{'fraction_non_alphanumeric': 0.029819760309521562, 'fraction_numerical': 0.01557044446541474, 'mean_word_length': 5.4859241126070994, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Rosacea Blepharoconjunctivitis Treated with a Novel Preparation of Dilute Povidone Iodine and Dimethylsulfoxide: a Case Report and Review of the Literature

Introduction Povidone iodine (PVP-I) 10% aqueous solution is a commonly utilized anti-septic employed for sterilization of the ocular surface prior to interventional procedures. Dimethylsulfoxide (DMSO) is a well-known skin penetration agent scarcely utilized in ophthalmic drug formulations. We describe here a low-dose formulation of 1% PVP-I (w/w) in a gel containing DMSO for use in the setting of recalcitrant rosacea blepharoconjunctivitis. A review of the ocular uses of dimethylsulfoxide is also presented. Case report A 78-year-old male presented with chronic, long-standing blepharitis involving both the anterior and posterior lid margins. Posterior lid and skin inflammatory changes were consistent with ocular rosacea. Previous oral and topical therapies had been largely ineffective at controlling his condition. Conclusion The topical PVP-I/DMSO system was effective in abating the signs and symptoms of rosacea blepharoconjunctivitis. Further investigation of this novel agent is warranted. Electronic supplementary material The online version of this article (doi:10.1007/s40123-015-0040-4) contains supplementary material, which is available to authorized users.


INTRODUCTION
Blepharitis is a common ocular condition presenting in a large percentage of the population [1,2]. For most sufferers profound visual impairment is rare, however, a majority will demonstrate chronic ocular surface dysfunction including evaporative dry eye [3]. There are a variety of causal factors implicated Electronic supplementary material The online version of this article (doi:10.1007/s40123-015-0040-4) contains supplementary material, which is available to authorized users. in blepharitis including bacterial overgrowth, yeast colonization, viral infection, Demodex mites, atopy, seborrhea, environmental factors, hormonal dysregulation, and rosacea [4].
Rosacea is a chronic inflammatory skin condition with multiple, distinct subtypes that affects approximately 16 million Americans [5].
Transient and nontransient facial flushing, telangiectasia, and inflammatory papules and pustules represent the most commonly recognized skin manifestations [5].
To more accurately diagnose and treat blepharitis, the disease is frequently subdivided based on anatomical position.
Anterior blepharitis is frequently associated with Gram-positive bacterial overgrowth or seborrhea [6]. Common findings include eyelid erythema, scurf, collarettes, lid margin thickening or tylosis ciliaris, and breakage or misdirection of cilia. Posterior blepharitis most commonly manifests as meibomian gland dysfunction with other findings that may include lid erythema, telangiectatic lid margin vasculature, hyperkeratosis, chalazia, and tarsal inflammation.
It is largely recognized that a spectrum of meibomian gland dysfunction exists in those patients suffering from chronic posterior blepharitis [7]. Each of these holocrine glands consists of multiple acini connected to a long central duct, which secretes lipids comprised mainly of wax and sterol esters. Under the effect of chronic inflammation, they may develop pouting, dropout, dilation, and epithelial hyperkeratinization. Furthermore, changes in the viscosity of lipid secretions due to structural shifts of saturated hydrocarbons and protein interaction may contribute to deranged tear homeostasis [7,8].
Microorganisms likely play a crucial role in the development of blepharitis. Normal ocular surface colonizers include Gram-positive bacteria, especially coagulase-negative Staph species (CoNS), Streptococcus, Corynebacterium, and Propionibacterium acnes [9]. In the setting of anterior blepharitis, CoNS are known to release toxic by-products thus triggering an inflammatory cascade. Acting upon the posterior lid, some bacterial species are imbued with lipases and esterases which cleave meibum into free fatty acids and soaps. Moreover, loss of polar lipids located between nonpolar and aqueous components of the tear film may also decrease lipid spreading. All these actions serve to propagate further inflammation and destabilize the tear film. Bacteria not only colonize the superficial ocular surface, but evidence suggests that they may be present within deeper structures like the meibomian orifices and ducts [10]. The pathophysiological process has not been fully elucidated; however, it can be postulated that deep intraductal bacteria may contribute to meibum alterations by acting upon them prior to formation of the mature secretion.  The patient was given a topical gel of 1%

DISCUSSION
Blepharitis is often a recalcitrant, chronic ocular condition with variable presentation.
Fortunately, sight-threatening manifestations of this disease such as lid cicatrization, malposition, trichiasis, and corneal infiltrates are rare. Nonetheless, morbidity imparted in the form of chalazia, rosacea, dry eye, contact lens intolerance, and even anxiety is significant [11,12]. The complex nature of blepharitis renders curative treatment challenging as there are currently no FDA-approved treatments. It has been postulated that because of the inflammatory and infectious natures of the disease that controlling both of these variables may form the bedrock for effective therapy [13]. PVP-I has been recognized as a safe, effective, broad-spectrum, biocidal agent for many years [14]. It is primarily utilized in ophthalmology for antisepsis prior to procedures that place patients at risk for endophthalmitis [14]. There are a variety of other indications within ophthalmology where low-dose (i.e., less than 10% w/w) PVP-I formulations have been shown to be useful [15,16]. Though incompletely understood, it is likely its mechanism of action relates to free iodide which poisons electron transport, inhibits cellular respiration, and destabilizes membranes. Ocular use of PVP-I has been highlighted previously by the authors [17].
DMSO is an organic, polar, aprotic molecule utilized as a pharmaceutical solvent for decades [18]. The term aprotic refers to the lack of H? ion available for proton donation in Brønsted acid reactions. DMSO was first synthesized by Alexander Saytzoff, a Russian chemist in 1867. After remaining shrouded in obscurity for almost a century, it was rediscovered in the 1950s for its ability to act as a ''super solvent''.
Notably, the DMSO chemical structure yields a polar solvent with a high dielectric constant. This property along with favorable stereochemistry is thought to contribute to its prodigious solvating ability [19].
DMSO is commonly produced as a by-product of paper manufacture from lignin, a fiber found in wood pulp. Its early utility was employed for various ophthalmic indications [24]. These patients were followed for a period of up to 19 months without the observation of any ocular toxicity. At that time, these were vital findings to the future of the solvent as early animal testing had demonstrated curious lenticular findings in canines [24]. These findings were not necessarily cataractous in nature, but represented changes in translucency between the lens nucleus and cortex along with myopic shift. Other studies performed on monkeys, guinea pigs, rabbits and later with cell culture corroborated these observations [25,26].In a more encompassing report on human utilization from the Second International DMSO Symposium in Vienna, an astounding 9521 patients were followed and treated with DMSO for up to 2.5 years [27]. There was not a single instance of lens toxicity reported in any of these study participants. In 1973, a landmark report published in the Annals New York Academy of Sciences further supported its safe human use. Here, a topical DMSO aqueous solution was administered daily to 65 patients with up to 4-7 years of follow-up. No observable toxicity was found outside of transient irritation and occasional conjunctival erythema [28].
More recently, one case report of DMSO-related lenticular pigmentary change was noted in a woman being treated for interstitial cystitis [29]. Her treatment was with RIMSO-50, administered via multiple bladder washouts. The pigmentary changes were thought to be responsible for mild hypermetropic shift; however, no change in best corrected visual acuity was noted.
Other animal studies with DMSO have also been performed yielding notable results. In 1977, a concentration-dependent exacerbation of conjunctival inflammation was observed for DMSO concentrations [90% (w/w, aqueous).
The authors found that 90% and 100% DMSO worsened ocular inflammation, while doses lower than 30% demonstrated anti-inflammatory properties [30]. Other studies conducted in 2010 and 2011 saw its administration both subconjunctivally and following trabeculotomy [31,32]. A synopsis of published DMSO ocular findings is detailed in Table 1.
Our current understanding with respect to preferential distribution of DMSO in the eye is that uptake is most consistently found in the cornea, aqueous, vitreous and sclera [33,34].
Much of this data stems from sacrificial animal studies performed in the 1960s. More recently, a vitrification study for cryoprotective purposes reconfirmed corneal uptake [35]. It is also interesting to note that although animal studies have endorsed lenticular alterations, to our knowledge, DMSO does not accumulate in the crystalline lens.
With respect to our patient in this case report, it is not surprising that there appears to be a demonstrable response in the setting of rosacea blepharoconjunctivitis. The eyelid structures represent therapeutic targets with architecture that is distinct in anatomy and function [36]. Notably, it is upon the lid margin skin where many of the microorganisms responsible for causing devastating post-surgical ocular infections reside [14]. Lid margin bacteria not only populate and thrive on the superficial lid tissues but may ensconce within the deep eyelid or within dead layers of skin cells, sweat glands, and hair follicles [37]. It is logical, therefore, that successful therapy should fundamentally offer both antisepsis and lid penetration with significant anti-inflammatory effect. This is the postulated mechanism of action the authors endorse with respect to the novel formulation discussed in this manuscript.
It is important to note the shortcomings of this case report. There was no utilization of a

ACKNOWLEDGMENTS
The article processing charges for this publication were funded by ALC Therapeutics,