Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.

Background: Chemotherapy-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.

Methods: CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin.

The Antiangiogenic Effect and Ocular Pharmacology of Novel Modified Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Oxygen-Induced Retinopathy.

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. 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.

Once-Daily Topical Phosphosulindac Is Efficacious in the Treatment of Dry Eye Disease: Studies in Rabbit Models of Its Main Clinical Subtypes.

Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day.

An Improved Ocular Impression Cytology Method: Quantitative Cell Transfer to Microscope Slides Using a Novel Polymer.

Purpose: To develop a more efficient impression cytology (IC) method for the transfer of ocular surface cells onto glass microscope slides for cytochemical, immunocytochemical, and immunofluorescence studies.

Methods: Cells are lifted off the ocular surface with a mixed cellulose ester membrane and then firmly attached to a glass slide using a novel triblock copolymer comprised of collagen type I, polyethylenimine and poly-L-lysine (CPP), and crosslinking cells and glass slide by heating and cooling. The membrane is removed intact after softening it with a butanol/ethanol solution.

Simplified ex-vivo drug evaluation in ocular surface cells: Culture on cellulose filters of cells obtained by impression cytology.

Drug development, resource- and time-intensive, extensively employs cell-based assays to assess the efficacy and safety of candidate drugs. The widely used immortalized cell lines, experimentally convenient, have limited predictive value. In contrast, ex-vivo models more faithfully reproduce diseases but are technically challenging to establish.

Animal models of dry eye disease: Useful, varied and evolving (Review).

Dry eye disease (DED), which is a prevalent disease that still lacks successful treatment options, remains a major challenge in ophthalmology. Multiple animal models of DED have been used to decipher its pathophysiology and to develop novel treatments. These models use mice, rats, rabbits, cats, dogs and non-human primates.

The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye.

The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. We explored the pathophysiology of DED using a rabbit model of chronic DED induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands. The transcriptome of full-thickness's conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays and, as needed, confirmatory real-time polymerase chain reactions.

Phospho-Sulindac (OXT-328) Inhibits Dry Eye Disease in Rabbits: A Dose-, Formulation- and Structure-Dependent Effect.

Inflammation of the ocular surface is central to dry eye disease (DED). The anti-inflammatory agent phospho-sulindac (PS) at a high dose was efficacious against DED in a rabbit model. We assessed the dose, formulation and structure dependence of PS's effect.

Diagnosis of Dry Eye Disease Using Principal Component Analysis: A Study in Animal Models of the Disease.

Purpose: To evaluate whether principal component analysis (PCA) can assess various diagnostic tests of dry eye disease (DED), providing a simplified, more informative measure of disease status than individual clinical test parameters (ICTP).

Materials And Methods: ICTP were analyzed using PCA in two groups of normal rabbits (Groups 1 and 2). Group 3, not truly normal, was also assessed.

A Rabbit Model of Aqueous-Deficient Dry Eye Disease Induced by Concanavalin A Injection into the Lacrimal Glands: Application to Drug Efficacy Studies.

Dry eye disease (DED), a multifactorial inflammatory disease of the ocular surface, affects 1 in 6 humans worldwide with staggering implications for quality of life and health care costs. The lack of informative animal models that recapitulate its key features impedes the search for new therapeutic agents for DED. Available DED animal models have limited reproducibility and efficacy.

Establishment of a Severe Dry Eye Model Using Complete Dacryoadenectomy in Rabbits.

Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models.

NSAID-induced corneal melt: Clinical importance, pathogenesis, and risk mitigation.

Corneal melt, an ophthalmological condition in which corneal epithelium is lost accompanied by thinning of the corneal stroma, can lead to corneal perforation and cause loss of vision. Corneal melt is the most serious side effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs), one of the topical treatments of ocular inflammation. NSAID-induced corneal melt (NICM), initially doubted, is real, having been reported by multiple groups.

Phospho-valproic acid (MDC-1112) suppresses glioblastoma growth in preclinical models through the inhibition of STAT3 phosphorylation.

New therapeutic strategies against glioblastoma multiforme (GBM) are urgently needed. Signal transducer and activator of transcription 3 (STAT3), constitutively active in many GBM tumors, plays a major role in GBM tumor growth and represents a potential therapeutic target. We have documented previously that phospho-valproic acid (MDC-1112), which inhibits STAT3 activation, possesses strong anticancer properties in multiple cancer types.

A New Rabbit Model of Chronic Dry Eye Disease Induced by Complete Surgical Dacryoadenectomy.

Unlabelled: Purpose/Aim: Dry eye disease (DED), common and suboptimally treated, is in need of novel animal models to understand its pathophysiology and assess the efficacy and other parameters of new pharmacological agents for its treatment. The more than 10 rabbit models of DED described to date have significant limitations including induction of mild disease, lack of consistency, and off-target effects when chemical agents are used for disease induction. Our aim was to develop a new model of chronic DED in rabbits that overcomes the limitations of existing models.

The ocular pharmacokinetics and biodistribution of phospho-sulindac (OXT-328) formulated in nanoparticles: Enhanced and targeted tissue drug delivery.

We studied the pharmacokinetics, biodistribution and metabolism of phospho-sulindac (PS), a novel agent efficacious in the treatment of dry eye, formulated in nanoparticles (PS-NPs) following its topical administration to the eye of New Zealand White rabbits. The nanoparticles were spherical with effective diameter = 108.9 ± 41.

The Chemoprevention of Ovarian Cancer: the Need and the Options.

Purpose Of Review: Ovarian cancer (OvCa) is the most lethal of all gynecological cancers, with a 5-year survival around 46%, mainly due to limitations in early diagnosis and treatment. Consequently, the chemoprevention of OvCa emerges as an important option to control this dismal disease. Here, we discuss the role of risk assessment in the design of chemoprevention strategies for OvCa, describe candidate agents, and assess future directions in this field.

[Corrigendum] Phospho‑valproic acid inhibits pancreatic cancer growth in mice: Enhanced efficacy by its formulation in poly‑(L)‑lactic acid‑poly(ethylene glycol) nanoparticles.

Subsequently to the publication of the aobve article, the authors have realized that they overlooked including a 'Competing Interests' section. This should have been included in the paper as follows: 'GM, RW and GGM declare they have no competing interests. BR has an equity position in Medicon Pharmaceuticals, Inc.

Phosphosulindac is efficacious in an improved concanavalin A-based rabbit model of chronic dry eye disease.

Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the concanavalin A (Con A) acute DED model: we injected all lacrimal glands with Con A weekly under ultrasound guidance, which prolonged DED to >3 weeks, and thoroughly assessed efficacy with tear break-up time (TBUT), tear osmolarity, Schirmer test, and tear lactoferrin levels. Rabbits with DED (n = 8-10 eyes per group) were treated topically with PS or vehicle 3×/day for 21days.

Correction: The Chemoprevention of Ovarian Cancer: the Need and the Options.

[This corrects the article DOI: 10.1007/s40495-018-0133-6.].

Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells.

Ceramides and their metabolites are important for the homeostasis of the epidermis, but much remains unknown about the roles of specific pathways of ceramide metabolism in skin biology. With a mouse model deficient in the alkaline ceramidase (Acer1) gene, we demonstrate that ACER1 plays a key role in the homeostasis of the epidermis and its appendages by controlling the metabolism of ceramides. Loss of Acer1 elevated the levels of various ceramides and sphingoid bases in the skin and caused progressive hair loss in mice.

Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles.

Pancreatic cancer (PC) is one of the most difficult cancers to treat. Since the current chemotherapy is inadequate and various biological approaches have failed, the need for agents that have a potential to treat PC is pressing. Phospho-valproic acid (P-V), a novel anticancer agent, is efficacious in xenograft models of human PC and is apparently safe.

Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice.

Pancreatic cancer is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for pancreatic cancer underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of pancreatic cancer.

The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1.

Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain.

NSAIDs and Colorectal Cancer Control: Promise and Challenges.

The chemoprevention of colorectal cancer (CRC) is a realistic option given the low acceptance and cost of screening colonoscopy. NSAIDs, currently not recommended for CRC prevention, are the most promising agents. Here, we review relevant work and assess the chemopreventive potential of NSAIDs.