Bridged bicyclic compounds: Comprehending a novel compound class as potential anti-seizure agents.

OBJECTIVE: In the present study, we describe a novel class of small-molecule synthetic compounds that ameliorate seizure-like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism. METHODS: Our electroshock assay examines seizure duration in C. elegans and can be used as a drug-screening platform for the identification of novel anti-seizure agents. The use of C. elegans allows for a rapid and efficient method of drug screening that may take years in other higher-order model organisms. A novel wash method, paired with our electroshock assay, allows us to discern differences in biological activity when the C. elegans are incubated in different drug solutions, to establish whether these compounds can be "washed" off. RESULTS: One of the RVMs (RVM-3), reported here for the first time, was found to be potent at picomolar concentrations. Insights also provided information on the potential mechanisms of action of this compound. Covalent binding is thought to provide a strong irreversible bond because of a change in structure between two of the novel RVMs described in this work. This was also discerned through the novel wash method paired with our electroshock assay. SIGNIFICANCE: RVM-3 was evaluated using our assay and found to possess anti-seizure activity at picomolar concentrations. These insights also provide information on the potential mechanisms of action of these compounds, which may include covalent binding. This was also discerned through a novel wash method paired with our electroshock assay.

A Potential Alternative Treatment for Vitiligo: An Observational Study on Tacrolimus 0.3% Lotion.

Vitiligo is a complex multifactorial disorder of depigmentation affecting 0.5 to 2% of the world's population without specific gender or racial prevalence.1 Though no treatments are FDA approved to repigment vitiligo, topical medications along with phototherapy alone or in combination remain the mainstay of therapy. While Janus Kinase inhibitors and other agents are in development, current topical options are mainly limited to steroid formulations of various potencies or immunomodulatory steroid-sparing agents such as tacrolimus 0.03% or 0.1%.

Significant improvement of dermatitis herpetiformis with tofacitinib.

Dermatitis herpetiformis (DH) is a rare autoimmune blistering disorder in which patients with celiac disease, a gluten-sensitive enteropathy, present with a severely pruritic papulovesicular eruption over extensor surfaces such as the knees, elbows, lower back, buttocks, and neck. Patients are instructed to adhere to a gluten-free diet for purposes of improving their skin disease and gluten-sensitive enteropathy; this is the only treatment that lowers risk of enteropathy-associated T cell lymphoma. Patients who adhere to a strict gluten-free diet often have remission of their skin disease over months to years. Dapsone is a rapid and extremely effective first-line treatment option and often used while transitioning to a gluten-free diet. Aside from gluten-free diet and dapsone, second-line treatment options include sulfapyridine, sulfasalazine, and colchicine. Some patients have difficulty adhering to a gluten-free diet or develop intolerable side effects to systemic therapies. Furthermore, there is limited data on the use of the second-line treatments. Recent studies have shed light on the role of JAK-STAT-dependent pathways in the pathogenesis of dermatitis herpetiformis. We present a patient treated with tofacitinib, 5mg twice daily, an oral JAK1/3 inhibitor, who demonstrated clinical improvement of DH and control of new lesion development.

Treatment of Psoriasis With Biologics and Apremilast in Patients With a History of Malignancy: A Retrospective Chart Review

Introduction: Biologics have transformed the management of moderate-to-severe psoriasis. The risk of developing a malignancy during treatment is an important consideration, and many studies have been conducted to determine the magnitude of this risk. However, there is little research on the use of biologic treatment in psoriasis patients with a history of established malignancy. Methods: We preformed a retrospective chart review of patients with psoriasis and a history of malignancy that were treated with biologics or apremilast. A list was created containing the 690 patients with psoriasis who were treated in our clinic with biologics or apremilast between January 1st, 2012 and May 31, 2018. The charts were examined, and 16 patients were found to have a history of malignancy excluding non-melanoma skin cancer. Results: Sixteen patients met criteria to be included in this review. The average time from cancer diagnosis to initiation of biologics or apremilast was 4.7 years, and 9 patients (56%) started treatment within five years. Three patients (19%) received concurrent cancer therapy during biologic treatment. None of the 16 patients had recurrence or progression of their cancer noted clinically or radiographically during biologic or apremilast treatment. Most patients had improvement of their psoriasis. Discussion: The data reviewed here show successful treatment on biologics despite concurrent malignancy, though confirmatory research is needed. J Drugs Dermatol. 2019;18(4):387-390.

JAK-STAT signaling pathway inhibition: a role for treatment of various dermatologic diseases.

Cutaneous inflammatory conditions such as psoriasis, atopic dermatitis, alopecia areata, vitiligo, and connective tissue diseases often remain a challenge to treat. Although there is an in-depth understanding of the clinical presentation of these diseases, much less is known regarding the pathophysiology. This has limited the effective treatment options for patients. A more detailed understanding of the pathogenesis of each disease will lead to newer targeted medications with less morbidity. Though there are different pathways involved in these diseases, the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription proteins (STAT) signaling pathway is common to them all. Therefore, this review article endeavors to substantiate the immunopathology and clinical utility of the JAK inhibitors as treatments for different chronic inflammatory diseases of the skin.

JAK-STAT signaling pathway inhibition: a role for treatment of discoid lupus erythematosus and dermatomyositis.

BACKGROUND: Discoid lupus erythematosus (DLE) and dermatomyositis (DM) are inflammatory autoimmune diseases that manifest primarily in the skin but can be linked to systemic complications. Although there is an in-depth understanding of the clinical presentation of these two diseases, much less is known regarding the pathophysiology. This has limited the effective treatment options for patients. OBJECTIVE: An understanding of the pathogenesis of each disease in greater detail will lead to newer targeted medications with less morbidity. This review article endeavors to substantiate the use of new treatments which target the JAK-STAT pathway while elaborating on the immunopathology as well. METHODS: PubMed was searched for relevant review articles, case reports, case series reports, randomized clinical trials (RCTs), basic science articles. Appropriate key terms and MeSH terms were utilized in the search. Clinicaltrials.gov was used to find relevant and current clinical trials being conducted in DLE and DM patients. RESULTS: A review of the literature supports the proposal that though there are likely many components and pathways involved in the destruction of keratinocytes, the Th1 cell immune response and specifically the JAK-STAT signaling pathway is common to both DLE and DM. CONCLUSION: Although further study is needed to determine the efficacy and benefits of JAK inhibitors over conventional therapy, these medications should be considered in refractory cases.

Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways.

Maintaining blood-brain barrier integrity and minimizing neuronal injury are critical components of any therapeutic intervention following ischemic stroke. However, a low level of vitamin D hormone is a risk factor for many vascular diseases including stroke. The neuroprotective effects of 1,25(OH)2D3 (vitamin D) after ischemic stroke have been studied, but it is not known whether it prevents ischemic injury to brain endothelial cells, a key component of the neurovascular unit. We analyzed the effect of 1,25(OH)2D3 on brain endothelial cell barrier integrity and tight junction proteins after hypoxia/reoxygenation in a mouse brain endothelial cell culture model that closely mimics many of the features of the blood-brain barrier in vitro. Following hypoxic injury in bEnd.3 cells, 1,25(OH)2D3 treatment prevented the decrease in barrier function as measured by transendothelial electrical resistance and permeability of FITC-dextran (40 kDa), the decrease in the expression of the tight junction proteins zonula occludin-1, claudin-5, and occludin, the activation of NF-kB, and the increase in matrix metalloproteinase-9 expression. These responses were blocked when the interaction of 1,25(OH) )2D3 with the vitamin D receptor (VDR) was inhibited by pyridoxal 5'-phosphate treatment. Our findings show a direct, VDR-mediated, protective effect of 1,25(OH) )2D3 against ischemic injury-induced blood-brain barrier dysfunction in cerebral endothelial cells.

The effects of short-term vitamin D supplementation on glucose metabolism in dialysis patients: a systematic review and meta-analysis.

PURPOSE: We tested whether short-term vitamin D supplementation improves insulin resistance in patients with kidney disease, a condition with little intrinsic vitamin D activity. METHODS: PubMed, EMBASE and CENTRAL were searched for relevant observational studies and randomized clinical trials (RCTs). Random-effects models were employed for meta-analysis, and effect sizes were summarized as standardized mean difference (SMD) with 95% confidence intervals. Separate analyses were done for RCTs and non-randomized intervention studies (NRIS). RESULTS: Seventeen studies (5 RCTs and 12 NRIS) were included. The meta-analysis population (n = 131) was mostly middle aged (40-50 years), male and non-diabetic, and on hemodialysis. The duration (4-12 weeks) and type of supplementation varied between studies. Among RCTs, compared to placebo, vitamin D supplementation was associated with significant decrease in fasting glucose [SMD -1.13, (-2.11 to -0.11)] and PTH levels [SMD -1.50, (-2.95 to -0.04)] but no difference in fasting insulin levels [SMD 1.32, (-0.15 to 2.79)]. Among NRIS, there was only a significant decrease in PTH levels [SMD -1.68, (-2.55 to -0.82)] between pre- and post-vitamin D treatment levels. CONCLUSIONS: Short-term (4-12 weeks) supplementation with vitamin D is associated with lower fasting glucose levels in ESRD with no change in fasting insulin levels. However, the findings from this study are limited by the studies that were used in the meta-analysis, which were mostly small, used multiple different vitamin D compounds and dosing regimens, and had large heterogeneity, and funnel plots showed that there was a dearth of studies with null or negative finding. Therefore, larger RCTs need to be performed to answer this important clinical question.