fibrogenic growth factors/cytokines produced by injured tissues orchestrate the process of EMT, transforming growth factor beta (TGFbeta) is believed to play a central role in the process. Unlike fibrotic lesions in kidney or other tissues where myofibroblasts are generated from both fibroblasts and epithelial cells, fibrotic lesions in the eye crystalline lens are derived only from lens epithelial cells without contamination of fibroblast-derived myofibroblasts. Thus, this tissue is suitable to investigate detailed mechanisms of EMT and subsequent tissue fibrosis. EMT in retinal pigment epithelium is involved in the development of another ocular fibrotic disease, proliferative vitreoretinopathy, a fibrosis in the retina. EMT-related signal transduction cascades, i. e., TGFbeta/Smad, are a target to prevent or treat unfavorable ocular tissue fibrosis, e. g., fibrotic diseases in the crystalline lens or retina, as well as possibly in other organs.     

Sustained ocular drug delivery from a temperature and pH triggered novel in situ gel system

Various ocular diseases like glaucoma, conjunctivitis, and dry eye syndrome require frequent drug administration. Poor ocular bioavailability of drugs (< 1%) from conventional eye drops is due mainly to the precorneal loss factors that include rapid tear turnover, nonproductive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the drugs to corneal epithelial membrane. These problems may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ocular delivery system of timolol maleate based on the concept of both temperature and pH-triggered in situ gelation. Pluronic F-127 (a thermosensitive polymer) in combination with chitosan (pH-sensitive polymer also acts as permeation enhancer) was used as gelling agent. The developed formulation was characterized for various in vitro parameters e.g., clarity, gelation temperature and pH, isotonicity, sterility, rheological behavior, drug release profile, transcorneal permeation profile, and ocular irritation. Developed formulation was clear, isotonic solution, that converted into gel at temperatures above 35 degrees C and pH 6.9-7.0. A significant higher drug transport across corneal membrane and increased ocular retention time was observed using the developed formulation. The developed system is a viable alternative to conventional eye drops for the treatment of glaucoma and various other ocular diseases.     

Sustained Ocular Drug Delivery from a Temperature and pH Triggered Novel In Situ Gel System

Various ocular diseases like glaucoma, conjunctivitis, and dry eye syndrome require frequent drug administration. Poor ocular bioavailability of drugs (< 1%) from conventional eye drops is due mainly to the precorneal loss factors that include rapid tear turnover, nonproductive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the drugs to corneal epithelial membrane. These problems may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ocular delivery system of timolol maleate based on the concept of both temperature and pH-triggered in situ gelation. Pluronic F-127 (a thermosensitive polymer) in combination with chitosan (pH-sensitive polymer also acts as permeation enhancer) was used as gelling agent. The developed formulation was characterized for various in vitro parameters e.g., clarity, gelation temperature and pH, isotonicity, sterility, rheological behavior, drug release profile, transcorneal permeation profile, and ocular irritation. Developed formulation was clear, isotonic solution, that converted into gel at temperatures above 35°C and pH 6.9–7.0. A significant higher drug transport across corneal membrane and increased ocular retention time was observed using the developed formulation. The developed system is a viable alternative to conventional eye drops for the treatment of glaucoma and various other ocular diseases.     

The side effects of the prostaglandin analogues

In the last decade topically applied prostaglandin F2alpha analogues (bimatoprost, latanoprost, travoprost and unoprostone) have become widely used as a means to reduce elevated intraocular pressure in patients with glaucoma and ocular hypertension. These molecules all have similar side-effect profiles, which include both side effects that occur frequently (e.g., conjunctiva hyperaemia, increase of iris pigmentation and eyelash changes) and rare adverse reactions (e.g., periocular pigmentation, damage to the blood-aqueous barrier and cystoid macular oedema). Conjunctiva hyperaemia, eyelash changes and cystoid macular oedema are reversible, but certain other side effects, such as increased iris pigmentation, are not. However, the systemic side-effect profile is favourable for all the prostaglandin analogues, and some of the local side effects are only of cosmetic significance. Numerous clinical studies suggest that discontinuing treatment with prostaglandin analogues on account of their side effects is rare in clinical practice.     

Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans

Accurate assessment of upper respiratory tract and ocular irritation is critical for identifying and remedying problems related to overexposure to volatile chemicals, as well as for establishing parameters of irritation useful for regulatory purposes. This article (a) describes the basic anatomy and physiology of the human upper respiratory tract and ocular mucosae, (b) discusses how airborne chemicals induce irritative sensations, and (c) reviews practical means employed for assessing such phenomena, including psychophysical (e.g., threshold and suprathreshold perceptual measures), physiological (e.g., cardiovascular responses), electrophysiological (e.g., event-related potentials), and imaging (e.g., magnetic resonance imaging) techniques. Although traditionally animal models have been used as the first step in assessing such irritation, they are not addressed here since (a) there are numerous reviews available on this topic and (b) many rodents and rabbits are obligate nose breathers whose nasal passages differ considerably from those of humans, potentially limiting generalization of animal-based data to humans. A major goal of this compendium is to inform the reader of procedures for assessing irritation in humans and to provide information of value in the continued interpretation and development of empirical databases upon which future reasoned regulatory health decisions can be made.     

Assessment of Upper Respiratory Tract and Ocular Irritative Effects of Volatile Chemicals in Humans

ABSTRACT

Accurate assessment of upper respiratory tract and ocular irritation is critical for identifying and remedying problems related to overexposure to volatile chemicals, as well as for establishing parameters of irritation useful for regulatory purposes. This article (a) describes the basic anatomy and physiology of the human upper respiratory tract and ocular mucosae, (b) discusses how airborne chemicals induce irritative sensations, and (c) reviews practical means employed for assessing such phenomena, including psychophysical (e.g., threshold and suprathreshold perceptual measures), physiological (e.g., cardiovascular responses), electrophysiological (e.g., event-related potentials), and imaging (e.g., magnetic resonance imaging) techniques. Although traditionally animal models have been used as the first step in assessing such irritation, they are not addressed here since (a) there are numerous reviews available on this topic and (b) many rodents and rabbits are obligate nose breathers whose nasal passages differ considerably from those of humans, potentially limiting generalization of animal-based data to humans. A major goal of this compendium is to inform the reader of procedures for assessing irritation in humans and to provide information of value in the continued interpretation and development of empirical databases upon which future reasoned regulatory health decisions can be made.     

Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis?

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Sparsely ionizing diagnostic and natural background radiations are likely preventing cancer and other genomic-instability-associated diseases

Routine diagnostic X-rays (e.g., chest X-rays, mammograms, computed tomography scans) and routine diagnostic nuclear medicine procedures using sparsely ionizing radiation forms (e.g., beta and gamma radiations) stimulate the removal of precancerous neo-plastically transformed and other genomically unstable cells from the body (medical radiation hormesis). The indicated radiation hormesis arises because radiation doses above an individual-specific stochastic threshold activate a system of cooperative protective processes that include high-fidelity DNA repair/apoptosis (presumed p53 related), an auxiliary apoptosis process (PAM process) that is presumed p53-independent, and stimulated immunity. These forms of induced protection are called adapted protection because they are associated with the radiation adaptive response. Diagnostic X-ray sources, other sources of sparsely ionizing radiation used in nuclear medicine diagnostic procedures, as well as radioisotope-labeled immunoglobulins could be used in conjunction with apoptosis-sensitizing agents (e.g., the natural phenolic compound resveratrol) in curing existing cancer via low-dose fractionated or low-dose, low-dose-rate therapy (therapeutic radiation hormesis). Evidence is provided to support the existence of both therapeutic (curing existing cancer) and medical (cancer prevention) radiation hormesis. Evidence is also provided demonstrating that exposure to environmental sparsely ionizing radiations, such as gamma rays, protect from cancer occurrence and the occurrence of other diseases via inducing adapted protection (environmental radiation hormesis).     

Clinical Trials Reports: Ongoing and planned clinical trials of antiarrhythmic drugs:Cardiovascular & Renal

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-γ (PPARγ) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-γ may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-γ agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-γ agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-γ-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-γ-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Potential Changes in Disease Patterns and Pharmaceutical Use in Response to Climate Change

As climate change alters environmental conditions, the incidence and global patterns of human diseases are changing. These modifications to disease profiles and the effects upon human pharmaceutical usage are discussed. Climate-related environmental changes are associated with a rise in the incidence of chronic diseases already prevalent in the Northern Hemisphere, for example, cardiovascular disease and mental illness, leading to greater use of associated heavily used Western medications. Sufferers of respiratory diseases may exhibit exacerbated symptoms due to altered environmental conditions (e.g., pollen). Respiratory, water-borne, and food-borne toxicants and infections, including those that are vector borne, may become more common in Western countries, central and eastern Asia, and across North America. As new disease threats emerge, substantially higher pharmaceutical use appears inevitable, especially of pharmaceuticals not commonly employed at present (e.g., antiprotozoals). The use of medications for the treatment of general symptoms (e.g., analgesics) will also rise. These developments need to be viewed in the context of other major environmental changes (e.g., industrial chemical pollution, biodiversity loss, reduced water and food security) as well as marked shifts in human demographics, including aging of the population. To identify, prevent, mitigate, and adapt to potential threats, one needs to be aware of the major factors underlying changes in the use of pharmaceuticals and their subsequent release, deliberately or unintentionally, into the environment. This review explores the likely consequences of climate change upon the use of medical pharmaceuticals in the Northern Hemisphere.     

Corticosteroids and glaucoma risk

Corticosteroids (glucocorticoids), used frequently as potent anti-inflammatory agents, increase the risk of glaucoma by raising the intraocular pressure (IOP) when administered exogenously (topically, periocularly or systemically) and in certain conditions of increased endogenous production (e.g. Cushing's syndrome). Approximately 18 to 36% of the general population are corticosteroid responders. This response is increased to 46 to 92% in patients with primary open-angle glaucoma (POAG). Patients over 40 years of age and with certain systemic diseases (e.g. diabetes mellitus, high myopia) as well as relatives of patients with POAG are more vulnerable to corticosteroid-induced glaucoma. The association of corticosteroid-induced ocular hypertension in other conditions which are considered as risk factors for glaucoma (racial origins, hypertension, migraine, vasospasm) is likely but not fully established. The proposed mechanism of corticosteroid-induced glaucoma includes morphological and functional changes in the trabecular meshwork system and is similar to the pathogenesis of POAG. Trabecular cells exposed to corticosteroids in vitro show endoreplication of nuclei, an increase in cell size and excessive production of an approximately 56kD glycoprotein, identified as myocilin and transcribed by the GLC1A gene. Induction of ocular hypertension after corticosteroid administration depends on the specific drug, the dose, the frequency of administration and the corticosteroid responsiveness of the patient. The risk of corticosteroid-induced glaucoma can be minimised with judicious use of corticosteroids, as well as education of patients and medical practitioners. New treatment modalities include modified steroids and nonsteroidal anti-inflammatory agents that will have less effect on the elevation of IOP.     

Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A

Present limitations in the management of extraocular diseases include the inability to provide long-term extraocular drug delivery without compromising intraocular structures and/or systemic drug exposure. In the present study, the potential of chitosan (CS) nanoparticles as a new vehicle for the improvement of the delivery of drugs to the ocular mucosa was investigated. Cyclosporin A (CyA) was chosen as a model compound because of its potential usefulness for the treatment of these local diseases. An ionic gelation technique was conveniently modified in order to produce CyA-loaded CS nanoparticles. These nanoparticles had a mean size of 293 nm, a zeta potential of +37 mV and high CyA association efficiency and loading (73 and 9%, respectively). In vitro release studies, performed under sink conditions, revealed a fast release during the first hour followed by a more gradual drug release during a 24-h period. In vivo experiments showed that, following topical instillation of CyA-loaded CS nanoparticles to rabbits, it was possible to achieve therapeutic concentrations in external ocular tissues (i.e., cornea and conjunctiva) during at least 48 h while maintaining negligible or undetectable CyA levels in inner ocular structures (i.e., iris/ciliary body and aqueous humour), blood and plasma. These levels were significantly higher than those obtained following instillation of a CS solution containing CyA and an aqueous CyA suspension. From these results, we can conclude that CS nanoparticles may represent an interesting vehicle in order to enhance the therapeutic index of clinically challenging drugs with potential application at extraocular level.     

Mutagenicity in drug development: interpretation and significance of test results

The use of mutagenicity data has been proposed and widely accepted as a relatively fast and inexpensive means of predicting long-term risk to man (i.e., cancer in somatic cells, heritable mutations in germ cells). This view is based on the universal nature of the genetic material, the somatic mutation model of carcinogenesis, and a number of studies showing correlations between mutagenicity and carcinogenicity. An uncritical acceptance of this approach by some regulatory and industrial concerns is over-conservative, naive, and scientifically unjustifiable on a number of grounds: Human cancers are largely life-style related (e.g., cigarettes, diet, tanning). Mutagens (both natural and man-made) are far more prevalent in the environment than was originally assumed (e.g., the natural bases and nucleosides, protein pyrolysates, fluorescent lights, typewriter ribbon, red wine, diesel fuel exhausts, viruses, our own leukocytes). "False-positive" (relative to carcinogenicity) and "false-negative" mutagenicity results occur, often with rational explanations (e.g., high threshold, inappropriate metabolism, inadequate genetic endpoint), and thereby confound any straightforward interpretation of mutagenicity test results. Test battery composition affects both the proper identification of mutagens and, in many instances, the ability to make preliminary risk assessments. In vitro mutagenicity assays ignore whole animal protective mechanisms, may provide unphysiological metabolism, and may be either too sensitive (e.g., testing at orders-of-magnitude higher doses than can be ingested) or not sensitive enough (e.g., short-term treatments inadequately model chronic exposure in bioassay). Bacterial systems, particularly the Ames assay, cannot in principle detect chromosomal events which are involved in both carcinogenesis and germ line mutations in man. Some compounds induce only chromosomal events and little or no detectable single-gene events (e.g., acyclovir, caffeine, methapyrilene). In vivo mutagenicity assays are more physiological but appear to be relatively insensitive due to the inability to achieve sufficiently high acute plasma levels to mimic cumulative long-term effects. Examination of the mutagenicity of naturally occurring analogs may indicate the irrelevance of a test compound's mutagenicity (e.g., deoxyguanosine and the structurally related antiviral drug, acyclovir, have identical mutagenicity patterns). Life-threatening or severe debilitating diseases (e.g., cancer, severe psychoses, severe crippling arthritis, sight-threatening diseases) may justify treatment with mutagenic or even carcinogenic therapeutic agents (benefit/risk considerations).(ABSTRACT TRUNCATED AT 400 WORDS)     

Fatty liver and drugs

Drug-induced liver diseases (DILD) are clinico-pathologic patterns of liver injury caused by drugs or other foreign compounds. Steatohepatitis is a rare form of DILD, and drugs account for fewer than 2% of non-alcoholic steatohepatitis (NASH). Drugs known to be capable of inducing steatosis and steatohepatitis can be divided into three broad groups: those that cause steatosis and steatohepatitis independently (e.g., amiodarone, perhexiline maleate); drugs which can precipitate latent NASH (e.g., tamoxifen); drugs whic duce sporadic events of steatosis/steatohepatitis (e.g., carbamazepine). Clinical DILD syndromes include acute viral hepatitis-like injury, acute liver failure, cholestatic hepatitis,liver disease with signs of hypersensitivity, autoimmune hepatitis-like injury, acute venous-Outflow obstruction, chronic cholestasis, ciirrhosis, steatosis and steatohepatitis. The clinical picture is by no means dependent on the mechanism of injury (direct hepatotoxicity, idiosyncratic reactions, hypersensitivity reactions). Reliable diagnosis of drug-induced liver disease requires demonstration of close correlation between the patient history and clinical, laboratory, and histological data.     

Drug-induced ocular inflammatory diseases

Ocular inflammation can arise in the form of conjunctivitis, uveitis, episcleritis and scleritis. The uveitides can be subdivided by anatomical location into anterior and posterior uveitis or categorized by location of inflammation, e.g., iritis, pars planitis or iridocyclitis. Multiple drugs have been associated with ocular inflammation and much has been written on the subject. Discussed here is a sampling of drugs representing classes of medication associated with ocular inflammation. However, this is not a comprehensive list and interested readers are encouraged to access the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon, www.eyedrugregistry.com) or the textbook Drug-Induced Ocular Side Effects for further information (1). The agents discussed may be administered systemically, topically or intracamerally (inside the eye). The mechanism behind ocular inflammation is frequently unknown. Prevention and treatment are based upon physician recognition and withdrawal of the drug in some instances. Consultation with an ophthalmologist is recommended, as many types of ocular inflammation can threaten vision.     

Physical health as a motivator for substance abuse treatment among medically ill adults: Is it enough to keep them in treatment?

Substance-using adults often present at medical facilities for acute complications of their drug or alcohol use with transiently high motivation for addiction treatment. We studied a cohort of medically ill polysubstance-using adults admitted to a partial hospitalization/day-hospital program in an acute hospital, serially tracking their reasons for treatment motivation, pain and withdrawal scores, and readiness for change. Physical health concerns were the most frequently cited reason for wanting to enter substance abuse treatment at baseline (27.8%), yet individuals who cited this as their primary motivator were significantly less likely to complete the treatment program (14.8% vs. 40.7%, p = .03). However, 43% of respondents also recorded a shift in their motivation during treatment; 100% of those transitioning from an extrinsic motivator (e.g., physical health concerns) to an intrinsic motivator (e.g., wanting to do more with one's life) completed treatment, compared with only 38.4% of those whose extrinsic motivating factors were static. This suggests that medical illness represents a "treatable moment" to engage individuals in substance abuse treatment.     

Inhibition of apoptosis: potential clinical targets

Recent advances in the understanding of the molecular mechanisms of apoptosis have allowed researchers to begin targeting undesired apoptosis, in an attempt to moderate its occurrence. Unscheduled apoptosis appears to transpire in numerous diseases, both acute (e.g., stroke, liver degeneration) and chronic (e.g., osteoarthritis, neurodegeneration). There is a clear unmet medical need for better therapies for such diseases. The most active area of research involves a novel family of cysteine proteases which have been termed the caspases. In a number of isolated cell systems, the caspases have been shown to be involved in molecular pathways leading to apoptosis in response to apoptotic stimuli and evidence is mounting for pivotal roles for members of this novel protease family in degenerative diseases. Inhibition of caspase activity is predicted to be beneficial for degenerative diseases and this review summarises the current status and some of the issues of targeting apoptosis as a disease-modifying therapy.     

Comprehensive review on natural pharmacophore tethered 1,2,3-triazoles as active pharmaceuticals

The privileged 1,2,3-triazole scaffold is drawing researcher's attention due to its widespread applications in diverse fields such as drug discovery (e.g., carboxyamidotriazole), organic synthesis (click-reaction template), polymeric materials (e.g., triazolamer), supramolecular receptors (e.g., triazolophane), fluorescent materials (e.g., metal–organic frameworks), and agricultural sectors (e.g., fungicides). Various 1,2,3-triazole persuasion modules are also currently available in the market that have multiple assets such as active pharmaceuticals and agricultural purposes. Owed to the highly consistent and firmest synthesis approach, that is, click reaction of various azides and acetylene derivatives by copper (I)-catalyzed 1,3-dipolar cycloaddition (CuAAC), highly functionalized 1,2,3-triazoles are prepared in scalar yields for drug discovery. Given the importance of 1,2,3-triazole chemistry, the present review focuses specifically on the synthesis of structurally diverse 1,2,3-triazoles linked to natural pharmacophores and their biological importance. Furthermore, the dual/multi-pharmacophores assimilated 1,2,3-triazoles have listed interesting biological activities that could be valuable as future drug leads. In addition, this comprehensive review can serve as a template for the development of new diverse scaffolds that will ensure for new therapeutic approaches for the existing myriad diseases and disorders.     

Therapeutic targets in dry eye syndrome

Dry eye is a multifactorial disease of the tears and the ocular surface that manifests with a wide variety of signs and symptoms. It is prevalent in about 33% of the population worldwide. Due to the importance of the pathology, new tests, drugs and technologies have been developed to assist the diagnosis, management and follow-up of the disease. Current available therapies try to alleviate symptoms and to reduce signs in order to restore the ocular surface. Depending on the etiology of the pathology it is possible to use lubricants, secretagogues, biological tear substitutes or antiinflammatory drugs, either independently or combined. Nowadays, the therapies under clinical trial are devoted to stimulating tear components (e.g., diquafosol, a P2Y receptor agonist), or mucin secretion (e.g., rebamipide, an amino acid analogue of quinolinone). Others include gefarnate, a water-insoluble terpene fatty acid that contributes to restoring mucins on the ocular surface, or cevimeline, an oral cholinergic agonist that reduces the symptoms associated with dry eye. Other potential compounds described in patents are in a lower phase of drug development. These compounds come from different families of therapies, and among others, can be found in the form of steroidal and nonsteroidal antiinflammatory agents, vitamins A and D, neurotransmitters and neuropeptides.