BackgroundThe symptoms of dry eye disease (DED) result from activation of ocular sensory nerves and constitute the dominant component of its clinical presentation. We assessed the effect of phosphosulindac (PS), a small molecule efficacious in the treatment of DED in preclinical models, on corneal sensitivity (CS).MethodsCS was determined with a Cochet-Bonnet esthesiometer in New Zealand white (NZW) and Dutch-belted black (DBB) rabbits. DED was induced by Concanavalin A injections into the rabbits’ lacrimal glands. Changes in CS, tear osmolarity, tear break up time (TBUT) and Schirmer tear test were measured before and after DED induction. PS in various formulations (emulsions, nanoparticles and hydrogels) and other ocular drugs were applied in eye drop form to normal rabbits and those with DED.Resultsnduction of DED caused a decrease in the CS, TBUT time as measured by fluorescein dye, in tear production as measured by Schirmer’s tear test and an increase in tear osmolarity. PS markedly restored the suppressed CS in dry eyes. The effect was immediate, fully reversible, lasted ∼26 h and appeared dissociated from its anti-inflammatory properties. The most efficacious formulation was a Carbopol-based hydrogel; cyclodextrin-based and emulsion formulations were also effective. The most optimal dose of PS was 0.2% and the optimal pH was 6.2. None of 7 compounds structurally related to PS affected CS nor did cyclosporine, lifitegrast and artificial tears. PS does not have an anesthetic effect on the cornea. In normal eyes, PS suppressed CS and this effect was concentration-, formulation-, and pH-dependent. Two non-steroidal anti-inflammatory drugs (NSAIDs), ketorolac and bromfenac, and lidocaine suppressed CS in normal but not in dry eyes.ConclusionPS restores the suppressed CS in dry eyes possiblely by a direct effect on corneal nerves. This effect appears unique to PS, distinct from all tested compounds including the two currently approved drugs for DED. PS, in addition to affecting CS of DED, may improve its symptoms and merits further evaluation for the treatment of DED.

Background: Our purpose was to determine the pharmacokinetics and biodistribution of phosphosulindac and its metabolites when applied to mouse skin. Phosphosulindac differs from sulindac by adding a diethyl-phospho-butane moiety, which enhances efficacy and safety. In preclinical studies, phosphosulindac has anti-cancer and anti-inflammatory properties and prevents and reverses chemotherapy-induced peripheral neuropathy Methods: Phosphosulindac gel was applied topically to the hind paws of normal mice and those with chemotherapy-induced peripheral neuropathy. Samples from the paw skin, paw muscle, leg muscle, sciatic nerve, dorsal root ganglia and blood, obtained at various time points, were assayed using HPLC for phosphosulindac, and its metabolites (sulindac, sulindac sulfide, sulindac sulfone). Results: Topically applied phosphosulindac was detected in paw skin, paw and adjacent leg muscles where it reached its Tmax in 0.5 h. Smaller amounts of phosphosulindac were detected in sciatic nerve (Tmax = 3 h) and dorsal root ganglia (at 24 h). Phosphosulindac was not found in blood. Absorption of phosphosulindac was concentration-dependent and pH-sensitive. Its metabolites were detected in paw skin, vicinal muscles, sciatic nerve, and blood but not in dorsal root ganglia. Topically applied equimolar sulindac was detected in paw skin and muscle and in smaller amounts in leg muscle and sciatic nerve. Conclusion: Phosphosulindac is absorbed through the paw skin and transported from paw and leg muscle to the sciatic nerve and dorsal root ganglia, its target tissues in normal and chemotherapy-induced peripheral neuropathy mice. In contrast, sulindac is transported through the same tissues as well as by the circulation.

PURPOSE:Experimental studies of Dry Eye Disease (DED) using animal models are hampered by the lack of reliable, easy-to-use assays that can adequately diagnose disease or monitor effects of novel treatments. The Oculus Keratograph 5 M, an advanced keratography unit (AKU), has shown promise, enjoying recent clinical use. We assessed whether this AKU could be used in DED studies in the rabbit, perhaps the ideal experimental animal for this disease. METHODS:All measures were made in strictly controlled temperature and humidity spaces. A panel of AKU parameters was measured in 15 New Zealand White rabbits at baseline, after Concanavalin A induced DED, and following recovery. Eyelid aperture and corneal irregularity were also measured. A subset of these parameters was measured in patients and compared with those from rabbits. RESULTS:AKU parameters in both humans and rabbits showed similar patterns and coefficients of variation (CV). Measurements of tear and eyelid architecture were more reproducible than tear film function in both species. The CV for most parameters were less than the observed changes in the respective parameters after DED induction. In rabbits, all parameters improved returning close to baseline following DED recovery. In the rabbit, additional measures (eyelid aperture and corneal irregularity) not traditionally associated with DED, also demonstrated changes that evolved over the development and recovery of DED. CONCLUSIONS:AKU technology can effectively detect changes in multiple parameters during the evolution and resolution of DED in rabbits. DED parameters showed similar patterns for most variables in both humans and rabbits demonstrating great potential of this device in translational research. The AKU can also follow additional parameters evaluating the responses of the lacrimal functional unit. Our findings document the applicability of this technology for translational studies of DED and underscores its potential to further refine understanding of the disease pathophysiology.

Dry eye disease (DED), a multifactorial disorder of the ocular surface and tear film, affects 5-50% of the global population. Currently, no satisfactory treatments of DED exist. Ongoing efforts to identify novel therapeutic agents are handicapped by the limitations of its preclinical animal models, which to some extent reflect the pathophysiological complexities of DED.. A plethora of DED models employing multiple animal species (mice, rats, cats, rabbits, dogs, and non-human primates) has been reported, each aiming to capture components of DED that appear to determine its pathophysiology and response to novel treatments. Here, we review the main animal models of DED and attempt to place each in the context of drug discovery. We also discuss a nascent method for ex vivo culture of human conjunctival cells that may abbreviate early screening of candidate therapeutics. Despite the remaining challenges, there is justified optimism that with the contribution of these preclinical models, the development of an efficacious and safe treatment of DED will be forthcoming.

Dry eye disease (DED) is a prevalent disorder of the ocular surface and tear film for which currently no fully satisfactory treatment exists, reflecting its multifactorial nature and perhaps inherent limitations of existing treatments. Responding to this unmet medical need, the research community and pharmaceutical industry display robust activity in the development of novel approaches to DED treatment. These efforts include pharmaceutical agents and devices directed at various pathogenetic aspects of this still incompletely understood disease. Here, we review current and under development treatments and assess the state of this evolving field.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN.MethodsCIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation.ResultsTreatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16–22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype.ConclusionTopically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.

The field of therapeutics is fundamentally and heavily dependent on drug discovery. The record number of new agents being developed probably conceals how ardent the task is [1]. Drug discovery is indeed a long, costly, and high-risk process that takes over 10-15 years with an average cost of over $1-2 billion for a new drug to be approved for clinical use [2]. What is astonishing is the failure rate of candidate drugs. By most accounts over 90% of drug candidates fail to be approved for clinical use. Lack of clinical efficacy and poor drug-like properties along with unmanageable toxicity are among the frequent reasons for their failure. The transition between basic and clinical science, known colloquially and the “valley of death”, is where most promising discoveries meet their demise [3]. Multiple efforts have been made to overcome this difficult situation that adversely affects modern therapeutics [2].

Purpose: To evaluate the hypothesis that 3 novel compounds, OXT-328, Q-922, and CL-717 show efficacy in the treatment of oxygen-induced retinopathy (OIR) and whether or not their route of administration is intravitreal, topical, or systemic. Methods: The OIR mouse model, characterized by an avascular area (AVA) and a neovascular area (NVA) of the retina, was used to study retinopathy of prematurity and other retinal diseases characterized by abnormal vessel growth. We measured the effect of our compounds on both the AVA and NVA in whole mounts of mouse retinal tissue. We also evaluated their ability to prevent new vessel formation in chicken chorioallantoic membranes (CAMs). Finally, we measured the in vitro uptake and biodistribution of topically applied CL-717 in human eye explants. Results: In mice with OIR, compared to controls, a single intravitreal administration of Q-922 or OXT-328 significantly reduced both AVA and NVA. CL-717 administered as eye drops over 5 days also reduced AVA and NVA, whereas OXT-328 eye drops had no effect. Q-922 given intraperitoneal (150 mg/kg/day × 5 days) reduced AVA and NVA. Remarkably, explanted human eyes bathed in CL-717 show rapid uptake and biodistribution in ocular tissues. In the chicken CAM model, all 3 compounds reduced the formation of new blood vessels by about one-third. No side effect in mice was observed, except for mild ocular surface irritation with Q-922. Conclusions: Systemic administration of Q-922 or topical administration of CL-717 holds particular promise for a simplified treatment of proliferative retinopathies without the necessity of intravitreal injections.

Supplementary Table 1 from Dietary Induction of Colonic Tumors in a Mouse Model of Sporadic Colon Cancer

Supplementary Figure 2 from Annexin 1 Induced by Anti-Inflammatory Drugs Binds to NF-κB and Inhibits Its Activation: Anticancer Effects In vitro and In vivo

Supplementary Figure 3 from Annexin 1 Induced by Anti-Inflammatory Drugs Binds to NF-κB and Inhibits Its Activation: Anticancer Effects In vitro and In vivo

Supplementary Figure 2 from The Thioredoxin System Mediates Redox-Induced Cell Death in Human Colon Cancer Cells: Implications for the Mechanism of Action of Anticancer Agents

Fig S1. Phospho-aspirin inhibits the growth of human PC cells. Figure S2. Phospho-aspirin induces apoptosis in human PC cells. Figure S3. Phospho-aspirin induces p53 acetylation in human PC cells and xenografts. Figure S4: PA does not inhibit PGE2 levels in PC cells. Figure S5. Expression levels of phospho-EGFR (p-EGFR) in multiple human PC cells. Figure S6. Phospho-aspirin inhibits EGFR phosphorylation in PC cells. Figure S7. Serum amylase and lipase levels. Figure S8. Representative images of acinar cells explants at day 0 and the resulting metaplasia (day 5).